Original Study. Abstract. Introduction. Clinical Breast Cancer February

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1 Outcomes of Clinically Node-Negative Breast Cancer Without Axillary Dissection: Can Preserved Axilla Be Safely Treated With Radiation After a Positive Sentinel Node Biopsy? Naoko Sanuki, 1 Atsuya Takeda, 1,2 Atsushi Amemiya, 3 Toru Ofuchi, 3 Masashi Ono, 3 Haruki Ogata, 3 Ryo Yamagami, 3 Jun Hatayama, 3 Takahisa Eriguchi, 1 Etsuo Kunieda 2 Abstract Original Study We analyzed whether axillary nodal irradiation could safely control early-stage breast cancer, including those patients with a positive sentinel lymph node biopsy. Axillary or regional nodal irradiation without axillary nodal dissection showed excellent outcomes, with negligible toxicity for patients with clinically node-negative disease. Regional nodal irradiation after a positive sentinel lymph node is a reasonable alternative to axillary dissection. Purpose: We analyzed whether axillary nodal irradiation could control clinically node-negative disease, including those patients with a positive sentinel lymph node biopsy (SLNB), most of whom received regional nodal irradiation. We also evaluated toxicity profiles that resulted from nodal irradiation. Patients and Methods: From 1988 to 2011, 2107 patients with ct1-t2n0m0 breast cancer underwent breast conservation therapy in the absence of axillary dissection: nx group (n 1548), without any axillary surgery; the sn group (n 518), with a negative SLNB; and sn group (n 104), with a positive SLNB. Results: The median follow-up times were 88, 56, and 55 months for the nx, sn, and sn groups, respectively. The nx group had more risk factors than did the other 2 groups in terms of age, grade, or T stage. Ninety-eight percent of the sn group received only tangent irradiation, and 100% and 83% of the sn and nx group, respectively, received additional regional nodal irradiation. The 5-year cumulative incidences of axillary failure and regional nodal failure were 34, 3, and 0 (2.7%, 0.7%, and 0%; P.02, log-rank test) and 57, 4, and 0 (4.4, 1%, and 0; P.04), respectively. Overall survival rates in 5 years were 96.4%, 98.9%, and 97.6% (P.03), respectively. Symptomatic but transient radiation pneumonitis developed in 31, 16, and 6 (2.0%, 3.1%, and 5.7%). Mild arm edema was observed in 1, 4, and 0 (0.06%, 0.8%, and 0%) in the nx, sn,sn groups, respectively. Conclusions: Treatment without axillary dissection showed excellent outcomes with negligible toxicity for patients with clinically node negative, including those with a positive SLNB. Regional nodal irradiation after a positive SLNB is a reasonable alternative to axillary dissection. Clinical Breast Cancer, Vol. 13, No. 1, Elsevier Inc. All rights reserved. Keywords: Axillary dissection, Axillary radiotherapy, Breast cancer, Regional node irradiation, Sentinel lymph node biopsy Introduction 1 Radiation Oncology Center, Ofuna Chuo Hospital, Kamakura, Kanagawa, Japan 2 Department of Radiology, Tokai University School of Medicine, Isehara, Kanagawa, Japan 3 Department of Surgery, Ofuna Chuo Hospital, Kamakura, Kanagawa, Japan Submitted: Jun 14, 2012; Revised Aug 23, 2012; Accepted: Sep 13, 2012; Epub: Oct 11, 2012 Address for correspondence: Etsuo Kunieda, Department of Radiation Oncology, Tokai University, 143 Shimokasuya, Isehara, Kanagawa , Japan contact: kunieda-mi@umin.ac.jp The introduction of sentinel node biopsy to the treatment of clinically node-negative (cn0) breast cancer has raised new clinical questions, including the appropriate management of the axilla after a positive sentinel lymph node (SLN) biopsy (SLNB). The American College of Surgeons Oncology Group (ACOSOG) trial Z0011 recently demonstrated equivalent survival in patients with breast cancer and 1 to 2 positive SLNs who were randomly assigned to SLNB alone or SLNB followed by axillary lymph node dissection (ALND). 1 Although regional nodal irradiation (RNI) was not /$ - see frontmatter 2013 Elsevier Inc. All rights reserved. Clinical Breast Cancer February

2 cn0 Breast Cancer Without Axillary Dissection Figure 1 Schema of the Treatment History; in Earlier Years, ALND Was Routinely Performed; Since 1988, ALND Was Substituted for Axillary Nodal Irradiation in Patients With cn0; SLNB Was Introduced in 2001; Three-Dimensional CT-Based Radiation Therapy Was Implemented in 2004 a Started breast conservation therapy ALND Started omitting ALND for patients with cn0 Introduced high tangent irradiation Started taxanes Started SLNB Started CT-based 3-dimensional conformal irradiation No axillary operation nx group (n = 1548) Negative SLNB sn group (n = 518) Positive SLNB sn + group (n = 104) Abbreviations: ALND axillary lymph node dissection; cn0 clinically negative node; CT computed tomography; SLNB sentinel lymph node biopsy. a nx group (n 1580), without any axillary surgery; sn group (n 518), with a negative SLNB; sn group (n 104), with a positive SLNB. allowed in the Z0011 trial, regional recurrence with SLNB alone was 1%, despite the fact that an estimated 27% of patients had additional metastases in the undissected axillary nodes. In contrast, a meta-analysis reported a 53% incidence of additional disease on ALND after a positive SLNB, 2 which indicates the need for treating the regional nodal area for such patients. With many other studies with supporting or contradicting results, it is still under debate whether leaving the regional nodal area untreated is safe. In 2004, we reported that patients with cn0 were safely treated with axillary lymph node irradiation (ALNI). 3 With a longer follow-up time, we analyzed whether ALNI could control cn0 disease, including those with a positive SLNB. We also calculated additional risks of having more positive nodes after a positive SLNB to estimate the possible benefit of RNI. Toxicity profiles that resulted from nodal irradiation were evaluated. Materials and Methods Patients At our institutions, breast-conservation therapy has been used with increasing frequency since In earlier years, ALND was performed routinely, regardless of clinical axillary lymph node status. Since 1988, we began to substitute ALNI for ALND in patients with cn0 disease. 3 From 2001, we introduced SLNB without changing our policy to preserve the axilla. Patients with a negative SLNB usually received ALNI by extended tangential fields, and those with a positive SLNB mainly received RNI by an additional third field to the supraclavicular fossa. From April 1983 to May 2011, 4277 women with invasive breast cancer without distant metastasis underwent curative treatment at our institutions. Of these, patients with ct1-2n0 breast carcinoma (tumor not more than 5 cm in greatest dimension, no regional lymph node metastasis [N0], and no distant metastasis [M0]) who received breast conservation therapy with a potential follow-up over 6 months constituted the analysis. Patients who underwent ALND in earlier years until 1988 or received neoadjuvant systemic therapy, or those who had synchronous bilateral breast carcinomas, were excluded from the analysis. The possible advantages and disadvantages of ALND, ALNI, and RNI were explained to each patient. Informed consent was obtained from all patients for the proposed treatment. The review board of our institution approved this retrospective study ( ). In total, 2170 patients were eligible and divided into 3 groups: nx group (n 1548), without any axillary surgery; sn group (n 518), with a negative SLNB; and sn group (n 104), with a positive SLNB. Historical changes of our treatment policies are shown in Figure 1. Details of Treatment The breast tumor was excised with a rim of healthy breast tissue to obtain clear macroscopic surgical margins. SLNBs were identified by using blue dye injection. After surgery, the whole breast was irradiated with tangential fields by using a 6-MV linear accelerator to a total dose of 50 Gy in 25 fractions. Boost irradiation was not routinely used in earlier years, but later it was used for those with positive margin. In earlier years, radiation treatment planning was performed by using a 2-dimensional x-ray simulator. The detailed method was previously reported. 4,5 70 Clinical Breast Cancer February 2013

3 Naoko Sanuki et al Since 2004, we began to introduce computed tomography based treatment planning. Details of treatment planning were previously reported. 6 In brief, for a typical tangential breast irradiation, the clinical target volume included the whole breast and the level I to II axillary nodal regions. The planning target volume was defined as the clinical target volume with a 3-mm margin except for the skin area. Small fields to compensate hot spots were added (a field-in-field technique). The superposition algorithm was used for dose calculations. For patients who had RNI, a separate, anterior field that was used to treat the supraclavicular fossa and axilla to a total of 50 Gy in 25 fractions prescribed to a depth of the supraclavicular fossa. The lateral border of the third field extended to the axilla; the humeral head was blocked. A half-beam block was used to match the caudal edge of the anterior field and the cranial edge of the tangential fields. In later years, when SLNB was initiated after 2001, RNI was routinely given for patients with a positive SLNB. Adjuvant systemic therapy with chemotherapy and/or hormonal therapy was given with the decision based on age, menopausal status, tumor size, hormone receptor status, human epidermal growth factor receptor 2 positivity, and nuclear grade. In earlier years, the patients treated with chemotherapy received cyclophosphamide, methotrexate, and fluorouracil based or doxorubicin-containing regimens. In later years, the addition of taxanes with or without trastuzumab to doxorubicin-based chemotherapy was started, depending on patients risk profiles. Tamoxifen with or without a luteinizing hormone-releasing hormone analogue agent or an aromatase inhibitor was also given as appropriate. Follow-up The patients were followed-up on an outpatient basis with interviews, laboratory data review, physical examination, mammography, and breast ultrasound during the first 2 years in 3- to 6-month intervals, then every 6 months thereafter. Follow-up was measured from the date of breast surgery. Local recurrences were determined by pathologic confirmation. Regional nodal failure (RNF) was diagnosed according to either radiologic findings or positive regional lymph node biopsy specimens. Although not all lymph node recurrences were confirmed by biopsy or cytology, all the patients who underwent salvage ALND were identified with lymph node involvement. Lymph node recurrences in the ipsilateral supraclavicular fossa, internal mammary area, and axilla were defined as RNF. Lymph node recurrences that occurred simultaneously with distant failure, in-breast recurrence, or a new contralateral breast carcinoma were scored as an event, but lymph node failures that occurred after these were not scored as events because further dissemination from these sites or any treatment after those events could alter the risk of RNF. Because of the retrospective nature of the data starting from 1988, toxicity was graded by using version 2.0 of the National Cancer Institute Common Toxicity Criteria. Nomogram to Predict 4 or More Node Metastases Katzet al 7 suggested a nomogram for predicting 4 positive nodes in patients with SLN breast cancer. To evaluate such risks in the sn group, we calculated the score, which consisted of a formula that used primary tumor size, the number of positive nodes, the presence of lymphovascular invasion, the presence of lobular histology, the presence of extranodal extension, the presence of macrometastasis, and the number of negative sentinel nodes. The score then was applied to a scale that predicted the likelihood of 4 axillary node positivity. Statistical Analysis Cumulative lymph node recurrence rates and overall survival rates were calculated by the Kaplan-Meier method, and survival curves classified by each axillary treatment were compared by the logrank test. We used the 2 test and the Mann-Whitney U test for comparing characteristics between groups. The statistical calculations were performed by using IBM SPSS Statics 20.0 (IBM Corp, Armonk, NY). Results As of May 31, 2011, the median follow-up time was 88 months (range, months), 56 months (range, months), and 55 months (range, months) in the nx (n 1548), sn (n 518), and sn (n 104) groups, respectively. Fifteen (0.7%) patients were lost to follow-up within 6 months. Another 25 (1.1%) survivors after 6 months dropped out from follow-up within 2 years. The patients demographics are shown in Table 1. The nx group had significantly younger patients and more estrogen receptor negative, higher-grade, and T2 tumors compared with other 2 groups. In contrast, median tumor size and the percentage of lymphovascular invasion were largest in the sn group. For most of the sn and sn groups, radiation fields were basically determined by SLNB results; 98% (n 507/ 518) in the sn group received only tangent irradiation, and 100% (n 104/104) of the sn group received additional RNI. In contrast, among the patients in the nx group, 17% (n 262/1548) received additional RNI. Adjuvant chemotherapy and hormonal therapy were administered to 74% (n 1149/1548), 26% (n 136/518), and 60% (n 62/104), and to 32% (n 495/1548), 71% (n 368/518), and 83% (n 86/104) of the patients, respectively. In the sn group, the median size of lymph node metastasis was 2.0 mm (range, mm), and macrometastasis 2.0 mm was observed in 34 (33%) of patients. The 5-year cumulative incidences of axillary failure and RNF were 34, 3, and 0 (2.7%, 0.7%, and 0%, respectively [P.02, log-rank test] between the nx and sn groups) and were 57, 4, and 0 (4.4, 1, and 0, P.04 between the nx and sn groups), respectively (Table 2) (Figure 2). Among RNF in the nx group, 39 developed isolated RNF; 15 patients had simultaneous distant recurrences; 3 had simultaneous local recurrence; axillary recurrence was found in 38 patients; infra- and supraclavicular and parasternal recurrences (with or without axillary recurrences) were observed in 30 and 3 patients, respectively. Accordingly, in the sn group, there were 4 RNFs: 2 with distant metastases and 2 as isolated RNFs. There was no RNF in the sn group. The 5-year cumulative local failure occurred in 53, 4, and 0 (3.8%,1.8%, and 0%; P.02 between the nx and sn groups) in the nx, sn, and sn groups, respectively. Cancer-specific survival rates in 5 years were 97.1%, 99.1%, and 97.6% in the nx, sn, and sn groups, respectively (P.09). The 5-year overall survival was 96.4%, 98.9%, and 97.6% (P.03; between the nx and sn groups) (Figure 3). In all outcomes mentioned above, there were no Clinical Breast Cancer February

4 cn0 Breast Cancer Without Axillary Dissection Table 1 Patient Characteristics According to Axillary Intervention: the nx Group, (Without Any Axillary Surgery), the sn Group (With a Negative SLNB), and the sn Group (With a Positive SLNB) Total No. nx Group % sn Group % sn Group % P No. Patients Age at Diagnosis Mean, y Median, y Range, y Premenopausal Tumor Stage (clinical) Size of Primary Tumor Mean, cm Median, cm Range, cm Estrogen Receptor Status Positive Negative Unknown Progesterone Receptor Status Positive Negative Unknown HER2 Expression Positive Negative Unknown Lymphatic Vessel Invasion Present Absent Unknown Nuclear Grade Unknown Histology Ductal Lobular Others Lymph Node Metastases Clinical Breast Cancer February 2013

5 Naoko Sanuki et al Table 1 Continued Total No. nx Group % sn Group % sn Group % P No. SLNs Positive SLNs 0 (positive non-slns) Margins Positive Negative Unknown Radiation Field Tangents only Tangents supraclavicular field Adjuvant Chemotherapy Adjuvant Hormone Therapy Abbreviations: HER2 human epidermal growth factor receptor 2; SLN sentinel lymph node; SLNB sentinel lymph node biopsy. Table 2 Five-Year Cumulative Incidence of Recurrences in the nx Group (Without Any Axillary Surgery), the sn Group (With a Negative SLNB), and the sn Group (With a Positive SLNB) nx Group, no. (%) sn Group, no. (%) sn Group, no. (%) P a Event 187 (13) 16 (5.2) 6 (11).0002 Ipsilateral Breast Failure 53 (3.9) 4 (1.8) 0 (0).02 Regional Nodal Failure 59 (4.4) 4 (1) 0 (0).04 Axillary Nodal Failure 38 (2.7) 3 (0.7) 0 (0).02 Infra- and/or Supraclavicular Failure 30 (2.3) 3 (0.8) 0 (0).14 Parasternal Failure 3 (0.2) 1 (0.2) 0 (0).89 Distant Failure 96 (7) 10 (3) 5 (8.9).08 Death From Cancer 40 (2.9) 2 (0.9) 1 (2.4).09 Death From Any Cause 51 (3.6) 3 (1.1) 1 (2.4).03 Abbreviation: SLNB sentinel lymph node biopsy. a P values are between the nx group and the sn group. significant differences between the sn group and either the nx group or the sn group. Risks of 4 or More Nodes Involved in the sn Group Among the sn group, 83 (80%) were evaluable for the risk of 4 or more nodal involvement. As a result, the median probability of the risk was 5% (range, 0.5%-80%). Thirty (30%) had more than 20% risk of 4 nodal metastases (Figure 4). Toxicity Symptomatic radiation pneumonitis that did not necessitate oxygen therapy developed in 31, 16, and 6 (2.0%, 3.1%, and 5.7%, respectively). Of these, 5, 0, and 6 had an additional RNI. However, the incidence of radiation pneumonitis was not different between tangents and RNI (2.0% and 3.0%, P.20). No patient had persistent pulmonary symptoms. In the 3 groups, 1, 4, and 0 (0.06%, 0.8%, and 0%) developed mild arm edema (grade 1), and 1 patient in the nx group had moderate arm edema (grade 2). Mild shoulder constriction due to SLNB was observed in 1 patient in the sn group. No brachial plexopathy was observed in any patient. Discussion This retrospective study reports on a longer-term follow-up results after the previous report 3 for a large number of patients with cn0 who received breast conservation therapy without ALND. The overall results were excellent across groups. However, the details of the results cannot be explained without considering historical changes of clinical practice over 2 decades (Figure 1). Overall survival was Clinical Breast Cancer February

6 cn0 Breast Cancer Without Axillary Dissection Figure 2 Axillary (A) and Regional (B) Nodal Control According to Axillary Intervention A 100 B % 80 % nx group sn group sn + group 70 nx group sn group sn + group mo (at risk) nx sn sn mo (at risk) nx sn sn Figure 3 Cancer-specific (A) and Overall (B) Survival According to Axillary Intervention A 100 B % 80 % nx group sn group sn + group 70 nx group sn group sn + group mo (at risk) nx sn sn mo (at risk) nx sn sn slightly worse and more regional, and axillary recurrences were observed in the nx group. These different results were probably due to bias in patients characteristics, such as younger age, more estrogen receptor negativity or higher grade, underestimation of cn0 disease due to poorer diagnostic imaging modality, less application of a boost to the tumor bed in earlier years, or a lack of new-generation chemotherapeutic agents at that time. Another possible explanation is that SLNB contributed to more accurate patient selection of patients who benefited from RNI and optimal systemic therapy. The sn group was well controlled despite having definite lymph node metastasis. All of the patients received RNI, and no patient had a recurrence in the regional lymphatics as a first event, which indicates a therapeutic effect of RNI for such patients. In contrast, the sn group was also well controlled; most of the patients received ALNI. Management of Patients With cn0 and Without ALND Our treatment policy to preserve the axilla for patients with cn0 has been supported by other studies and reports. The National Surgical Adjuvant Breast and Bowel Project B-04 trial showed that survival for mastectomy without ALND and for radical mastectomy are 74 Clinical Breast Cancer February 2013

7 Naoko Sanuki et al Figure 4 Distribution (%) Distribution of Risks for Having 4 or More Nodes Involved According to a Nomogram by Katz et al Probability of 4 nodal involvement equivalent, which indicates that ALND is only a staging procedure that provides no survival benefit. 8 The introduction of SLNB allowed an alternative method for nodal staging with less morbidity with the increasing population of patients with cn0 disease. 9 It is also argued that, because patients with SLN metastases will generally receive systemic therapy regardless of the presence of any additional nodal metastases, any residual disease does not influence the choice of therapy and may itself be eradicated by the systemic therapy. 10,11 Clinical practice has preceded the evidence. Reports from analysis of the SEER (surveillance, epidemiology, and end results) database on nearly 27,000 US patients with breast cancer between 1998 and 2004 suggest that surgeons are already omitting ALND even for a percentage of patients with a positive SLN, especially those with small-volume metastases. 12 In terms of our practice that we had already omitted ALND for patients with cn0 with an excellent regional control rate, 3 we did not change our policy to preserve the axilla even after a positive SLNB. The ACOSOG Z0011 trial demonstrated equivalent outcomes between ALND and no ALND for patients who were positive for SLNB. 1 However, generalizability of these trial results is questioned. The patients characteristics in this trial were relatively favorable; approximately 70% had T1 tumors, 82% had estrogen receptor positive disease, and median tumor size was 1.7 cm. 1 Compared with the Z0011 trial, our subjects had more T2 tumors, and the median tumor size was 2.3 cm. In a similar trial, International Breast Cancer Study Group 23-01, 13 the results were consistent with those of the Z0011 trial. However, the objectives consisted of patients with one or more micrometastatic ( 2 mm) SLNs, and a majority was postmenopausal. Among patients in the sn group in our study, approximately 30% had macrometastasis in the SLNs. A careful discussion is necessary to apply these trial results into clinical practice. The Role of RNI in the Treatment of Patients With cn0 ALND findings also provide information concerning the risk of involvement in the supraclavicular nodes and influence the design of the radiation treatment fields. 14 For patients with 4 or more positive nodes, radiation oncologists commonly treat the supraclavicular region with an additional field as well as treat the breast or chest wall. The value of RNI, especially for patients with 1 to 3 positive nodes has more recently been confirmed in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.20 trial, which was predominantly composed of patients with 1 to 3 positive nodes. 15 Another report also supports the benefit of treating the axilla for patients with 1 to 3 positive nodes regardless of the use of adjuvant systemic treatment. 16,17 Although the situation is somewhat different in terms of breast surgery (mastectomy with ALND) or radiation method (radiation to the parasternal lymph nodes), the results from the current study may also justify the use of RNI. The nx group (mainly with tangents) showed worse regional control than the sn group (mainly with tangents) or the sn group (mainly with RNI). This result could be partially attributed to the more unfavorable patients characteristics of the nx group and different chemotherapy intensity in earlier years. Another possible explanation is that we could not select optimal candidates from the patients in the nx group who might benefit from RNI in early years when SLNB was not introduced. In the sn group, 36% of patients had more than a 20% risk of having 4 nodal involvement, and this condition applies to an indication for RNI in radiation oncology. Treating those patients only with tangents might be insufficient. One of the questions with limited data are whether RNI is more effective than ALNI in cases of positive SLNB (without ALND). The first issue to consider is the probability of residual disease burden. 7 Another consideration is relevant to the volume covered by tangential field irradiation, which possibly eradicates the potential nodal disease. By using a so-called high-tangent field as well as computed tomography based conformal radiation planning, the area around the SLN is completely covered, and 87% of level I receives more than 95% of the prescribed dose. 6 It seems to be critical to predict whether residual disease after a positive SLNB is beyond the volume that high-tangential fields can cover. One practical way is to customize radiation coverage according to each patient s risk, although a careful consideration is necessary to be aware of the amount of false negativity of SLNB at each institution. 18 Detailed analysis of a relationship between irradiated volume and outcomes in our hospital is underway. There was another reason for us to treat the regional lymph nodes with radiation. Although technetium-99m sulfur colloid is used as a standard SLNB procedure, we have only used blue dye to identify SLN, which may possibly result in a false-negative SLNB in some cases. Furthermore, the result of SLNB is greatly influenced by how SLNs are examined. With this situation, we started to perform ALNI. Toxicity from Axillary Treatment There are several reports that support ALNI as a safe alternative to ALND for patients with cn Although not all researchers reported on detailed toxicity from ALNI without ALND, the frequency of radiation pneumonitis, brachial plexopathy, and arm edema seemed to be acceptably low. Although the combination of ALND and ALNI, especially by RNI, increases the risk of lymphedema, minimal morbidity is associated with radiation to the undissected regional lymphatics. 23,24 In the current study, toxicity Clinical Breast Cancer February

8 cn0 Breast Cancer Without Axillary Dissection was minimal in each group, including those with RNI (without ALND), although longer-term data are still to be evaluated. Limitations of our study include different follow-up times, different chemotherapy agents over years (especially before and after introducing taxane or trastuzumab), or less boost application to the tumor bed in earlier years, all of which are associated with the retrospective nature of this study in a long period of time since In contrast, the strength of this study is a large cohort of patients with cn0 treated without ALND. If the axilla is clinically negative and if information from additional ALND on pathologic lymph node status will not affect the decision of adjuvant systemic therapy, then ALNI or RNI, which has negligible morbidity, is a reasonable alternative to ALND, which entails a lifelong risk of arm edema. Conclusion Treatment without ALND showed excellent outcomes with negligible toxicity for patients with cn0, including those with a positive SLNB. For breast cancer patients with negative and positive sentinel nodes, ALNI and RNI, respectively appeared to result in satisfactory regional control, with negligible morbidity. Clinical Practice Points The introduction of SLNB to the treatment of cn0 breast cancer has raised new clinical questions, including the appropriate management of the axilla after a positive SLNB. Although emerging evidences showed equivalent survival in patients with positive SLN with or without ALND, it is also known that a substantial portion of such patients have pathologic lymph node metastases, which indicates a potential need for treating regional nodal area. With many other studies with supporting or contradicting results, it is still under debate whether leaving the regional nodal area untreated is safe. We analyzed whether axillary nodal irradiation could control cn0 disease, including patients with a positive SLNB without ALND. Toxicity profiles were also evaluated. From 1988 to 2011, 2107 patients ct1-t2n0m0 underwent breast conservation therapy in the absence of ALND: the nx group (n 1548), without any axillary surgery; the sn group (n 518), with a negative SLNB; and the sn group (n 104), with a positive SLNB. Ninety-eight percent of the sn group received only tangent irradiation, and 100% and 83% of the sn and nx groups, respectively, received additional regional nodal irradiation. The 5-year cumulative incidences of axillary and RNF were 34, 3, and 0 (2.7%, 0.7%, 0%, respectively; P.02, log-rank test), and 57, 4, and 0 (4.4, 1, and 0), P.04). The 5-year overall survival rates were 96.4%, 98.9%, 97.6% (P.03). Mild arm edema was observed in 1, 4, and 0 (0.06%, 0.8%, and 0%). Treatment without ALND showed excellent outcomes with negligible toxicity for patients with cn0, including those with a positive SLNB. Regional nodal irradiation after a positive SLNB is a reasonable alternative to ALND. Disclosure The authors have stated that they have no conflicts of interest. References 1. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011; 305: Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a meta-analysis. Cancer 2006; 106: Fujimoto N, Amemiya A, Kondo M, et al. Treatment of breast carcinoma in patients with clinically negative axillary lymph nodes using radiotherapy versus axillary dissection. Cancer 2004; 101: Takeda A, Shigematsu N, Kondo M, et al. The modified tangential irradiation technique for breast cancer: how to cover the entire axillary region. 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