Originally published as JCO Early Release 10.1200/JCO.2009.24.3311 on October 13 2009

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Axillary Reverse Mapping to Prevent Lymphedema After Breast Cancer Surgery: Defining the Limits of the Concept

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine of Northwestern University, Chicago, IL

As surgical interventions for breast cancer therapy have become progressively less morbid during the past half century, the Halsted radical mastectomy has metamorphosed into the skin-sparing modified radical mastectomy or breast-conserving tumorectomy, and complete axillary clearance has been replaced with sentinel node biopsy. The latter is widely used for nodal staging in women with clinically node-negative breast cancer, but many women still require axillary dissection, with its attendant risk of upper extremity lymphedema. This is a widely feared complication, the true incidence of which is uncertain,¹ but which has been reported to be as high as 56%.² This variation in the reporting of incidence is partly explained by treatment variables. That is, when axillary dissection is combined with axillary radiotherapy, lymphedema frequency in the 30% to 50% range is common.^3,4 However, a frequency of 10% to 20% is more common when axillary dissection is used without axillary radiation,⁵ and studies of women undergoing sentinel node biopsy report lymphedema incidence of 0% to 10%.⁶ Another important factor affecting lymphedema prevalence is the time period when surgical and radiation therapy were performed, given the modifications that have occurred during the past 25 years, in contemporary surgical techniques (avoid stripping of the axillary vein) and improvements in radiation dosimetry. Thus, a study showing a 49% lymphedema incidence in a group of 20-year breast cancer survivors included women who were treated by modified radical or radical mastectomy (43% and 57% respectively), with removal of the thoracodorsal nerve bundle in 35% and excision of the pectoralis minor muscle in 95% of patients.⁷

The methods of assessing lymphedema have also varied, and there is at present no gold-standard measurement tool and no widely agreed on definition. A recent population-based study from the Iowa cohort described the frequency of lymphedema diagnosis to be 8%, but an additional 32% of women reported symptoms affecting the arm and hand without having a lymphedema diagnosis.⁸ A welcome development in this field has been the validation of a survey instrument for lymphedema assessment where arm and hand symptoms reported by breast cancer survivors have been tested against assessment by physical therapists.⁹ A recent analysis of data from 631 women using this instrument generated an estimated lymphedema incidence of 42%, but this decreased to 11.5% when only women with moderate or severe symptoms were included, and those with waxing/waning/improving lymphedema (mild to none) were excluded.¹⁰

Lymphedema of the arm and hand undoubtedly impairs quality of life (QOL) after local therapy for breast cancer.¹¹ However, there are other sources that can affect QOL after axillary surgery, such as sensory loss related to nerve damage and restriction of arm and shoulder mobility. In a recent study, the most prevalent problems reported by women at follow-up were menopausal symptoms (hot flashes and vaginal dryness in 64%) or osteoporosis (25%), whereas lymphedema affected 23% of women and was not a statistically significant parameter in the final analysis. Other physical factors that were significantly related to global health-related QOL included having heart disease, fatigue, and one or two or more comorbidities.¹²

Although the strongest force driving the development of lymphedema is clearly the removal of axillary lymph nodes, other factors are also implicated. In the population-based study by Ahmed et al,⁸ women diagnosed with lymphedema had higher BMI, more often had distant metastases, larger tumor size, more advanced surgery, more lymph nodes examined, tumor-positive nodes, radiation treatment, and chemotherapy use. In particular, the use of radiotherapy, particularly when a posterior axillary field is used, increases lymphedema rates significantly.¹³

Decompressive and massage therapy for lymphedema provide variable results, and require significant resources and commitment from the patient.^14,15 Other treatment techniques, including surgical and pharmacologic approaches, are not generally successful. In view of its burden on QOL, and the substantial effort required to control it once it appears, the concept of lymphedema prevention is naturally attractive. The idea that prevention can consist of a relatively simple modification of the surgical procedure that causes it has considerable appeal. The initial reports from Thompson et al¹⁶ and Nos et al¹⁷ describing the existence of distinct and nonoverlapping sentinel nodes for the arm and the breast, using two different tracers, one injected in the breast and the other in the arm, offered the possibility that resection of axillary breast nodes may be accomplished, while sparing arm nodes and lymph channels. This procedure, termed axillary reverse mapping (ARM), entails injection of blue dye in the intermuscular groove of the upper inner arm to define the lymph channels and nodes draining the arm. When it is combined with sentinel node biopsy for breast cancer, technetium sulfur colloid injected in the breast defines the breast-draining nodes and allows the surgeon to excise those while sparing the arm-draining nodes. It is an elegant and simple concept, supported by recent meticulous studies of the lymphatic anatomy of the arm and breast,^18,19 and has been tested in a series of preliminary studies demonstrating its feasibility.^16,17,20,21 This concept will hold if additional investigations continue to show that the lymph drainage for the breast and the arm are invariably (or almost invariably) distinct, that the arm nodes are never (or almost never) involved by breast cancer, that the procedure is feasible in the wider surgical community, that it does in fact prevent arm and hand lymphedema, and that there is not an adverse effect on disease outcomes. Among six studies reported so far, with sample sizes ranging from 20 to 131, the success rate for identifying arm nodes has ranged from 40% to 90%, the fraction of women with overlapping breast and arm drainage (ie, nondistinct lymphatic pathways) has ranged from none¹⁶ to 20%,²² and the presence of metastatic disease in the arm nodes seems to be in the range of 10%.^22,23

Although the initial reports seem promising, the next steps in defining the utility of this concept remain to be accomplished. The report by Ponzone et al²⁴ in this issue of Journal of Clinical Oncology is therefore of considerable interest. This is a single-surgeon, single-institution experience that cannot tell us much about the generalizability of the technique. However, this experience does illustrate that the technique is transferable to the hands of specialist surgeons, and that successful mapping of arm lymph channels or sentinel nodes can be accomplished in just less than two thirds of women (27 of 49) undergoing axillary dissection. However, the study by Ponzone et al²⁴ also shows that there are limits to the principle of nonoverlap between breast and arm nodes; when there is heavy nodal involvement of the axilla by breast cancer, arm nodes are involved in 11% (three of 27 women). Of note, 14 women had four or more involved nodes; six of these experienced unsuccessful arm mapping, and four had involvement of arm nodes. Thus in 10 of 14 women (71%), the concept failed, either at the level of feasibility (no arm mapping) or validity (arm nodes showing metastatic disease). Similar results are reported by Kang et al²² in a study involving 129 women, in which approximately 20% of women were found to have overlapping drainage between arm and breast and 9% were found to have arm nodes involved with breast carcinoma. These findings bring us back to the question discussed above: who is at risk for lymphedema, and who is therefore likely to benefit from an innovative surgical technique promising to decrease this risk? Some of the risk factors for lymphedema (such as obesity, weight gain after breast cancer therapy, extent of disease) will not be influenced by the use of ARM. The answer inevitably points to women who receive more extensive axillary surgery, because of the presence of one or more involved nodes, and are therefore more likely to receive radiotherapy. In an era when axillary dissection is increasingly reserved for women who have a significant probability of nonsentinel node involvement, those with four or more axillary nodes involved are particularly germane to the concept of ARM, given that they are the most likely to need therapeutic axillary dissection and to receive nodal radiation. If the combined success rate of the ARM procedure (technical success plus accuracy) remains in the range of less than 50% in this group, the argument for additional development, and the need for investment in larger randomized trials that are necessary for final validation and definition of long-term outcomes, become questionable.

As to the success of ARM in preventing lymphedema, the data are scant. Two groups have described absence of lymphedema in women with successful ARM procedures,^20,21 but disconcertingly, neither have described the definition of lymphedema used or the method of measuring it. This is a surprising omission in reports of a procedure with the primary intent of avoiding lymphedema; future publications should address this all-important aspect more fully.

As we begin to consider the merits of additional evaluation of the ARM procedure for the prevention of lymphedema, several important issues in trial design deserve attention. One of the first is a consensus definition of lymphedema, and the most appropriate and unbiased method for its measurement. The existing literature highlights the deficiencies of definition and measurement to date, and investigators who pursue this farther will be well rewarded by rigorous preliminary data that address the inconsistencies between self-report of lymphedema, arm circumference measures, and two newer methods, bioelectrical impedance²⁵ and infrared optoelectronic volumetry.²⁶ Appropriate attention will also need to be paid to such issues as baseline measurements of both arms before surgery, sufficient frequency of measurement, and adequate long-term follow-up. In fact, the progress of this field would most efficiently proceed along two paths. The first would include multicenter prospective studies to define the natural history, QOL impact, and robust, reproducible measurement of lymphedema. The second would include continued single-institution or limited-access phase II trials to better define the limits of the ARM concept. In particular, these would evaluate success rates of arm mapping, frequency of overlap in arm and breast lymphatics, and of arm node involvement by breast cancer, to frame the questions that can reasonably and efficiently be taken to a randomized trial.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

See accompanying article on page 5547

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