Randomized data suggest that axillary clearance is not necessary in select, clinically lymph node-negative women with positive sentinel lymph node (SLN) biopsies (SLNBs) who undergo breast-conserving surgery or receive whole-breast radiotherapy and systemic therapy. The additional value of axillary radiotherapy in these patients is unknown.
The authors identified 326 patients with positive SLNBs who underwent breast-conserving surgery without axillary lymph node dissection from 1997 to 2009. SLN tumor deposits measured ≤0.2 mm in 58% of patients, 0.3 to 2.0 mm in 35% of patients, and >2 mm in 7% Patients. Ninety-three percent of patients received adjuvant radiotherapy. Radiation fields were categorized as standard tangents, high tangents, comprehensive (tangents plus supraclavicular), or partial breast to reflect coverage of the axilla. Standard tangents included both prone and supine positions. Regional failure was defined as recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes.
The median follow-up was 55 months (range, 1-158 months). The 4-year rates of regional control, local control, disease-free survival, and overall survival were 99%, 98%, 95%, and 91%, respectively. Three patients had regional recurrences. Two of those patients received adjuvant radiotherapy with standard supine tangents, and 1 patient did not receive radiotherapy. No regional recurrences occurred among 66 patients who received radiotherapy in the prone position.
The traditional paradigms of axillary management in patients with breast cancer patients who have a positive sentinel lymph node (SLN) biopsy (SLNB) have been challenged by several diagnostic and clinical advances over the past decade. Methods of enhanced pathologic assessment of the SLN node have resulted in the increased detection of small-volume (micrometastases and isolated tumor cells) SLN metastases.1, 2 Nomograms that identify patients at low risk for additional lymph node metastases have guided the selection of patients for SLNB alone,3 leading to a nationwide decline in the performance of completion axillary dissection (cALND).1 These trends are reflected at our own institution, where cALND rates between 1998 to 2008 decreased from 85% to 73%.4
The recent publications of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial confirmed the low axillary recurrence rates observed in multiple studies of SLN-positive patients who did not undergo cALND and extended those observations to patients with macrometastases.1, 5-15 The results suggested that SLNB alone in patients with early stage breast cancer who have low tumor burden in the SLNs, the receipt of adjuvant radiotherapy (RT) and systemic therapy is adequate for locoregional control.14 Although the ACOSOG Z0011 protocol specified that all patients receive standard tangent field irradiation to the whole breast, details of the RT were not published, raising the question of whether the low regional recurrence rates observed in Z0011 were caused by the treatment of a portion of the axilla with the tangent fields16 or by radiation oncologists opting to use high tangents to improve axillary coverage.14, 15 Uncertainty regarding the importance of RT to the high rates of local control (LC) led the ACOSOG Z0011 investigators to caution that the findings should not be extrapolated to patients who receive partial breast irradiation and those who undergo mastectomy without RT. The objective of the current study was to examine the impact of radiation field design, including whole-breast radiation in the prone position, on regional recurrence rates in patients with low-volume SLN breast cancer who undergo breast-conserving surgery and omit cALND in an era of contemporaneous systemic therapy and modern radiation techniques.
MATERIALS AND METHODS
We identified 3508 consecutive women who underwent breast-conserving surgery at Memorial Sloan-Kettering Cancer Center (MSKCC) between November 1997 and May 2009 and had tumor identified in an SLN by either frozen section, routine hematoxylin and eosin (H&E) staining, serial sectioning, or immunohistochemistry (IHC). Of these, 2866 women underwent cALND, and 642 women did not. Axillary dissection was defined according to surgical intent and/or the removal of ≥10 axillary lymph nodes. After we excluded patients who underwent mastectomy and those with stage IV disease, synchronous bilateral breast cancer, male breast cancer, inflammatory breast cancer, progression of disease before planned ALND, or insufficient follow-up to determine whether or not they received RT, 326 patients remained eligible for analysis.
Our institutional approach to lymphatic mapping, lymphoscintigraphy, and SLNB was detailed previously.17, 18 Intraoperative frozen-section analysis of the SLN was performed in 74% of patients. If frozen section was negative or not performed, then standard pathologic examination included a frozen-section control (routine H&E) and 2 pairs of consecutive sections taken from the paraffin block at each of 2 levels 50 μm apart. One of these consecutive sections was stained with H&E (serial sectioning), and the other was stained with cytokeratin (AE1:AE3) IHC. A team of dedicated breast pathologists reviewed all slides and categorized SLN status according to American Joint Committee on Cancer sixth edition pathologic criteria.
Primary tumors were evaluated for pathologic size, histologic type, histologic grade (modified Bloom-Richardson), nuclear grade (modified Black), lymphovascular invasion, estrogen receptor status, progesterone receptor status, human epidermal growth factor (HER-2/neu) status, and the presence of multifocal disease. Positive HER-2/neu status was defined as either 3+ overexpression by IHC or gene amplification by fluorescence in situ hybridization. The probability of additional non-SLN metastasis was calculated using the MSKCC nomogram developed by Van Zee et al for patients with complete pathologic information who fit the nomogram inclusion criteria.3
Among the 302 patients who received RT, 174 received RT at MSKCC, and 128 received RT at outside institutions. RT volumes were classified as standard tangents, high tangents, comprehensive, or partial breast. Standard tangents consisted of 2 opposing tangential fields designed to treat the whole breast, delivered in either the supine or prone position. High-tangent plans intentionally targeted the contoured level I and middle to upper-level II axillary lymph nodes, which were identified after computed tomography-based planning. Radiation plans that targeted the supraclavicular lymph nodes with or without an additional dose to the upper axillary lymph nodes (axillary boost) were classified as comprehensive fields. All patients who received high-tangent or comprehensive radiation were treated in the supine position. Patients who received partial breast irradiation were grouped with patients who did not receive RT, because no appreciable dose to the axilla is delivered with this technique. Data regarding radiation position were not available for 53 of 302 patients (18%) who received RT. In these patients, all of whom received RT at outside institutions, treatment with standard supine tangents was assumed.
After they underwent definitive surgery, patients were evaluated with annual mammograms and routine interval history and physical examination at least every 6 months. Regional failure was defined as biopsy-proven recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes. The rates of regional control (RC), LC, disease-free survival (DFS), and overall survival (OS) were assessed using the Kaplan-Meier method. The date of histologic diagnosis was used as the starting time point for treatment-outcome calculations. The Cochran-Armitage test was used to assess trends in RT field design over time. Fisher exact tests, chi-square tests, and analyses of variance were used to assess differences in the distribution of patient and treatment characteristics between groups.
Patient and tumor characteristics are summarized in Table 1, in which patients are stratified according RT field type to reflect coverage of the axilla. The median patient age at diagnosis was 60 years (range, 28-90 years). The mean probability of additional non-SLN metastasis, which was calculated using the MSKCC nomogram, was 9.7%.
Table 1. Patient and Treatment Characteristics
No. of Patients (%)
No RT or PBI
Supine Standard Tangents
Prone Standard Tangents
Abbreviations: Her2/neu, human epidermal growth factor receptor; (i+), isolated tumor cells; mic, micrometastases; MSKCC, Memorial Sloan-Kettering Cancer Center. PBI, partial breast irradiation; RT, radiotherapy; SLN, sentinel lymph node.
This category was unspecified for patients with infiltrating lobular carcinoma.
SLN characteristics are illustrated in Figure 1. The median number of SLNs removed was 3, and the median number of positive SLNs was 1. The size of the largest metastatic tumor cell cluster in the SLN was ≤0.2 mm in 58% of patients (n = 188), 0.3 mm to 2.0 mm in 35% of patients (n = 114), and >2 mm in 7% of patients (n = 24).
RT characteristics are outlined in Table 2. The majority of patients (77%) received standard-tangent RT fields. Among the patients who received standard-tangent fields, 72% (n = 168) were treated in the supine position, and 28% (n = 66) were treated in the prone position. There was a trend toward increased treatment in the prone position and decreased treatment in the supine position over time (Fig. 2). Among 20 patients who received comprehensive RT, 8 patients also received an axillary boost. Figure 3 illustrates differences in lymph node coverage between patients who were treated with supine and prone standard tangent fields, high tangent fields, and comprehensive radiation fields. Among all 326 patients, 180 (56%) received adjuvant chemotherapy. The most commonly administered agents were anthracycline and taxane-based combination regimens. Seventy-seven percent of patients received adjuvant endocrine therapy, and 93% received either chemotherapy or endocrine therapy.
Table 2. Radiotherapy Characteristics
No. of Patients (%)
Abbreviation: RT, radiotherapy.
This category excluded patients who received partial breast irradiation (n = 7).
The median follow-up for the entire cohort was 55 months (range, 1-158 months). Among the entire cohort, the 4-year rates of RC, LC, DFS, and OS were 99%, 98%, 95%, and 91%, respectively (Fig. 4). Among the patients who received RT, the 4-year rates of RC, LC, DFS, and OS were 99%, 99.5%, 96%, and 92%, respectively. Treatment outcomes stratified by radiation target volumes are listed in Table 3.
Table 3. Treatment Outcomes Stratified by Radiotherapy Field
No RT or PBI
Supine Standard Tangents
Prone Standard Tangents
Abbreviations: DFS, disease-free survival; LC, local control; OS, overall survival; PBI, partial breast irradiation; RC, regional control; RT, radiotherapy.
No. of patients
RT, 25; PBI, 7
Median follow-up, mo
4-y RC, %
4-y LC, %
4-y DFS, %
4-y OS, %
Three patients developed a regional failure (Table 4). One of these patients was a woman aged 72 years with histologic grade 3 infiltrating ductal carcinoma who had 2 of 2 SLNs positive for micrometastatic disease. She was not a candidate for chemotherapy or RT because of significant medical comorbidities. Eighteen months after her diagnosis, she developed both ipsilateral in-breast and axillary recurrences. She eventually developed distant metastases and died 69 months after the initial diagnosis. The second patient was a woman aged 70 years with infiltrating lobular carcinoma who had 2 of 2 SLNs positive for isolated tumor cells and who declined chemotherapy and received adjuvant supine RT at an outside institution. She developed an ipsilateral axillary recurrence at 36 months that was salvaged with cALND. She developed distant metastases at 78 months and, at last follow-up, was alive with disease 101 months after diagnosis. The third patient was a woman aged 49 years with histologic grade 3 infiltrating ductal carcinoma who had 1 of 3 SLNs positive for micrometastatic disease and received supine RT at an outside institution. She developed an ipsilateral supraclavicular recurrence at 25 months. Workup at that time revealed distant metastases, for which she received chemotherapy at an outside institution before she died 7 months later.
Axillary dissection historically was considered standard management for patients with breast cancer who had histologically positive SLNs. The locoregional control benefit of axillary treatment in invasive breast cancer was established first by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial, which randomized patients with clinically lymph node-negative disease to 1 of 3 arms: radical mastectomy, total mastectomy with axillary irradiation, or total mastectomy alone without axillary treatment.19 Patients with an untreated axilla had a significantly greater risk of regional failure compared with those who either received axillary RT or underwent dissection, although no survival differences were observed between groups. Surgery and RT were equally efficacious for axillary control.
Currently, SLNB is the accepted procedure for axillary staging. When the SLN does not contain metastases, axillary recurrence is observed in <1% of patients.20 In patients with positive SLNs, axillary dissection remained standard practice, despite the finding that the SLNs were the only involved lymph nodes in 40% to 60% of patients.21-27 The rationale for completion axillary dissection was based on 2 assumptions: 1) the presence of tumor-containing SLNs signifies potential residual tumor in the remaining the axillary lymph nodes, and 2) these lymph nodes require removal to prevent progression to clinically manifest axillary recurrence.
Select studies of patients with positive SLN and who did not undergo ALND have demonstrated low regional recurrence rates in the setting of adjuvant systemic therapy and RT (Table 5).1, 5-14, 28 Those series differed with respect to the length of median follow-up, the definition of a positive SLN, reasons for omitting ALND, and the receipt of systemic therapy. Although several of those reports1, 5, 7, 11 described the RT fields used, none reported treatment outcomes stratified by RT field design. More important, the use of contemporary RT techniques in patients who received whole-breast RT alone, such as high tangents or prone RT, was not well delineated.
Table 5. Select Series of Patients With Positive Sentinel Lymph Nodes who Omitted Axillary Lymph Node Dissectiona
The largest of these studies, an analysis of the National Cancer Database that reported outcomes of 5596 patients with positive SLNs who omitted ALND, did not specify the radiation fields used.1 Hwang et al reported results from 196 patients who were treated at The University of Texas M. D. Anderson Cancer Center.6 In that study, among 89 patients who received RT, 56 received axillary-specific RT. At a median follow-up of 30 months, only 1 patient had a regional recurrence. Barkley et al reported a prospective series of 131 patients in which 38% received standard tangents and 50% received axillary-specific RT. At median follow-up of 59 months, there were no axillary failures.13
The most compelling evidence for standard tangential radiation is from the ACOSOG Z0011 trial, in which women with 1 or 2 H&E-detected, positive SLNs were randomized to either observation or cALND. In that trial, all patients underwent breast-conserving surgery followed by adjuvant whole-breast RT with standard tangential radiation in the supine position, and 96% of patients received systemic therapy. At a median follow-up of 6.3 years, there was no significant difference in regional recurrence between the 2 arms (0.9% vs 0.5% for observation vs cALND; P = .45). Given the low regional lymph node failure rates overall, the Z0011 trial suggested that standard tangential radiation may provide adequate axillary control in select patients with early stage breast cancer who have low SLN burden and receive systemic therapy. Although the addition of a supraclavicular radiation field specifically targeting the upper axillary and supraclavicular lymph nodes was not permitted, a portion of the axilla may have been treated by the whole-breast radiation fields.16
In the absence of a supraclavicular field, the use of high tangents is one means of improving axillary coverage with tangential whole breast radiation fields. Schlembech et al reported that the entire level I-II axillary dissection field could be covered in 82% of cases by extending the cranial tangent border to 2 cm below the humeral head, and the posterior border to 2 cm deep to the chest wall-lung interface.29 Forty-one patients in our series received high tangents, in which the superior aspect of the tangential field was customized to maximally cover the level II lymph nodes, as coverage of these nodes with standard tangents can often vary depending on patient body habitus. Although no patient treated with high tangents or comprehensive RT developed a regional recurrence, additional coverage of the axilla was not associated with a significant improvement in RC due to lack of events (P = .49).
The most interesting finding in our study was the excellent outcomes seen in the patients who received RT in the prone position. To our knowledge, this is the first study to report outcomes of patients with tumor-containing sentinel nodes treated with prone radiation after omission of cALND. Radiation in the prone position is a popular technique that has been used in an effort to minimize the degree of lung and heart dose in women with pendulous breasts receiving adjuvant whole breast radiation. Prone radiation has been shown to result in significantly reduced coverage of the level I-II axilla. Alonso-Basanta et al demonstrated that prone tangents decrease the mean dose to levels I-II by approximately 50% when compared with supine tangents.30 Among twenty patients planned in both the supine and prone positions, the mean dose to the level I axilla was 21.0 Gy and 11.2 Gy, respectively. In our study, the median follow-up among patients treated in the prone position was shorter (41 months) than that of the overall cohort due to treatment era effect, as prone and high-tangent RT are more contemporary techniques relative to supine and comprehensive radiation (Fig. 2).
Given the low number of events, we were unable to identify a subset of patients who stand to benefit from axillary-specific RT. This is not to suggest that omission of axillary RT is appropriate for all SLN-positive patients who do not undergo ALND, as there may be a subset of high-risk patients who would benefit from regional lymph node irradiation, namely those with more advanced nodal burden. Support for regional nodal irradiation in all lymph node-positive women was recently provided by the National Cancer Institute of Canada-Clinical Trials Group MA.20 intergroup trial, which demonstrated a DFS benefit for comprehensive lymph node irradiation in lymph node-positive or high-risk lymph node-negative women who underwent breast-conserving surgery.31 It is important to recognize, however, that the MA.20 trial included patients with more advanced lymph node disease compared with patients in the current study and in the ACOSOG Z0011 trial. Moreover, women with 1 to 3 positive lymph nodes represent a heterogeneous group with various risks of lymph node relapse. Therefore, the applicability of these results to all subsets of women with positive lymph nodes is limited. The optimal selection of women who will benefit from axillary radiation, and particularly those who undergo SLNB alone, has yet to be defined.
In an effort to identify patients who would benefit from the addition of a supraclavicular and/or axillary apex field, nomograms that predict for the risk of ≥4 positive lymph nodes have been developed, although, to date, their clinical utility has been limited by a low positive predictive value.32 Conversely, the ability to accurately stratify patients according to risk would help spare low-risk patients from the toxicity associated with additional radiation fields. It has been demonstrated that the addition of supraclavicular and axillary fields to standard tangents increases the 2% to 8% risk of lymphedema to approximately 9% to 24% in patients who undergo axillary dissection,33, 34 although the risk of arm edema may be considerably lower in patients who do not undergo cALND.35 It also has been noted that such fields increase the incidence of pneumonitis and brachial plexopathy.36
Potential limitations in our study warrant explanation. Details regarding RT fields and position were not always available in the patients who were treated at outside institutions; therefore, we assumed that, unless otherwise specified, those patients received RT with standard supine tangents. Second, our study cohort represented a low-risk group of patients whose average risk of additional non-SLN disease for residual tumor-containing lymph nodes in the axilla was 10.6% according to the MSKCC nomogram. This is indicative of lesser tumor burden than would be expected in a randomized trial of patients with positive SLNs on routine H&E-stained sections, as evidenced by the 27.3% of patients in the ALND arm of the Z0011 trial who had additional metastasis in lymph nodes removed by ALND. Although there was no institutional policy regarding the omission of ALND during our study period, patients who did not undergo ALND were more likely to be aged >70 years, to have moderate-severe comorbidities, to undergo breast-conservation surgery, and to have smaller primary tumor size (T1 vs T2-T3) than the patients who underwent ALND during the same period.37 Extrapolation of these data to patients with low-volume SLN disease who undergo mastectomy or receive partial breast irradiation must be approached with caution, because our study population was too small to draw any definitive conclusions regarding the applicability of the data to these subsets.
The median follow-up in our study was 55 months, which some may consider too brief to assess the endpoint of regional recurrence. However, we believe it was adequate, because >75% of the regional recurrences observed in the NSABP B-04 trial occurred within the first 24 months of surgery.38 In contrast to the B-04 trial, a high percentage of patients in our study received systemic therapy, which greatly contributes to the low locoregional recurrence rates reported in patients with early stage breast cancer.39, 40 It is possible that longer surveillance may reveal an increase in axillary recurrences that initially were tempered by the receipt of systemic therapy.
In conclusion, the RC rate was high (99% at 4 years) in patients with low-volume SLN disease who underwent SLNB alone, independent of whether or not they received axillary radiation. The current results suggest that the absence of axillary-specific radiation does not affect regional recurrence rates in patients with breast cancer who have small-volume lymph node disease after breast-conserving surgery and SLNB alone. Irradiation of the breast alone in the prone position provides sufficient locoregional control in this select population of patients.