Accepted Manuscript

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

Á. Sávolt, G. Péley, C. Polgár, N. Udvarhelyi, G. Rubovszky, E. Kovács, B. Győrffy,

M. Kásler, Z. Mátrai
PII: S0748-7983(17)30038-0
DOI: 10.1016/j.ejso.2016.12.011
Reference: YEJSO 4558

To appear in: European Journal of Surgical Oncology

Received Date: 29 August 2016

Revised Date: 3 November 2016
Accepted Date: 5 December 2016

Please cite this article as: Sávolt Á, Péley G, Polgár C, Udvarhelyi N, Rubovszky G, Kovács E, Győrffy
B, Kásler M, Mátrai Z, 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, European Journal of Surgical Oncology
(2017), doi: 10.1016/j.ejso.2016.12.011.

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 ACCEPTED MANUSCRIPT

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.

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A randomized, single centre, phase III, non-inferiority trial

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Á. Sávolt 1,*, G. Péley2††, C. Polgár3, N. Udvarhelyi4,

G. Rubovszky4, E. Kovács 5, B. Győrffy6, M. Kásler1, Z. Mátrai1

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1
Department of Breast and Sarcoma Surgery, National Institute of Oncology, Budapest, Hungary
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2
Department of General Surgery, Norfolk and Norwich University Hospital, Norwich, UK (deceased)

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Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary
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4
Department of Pathology, National Institute of Oncology, Budapest, Hungary
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5
Department of Diagnostic Imaging, National Institute of Oncology, Budapest, Hungary

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MTA TTK Momentum Cancer Biomarker Res. Group, Hungarian Academy of Sciences, Budapest,
Hungary
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* Corresponding author. Department of Breast and Sarcoma Surgery, National Institute of Oncology,
H-1122, Rath Gy. u. 7.-9., Budapest, Hungary Tel.: +36-1-2248600/3444
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E-mail address: drsavolt@hotmail.com(Á. Sávolt).

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ABSTRACT

Introduction The National Institute of Oncology, Budapest conducted a single centre

randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla – Surgery Or

Radiotherapy) trial compares completion of axillary lymph node dissection (cALND) to

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regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in

stage I-II breast cancer.

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Patients and Methods Patients with primary invasive breast cancer (cN0 and cT≤3cm) were

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randomized before surgery for cALND (standard treatment) or RNI (investigational

treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm

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levels by haematoxylin-eosin staining. Investigational treatment arm patients received 50Gy
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RNI instead of cALND. Adjuvant treatment and follow up were performed according to the

actual guidelines. Between August 2002 and June 2009, 1,054 patients were randomized for
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cALND and 1052 patients for RNI. SN was evaluated in 2,073 patients and was positive in
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526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm),
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and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary

surgery has additional positive nodes. The two arms were well balanced according to the
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majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary

endpoints were overall survival (OS) and disease-free survival (DFS).

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Results Mean follow-up was 97 months (Q1-Q3 80-120). Axillary recurrence was 2.0% in

cALND arm vs. 1.7% in RNI arm (P=1.00). OS at 8 years was 77.9% vs. 84.8% (P=0.060),

and DFS was 72.1% in cALND arm and 77.4% after RNI (P=0.51). The results show that

RNI is statistically not inferior to cALND treatment.

Conclusions The long term follow-up results of this prospective-randomized trial suggest that

RNI without cALND does not increase the risk of axillary failure in selected patients with

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early-stage invasive breast cancer (cT≤3 cm, cN0) and pN1(sn). Axillary radiotherapy should

be an alternative treatment for selected patients with sentinel lymph node metastases.

Keywords breast cancer, sentinel lymph node biopsy, regional nodal irradiation, axillary

recurrence

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Introduction

Axillary lymph node metastasis in patients with early-stage breast cancer is still the

most important prognostic factor for recurrence and survival and strongly influencing
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therapeutic decisions . For decades, axillary lymph node dissection (ALND) has been an

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essential component of the staging and axillary control of invasive breast cancer. In the mid-

1990s the standard of surgical practice has moved from complete (level I-III) ALND to

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sampling level I and II lymph nodes. The most recent development is performing axillary
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sentinel lymph node biopsy (SLNB) . Patients without clinical involvement of the axilla

should undergo SLNB routinely, and no additional lymph node surgery is needed when the

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sentinel node is disease-free . The current standard is to make cALND in patients with a
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positive sentinel lymph node biopsy . Among SLNB positive patients, about 25-50% have
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metastases in the remaining non-SN(s), but the remaining number of patients have no further
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involved nodes and would not be expected to benefit from cALND . For patients with breast
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cancer, SLNB delivers decreased morbidity compared with ALND, including a lower rate of
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lymphedema, seroma, pain, and sensory changes . In selected cases RNI may replace cALND

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in case of positive SN . As irradiation is generally indicated after breast conserving surgery,

in case of positive sentinel lymph nodes, radiation therapy may be given to the axillary tail at
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the same time .
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Optimal treatment of the axilla for patients with cN0 and pN1(sn) is still controversial.

According to the latest St. Gallen statement the axillary dissection can be avoided for cT1-2
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cN0 patients with micrometastasis or one or two macrometastatic lymph nodes . The

Hungarian National Institute of Oncology, Budapest designed the OTOASOR (Optimal

Treatment of the Axilla – Surgery or Radiotherapy) single centre randomized controlled

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clinical trial to compare cALND to RNI in patients with sentinel lymph node-positive (micro-

and macrometastases) primary invasive breast cancer. Main objective of the trial was to

prove equivalent survival and locoregional control for patients with axillary lymph node

metastasis by SLNB with reduced morbidity if treated with RNI instead of cALND. Axillary

recurrence free rate in the cALND treatment group was assumed to be in the range of 97-99%.

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The primary end point of the study was to compare axillary control in the cALND and in the

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RNI group (not less than 96-97%). Secondary outcomes were to compare the DFS, and the

OS rate of patients in the two treatment arms. As quality of life indicators shoulder functions

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and validated quality of life questionnaire (QLQ-C30) were also analyzed postoperatively.

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Patients and Methods

Patients with cT≤3 cm, cN0 primary invasive breast cancer were randomized before

surgery for cALND or RNI. Preoperative assessment was carried out in accordance with local

practice with triple test (clinical breast exam, mammogram, ultrasound, and fine needle

aspiration cytology). Ultrasound of the axillary region was performed and suspected node

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metastases were biopsied. The study design and patient flow chart of the OTOASOR trial are

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shown in Figure 1.

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Overall, 2,106 patients were randomized for cALND (standard treatment, 1054
patients) or RNI (investigational treatment, 1052 patients). We used the Zelen’s design
randomisation (randomized consent design). In this design, those patients receiving

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standard care need not be consented for participation in the study other than possibly
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for privacy issues. On the other hand, those patients randomized to the experimental
group are consented as usual, except that they are consenting to the certainty of
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receiving the experimental treatment only; alternatively these patients can decline and
receive the standard treatment instead.
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SN was not identified in 33 patients (1.6%), 15 patients (1.4%) in the cALND arm and
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in 18 patients (1.7%) in the RNI arm; these patients were excluded and had cALND. SN was
identified in 2,073 patients (98.4%), 1,039 patients in the cALND arm and 1,034 patients in
the RNI arm. SN was positive in 526 patients (25.4%). Overall, 52 SN+ patients were
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excluded from the study because of protocol violation or patients’ preference (17 from
cALND arm and 35 from RNI arm). The remaining 474 patients with positive sentinel nodes
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underwent cALND (244 patients) or RNI (230 patients) according to their random
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assignment.

Surgery Breast-conserving surgery or mastectomy was performed in all patients according to

current surgical protocols. If the primary tumor was not palpable, the radio-guided occult

lesion localization (ROLL) procedure was performed to detect the tumor. The SLNB

procedure was performed using the combined method of blue dye (2ml patent-blau

subareolar) and technetium (99Tc) isotope in the early phase of the trial, but later the use of

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blue-dye was optional and solely the isotope method was used to detect SN(s). During

surgery, we used a gamma probe to detect SN(s). Ten minutes after the injection all

radioactive and blue-stained SN(s) were removed together with all lymph nodes that were

suspicious for metastasis by palpation. Patients who were assigned to the cALND arm

underwent level I-II completion axillary surgery during the first operation if the imprint

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cytology was positive for the removed SN(s). When the SNs were found to be positive solely

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by immunohistochemistry or hematoxyline-eosin staining, the patients underwent cALND

within 4 to 6 weeks. Removal of at least 10 lymph nodes was mandatory. Those patients who

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were allocated to the RNI arm underwent no further axillary surgery. Extra-axillary SNs were

not removed.

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Pathology Breast tumor pathologic workup was done according to the routine institutional

guidelines (tumor type, tumor size, excision margins, histologic and nuclear grade, estrogen
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receptor, progesterone receptor, and human epidermal growth factor receptor type 2 status
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determined by immunohistochemistry or fluorescence in situ hybridization). During SLNB,

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intraoperative imprint cytology was performed routinely for patients randomized to the

ALND arm. The SNs were finally processed for histology by serial sectioning (0.5 mm levels)
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and hematoxylin eosin staining but no immunohistochemistry. All negative SNs were

investigated further by immunohistochemistry with a cytokeratin cocktail and epithelial

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membrane antigen. Lymph node metastases were categorized according to the 7th TNM of
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AJCC .

Radiotherapy and Adjuvant Systemic Therapy After breast-conserving surgery, patients

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underwent postoperative whole breast irradiation . Patients with pN1(sn) randomized to the

RNI arm were irradiated within 8-12 weeks after surgery. The whole breast plus all 3 levels of

the axilla and the supraclavicular fossa were considered target volume. The dose of RNI was

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50 Gy in 25 fractions of 2 Gy, 5 days per week. According to our institutional protocol,

postoperative RNI in patients undergoing cALND was given to all patients with 4 or more

positive nodes (pN2a-3a) and to patients with 1 to 3 positive nodes (pN1a) having other high-

risk patient and tumor characteristics (e.g., premenopausal status, lymphovascular invasion,

histologic grade III tumor). Adjuvant systemic therapies were administered in accordance

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with our institutional protocols . Adjuvant trastuzumab treatment has been available since

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January 2008 in Hungary. All patients were monitored with yearly clinical follow ups of

physical investigation and using roentgen and ultrasound mammography for at least five

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years. The trial was approved by the National Institute of Oncology’s Ethical Committee.

Written informed consent was obtained from all patients.

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Statistical Analysis The main objective of the trial was to prove equivalent OS, DFS and
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locoregional control of the axilla for patients with SN+ with reduced morbidity if treated with

RNI instead of cALND.Statistical analysis was performed with IBM SPSS version 12.0
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package (IBM Corp., Armonk, NY). Discrete patient and tumor characteristics of the 2
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treatment arms were compared using the chi-square test. Continuous variables were evaluated

using the Mann-Whitney U-test. We assessed 8-year axillary recurrence using the cumulative
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incidence method, with death as a competing risk. We made a power calculation to assess the
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number of samples needed when comparing the eight-year disease-free survival. In this, at
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α=5%, a 95% power, and a non-inferiority limit of 5%, 238 samples were needed in each
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cohort .

OS, DFS and progression-free survival were analyzed by Cox proportional hazards

regression and Kaplan-Meier survival plots were generated. Multivariate Cox regression was

computed to compare the effects of clinical and interventional variables on survival. Post

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progression survival (PPS) was computed for patients with a first progression event and

available OS data. The threshold for statistical significance was set at p=0.05.

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Results

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A total of 474 patients with positive sentinel nodes who underwent cALND (244

patients) or RNI (230 patients) according to their random assignment remained in the final

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analysis. Basic patient and tumor characteristics are listed in Table 1. The two arms were well

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balanced according to the majority of main prognostic factors. However, more patients were
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premenopausal (34% vs. 27%; p=0.095) and had pT2-3 tumors (57% vs. 40%; p=0.003) in the

cALND arm. Two-hundred patients (82%) in the cALND arm, and 200 patients (84%) in the
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RNI arm underwent breast conserving surgery. Forty-four patients (18%) in cALND arm, and

in 30 patients (16%) in RNI arm underwent mastectomy (p=0.164). Among those who
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underwent breast conserving surgery, 71 patients (29%) in the cALND arm and 76 patients
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(33%) in the RNI arm had non-palpable tumor, so they underwent ROLL procedure.
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Histological tumor characteristics of the two arms were well balanced. Histology was invasive

ductal carcinoma in 193 patients (79%) in the cALND arm, and in 188 patients (82%) in the
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RNI arm. On the other hand, the histology was invasive lobular carcinoma in 40 patients
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(16%) in cALND arm, and in 28 patients (12%) in RNI arm (p=0.397).

Lymph node characteristics of the two arms are listed in Table 2. The mean number of

removed sentinel lymph node was 1.83 (QR 1-5) on the cALND arm, and 1.95 (QR 1-5) on

the RNI arm (p=0.674). The mean number of removed lymph nodes was 14.31 (QR 7-32) in

the cALND treatment arm. The number of removed positive lymph nodes was 2.77 (QR 1-24)

in the cALND arm, and 1.17 (QR 1-4) in the RNI arm.

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In the investigational treatment arm (RNI arm) patients received 50 Gy RNI instead of

cALND, therefore in these patients we only had information about the SN status, but the

further axillary nodal involvement remained unknown. Therefore the pN category is not

applicable for RNI arm patients. A total of 139 patients (60.4%) had macrometastasis, 77

patients (33.5%) had micrometastasis in the RNI arm patients. In the remaining 14 patients

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(6.1%) we found isolated tumor cells in the positive sentinel lymph node(s).

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In the cALND group, a median of 12.5 (QR 8–31) additional nodes were removed

besides the SNs. Histological examination revealed additional lymph nodes with metastases in

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94 (38.5%) of 244 patients who underwent cALND, 54 (22%) of whom had four or more total

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metastatic nodes. In the non-sentinel positive group a total of 77 patients (31.5%) had
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macrometastasis and 17 patients (7%) had micrometastasis. Combined axillary treatment

(cALND followed byRNI) was administered to 57 patients (23.3%) randomly assigned to the
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cALND group.
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The mean length of follow-up was 97 months (range 54 – 134, Q1-Q3: 80-120), 97.7
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months (range 55-134) in cALND arm and 95.6 months (range 54-133) in RNI arm. Axillary

recurrence occurred in five of 244 patients (2%) in the cALND group and four of 230 (1.7%)
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in the RNI group over the entire follow-up period (p=1.00). One of the five recurrences in the

cALND group and two of the four recurrences in the RNI group were isolated axillary
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recurrence as a first event. The use of RNI compared with cALND did not appear to result in
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statistically inferior survival. As we had 160 samples with 8 year follow-up in cALND arm

and 152 samples in RNI arm, the planned statistical analysis had sufficient power. There were

no significant differences between treatment groups in DFS (P=0.51) and OS (P=0.060,

HR=0.59). During the 8 year of follow-up 34 (13.9%) of 244 patients in the cALND group

and 20 (8.7%) of 230 in the RNI group died because of breast cancer, and 20 (8.2%) patients

in the cALND group and 15 (6.5%) in the RNI group died of other reason (see Table 3.).
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There was no event or the follow-up was shorter than 8 years for 85 patients in the cALND

group and 75 patients in the RNI group. All together the 8-year OS rate was substantially

higher than the 70% anticipated at protocol design. Kaplan-Meier survival curves show that

the DFS and OS times were similar in both treatment arms (see Figure 2). When comparing

PPS in the two arms, RNI arm had better prognosis (p=0.0197, HR=0.52, see Figure 3.).

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The rates of (any clinical sign of) lymphoedema, paresthesia, swelling, arm pain, and

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shoulder mobility and were higher in the cALND group (15.3%) than in the RNI group at one

year (4.7%). Combining cALND and radiotherapy in the axillary treatment in the cALND arm

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further increased morbidity in those 18/57 patients (31.5%). No statistically significant and

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clinically relevant differences in QoL were noted between the two groups used by the EORTC
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QLQ BR23 and QLQ C3 (version3) questionnaires (data not shown).
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Discussion

The standard of care for early-stage breast cancer patients is based on radical tumor

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excision and SLNB. The next step of clinical practice was directed to understand whether
cALND is always necessary after positive SLNB and this is now one of the most exciting

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topics among breast surgeons. Several single-institution retrospective reports have described
the outcome of patients with metastases that were identified by SLNB who did not undergo

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cALND . But there are only a few major clinical trials published so far on this subject.

The results of the National Surgical Adjuvant Breast and Bowel Project B-32 (NSABP

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B-32) trial supports this concept - at a median follow-up of 25 years it failed to show a
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significant survival advantage from removing occult positive nodes with cALND or from
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axillary RNI . The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial
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was, perhaps, among the most influential and landmark studies demonstrating that cALND is
not necessary in clinically node negative (cN0) women with T1-T2 breast cancer undergoing
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breast conserving therapy after having macrometastases to one or two sentinel nodes . The
planned accrual was 1,900; the study closed with 891 patients due to slow accrual and a low
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event rate. At a median follow-up of 6.3 years, no differences in DFS or OS were observed
between groups. The axillary recurrence was remarkably low (0.9 %), despite the finding of
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additional positive nodes in 27.4% of patients having cALND. The majority of patients had
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systemic therapy and all received tangential whole breast radiotherapy . Other randomized
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trials support these findings. The International Breast Cancer Study Group (IBCSG) 23-01
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trial randomized patients with micrometastases in the sentinel node to cALND or SLNB
alone. After a median follow-up of 5 years, regional recurrence was 1% of the SLNB group
and 0.2% of the cALND group, and no significant differences in DFS were noted, but 13% of
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patients in the cALND arm had additional nodal metastases .

In the EORTC AMAROS trial (After Mapping of the Axilla: Radiotherapy Or

Surgery?), axillary radiotherapy and ALND both provided excellent and comparable
locoregional control in patients with T1–2 primary breast cancer and no palpable
lymphadenopathy who are found to have a positive sentinel node. There were no significant

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differences between the two groups in 5-year axillary recurrence, DFS, and OS and the
axillary recurrence rate was 0.43% in the ALND group and 1.19% in the axillary radiotherapy
group, in spite of the finding that 32.8% of patients having cALND had additional positive
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nodes . The results of the AMAROS trial are in accordance with findings from the NSABP-
04 randomized trial started before the introduction of sentinel node biopsy that compared
axillary radiotherapy with ALND in clinically node-negative patients. Axillary lymph node

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dissection andRNI were the only treatments indicated to treat the axilla in this trial and the
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axillary recurrence rate after a 25-year follow-up was 4% in both treatment groups .

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In our single centre, phase 3 OTOASOR trial, axillary radiotherapy and axillary lymph
node dissection both provided excellent and comparable locoregional control in patients with

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T1–2 primary breast cancer and no palpable lymphadenopathy who were found to have a
positive sentinel node. The two arms of our trial were well balanced according to the majority

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of main prognostic factors. However, slightly more patients were premenopausal (34% vs.
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27%; p=.095) and had pT2-3 tumors (57% vs. 40%; p= 0.003) in the cALND arm . At a
median follow-up of 8.0 years, we found no difference between the two arms for the primary
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endpoint of axillary recurrence. Five patients (2.0%) in the cALNB arm, and four (1.7%) in
the RNI arm (P=1.00), altogether only 9 locoregional relapse, which was far less than we
expected 12 years ago at the start of the trial.On the other hand, 38.5% of patients had
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additional lymph node metastases in the cALND arm, but 7,4% of them had only
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micrometastasis in their non-sentinel lymph nodes.

The OTOASOR trial and the AMAROS study included patients undergoing
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mastectomy, who were excluded from the ACOSOG Z0011 trial, and our results suggests that
in patients after mastectomy who receive chest-wall + reginal nodal irradiation after positive
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sentinel node, cALND can be avoided as well .
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The Intergroup/National Cancer Institute of Canada Clinical Trials Group MA.20 was
a randomized trial that enrolled women at moderate to high risk of regional recurrence based
on involved axillary nodes or high-risk node negative disease. The patients underwent ALND
(or SLNB only if node negative) and whole breast irradiation with randomization to RNI or
not. With a median follow-up of 9.5 years, patients randomized to RNI had a statistically
significant improved isolated locoregional and distant DFS and a non-significant trend to
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improved OS, as well . These results suggest that RNI after positive SLNB and breast

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conserving surgery not only improves locoregional disease control, but also prevent
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secondary dissemination .

Conclusions

The long-term results of the OTOASOR trial confirm the concept that in patients with

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limited sentinel node metastasis axillary radiotherapy could be an alternative treatment for
selected patients. The trial shown equivalent survival and locoregional control for patients

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with axillary lymph node metastasis by SLNB with reduced morbidity if treated with RNI
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instead of cALND .

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The authors declare that they have no competing interests.
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Acknowledgements
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B.G. was supported by the OTKA K 108655 grant.

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Authors’ note
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Gábor Péley MD., PhD. was born on 24 March 1961, in Hungary. He completed his medical studies at
the Faculty of Medicine at the University of Szeged. His professional activity as surgical oncologist
and breast surgeon flourished at the National Institute of Oncology, Budapest, where he attained his
PhD degree, as well his special exam in surgical oncology by the European Society of Surgical
Oncology. Later he became an examiner for breast surgery special exam by ESSO, as well a honorary
breast surgeon awarded by ESSO. Dr Péley was one of the pioneers who started sentinel lymph node
biopsy in breast cancer and melanoma malignum in Hungary in the late nineties. Thanks to his
scientific activity nowdays these surgical techniques are counted as the as gold standard in Hungary.
He was the main investigator of the randomized, single centre, phase III, non-inferiority trial titled

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"Optimal treatment of the axilla after positive sentinel lymph node biopsy in primary invasive breast
cancer: OTOASOR", initiated in 2002, until he went to Norfolk & Norwich University NHS Trust as a
consultant breast surgeon. Unfortunately he was not able to be proud at the time of the publication
of the end results of OTOASOR study in EJSO because of his sudden death on 6th September 2016.
The co-authors and the editors of the journal pay tribute to his memory.

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References
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1. Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and
survival in 124,740 breast cancer cases. Cancer 1989; 63:181-7.
C

2. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary
AC

dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999; 91: 368-
73.
3. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel node
biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003; 349: 546-
53.
4. Giuliano AE, Haigh PI, Brennan MB, et al. Prospective observational study of sentinel
lymphadenectomy without further axillary dissection in patients with sentinel node-
negative breast cancer. J ClinOncol 2000; 18:2553-9.

15
 ACCEPTED MANUSCRIPT
5. Guenther JM, Hansen NM, DiFronzo LA, et al. Axillary dissection is not required for
all patients with breast cancer and positive sentinel nodes. Arch Surg 2003; 138: 52-6.
6. Fant JS, Grant MD, Knox SM, et al. Preliminary outcome analysis in patients with
breast cancer and a positive sentinel lymph node who declined axillary dissection. Ann
SurgOncol 2003; 10:126-30.
7. Noguchi M. Avoidance of axillary lymph node dissection in selected patients with

PT
node-positive breast cancer. Eur J SurgOncol 2008; 34:129-34
8. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared

RI
with conventional axillary-lymph-node dissection in clinically node-negative patients
with breast cancer: overall survival findings from the NSABP B-32 randomised phase

SC
3 trial. Lancet Oncol 2010;11(10):927–33.
9. Haffty BG, Hunt KK, Harris JR, Buchholz TA. Positive sentinel nodes without
axillary dissection: implications for the radiation oncologist. J ClinOncol 2011; 29:

U
4479-8 1.
AN
10. Sealed Envelope Ltd. 2012. Power calculator for binary outcome non-inferiority trial.
[Online] Available from: https://www.sealedenvelope.com/power/binary-noninferior/
M

[Accessed Dec 26 2015].

11. Yi M, Giordano SH, Meric-Bernstam F, et al. Trends in and outcomes from sentinel
D

lymph node biopsy (SLNB) alone vs. SLNB with axillary lymph node dissection for
TE

node-positive breast cancer patients: experience from the SEER database. Ann
SurgOncol 2010; 17:S343-51.
EP

12. Langer I, Guller U, Viehl CT, et al. Axillary lymph node dissection for sentinel lymph
node micrometastases may be safely omitted in early-stage breast cancer patients:
long-term outcomes of a prospective study. Ann SurgOncol 2009; 16:3366 -74
C
AC

13. Hwang RF, Gonzalez-Angulo AM, Yi M, et al. Low locoregional failure rates in
selected breast cancer patients with tumor-positive sentinel lymph nodes who do not
undergo completion axillary dissection. Cancer 2007; 110:723-30.

14. Giuliano AE, Hunt KK, Ball man 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; 305:569-75.

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15. Morrow M, Giuliano AE. To cut is to cure: can we really apply Z0011 in practice?
Ann Surg Oncol2011; 18:2413-5.

16. Galimberti, Viviana, et al. Axillary dissection versus no axillary dissection in patients
with sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised controlled
trial. The lancet oncology 14.4 (2013): 297-305.

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17. Donker, Mila, et al. Radiotherapy or surgery of the axilla after a positive sentinel node
in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-

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label, phase 3 non-inferiority trial. The Lancet Oncology15.12 (2014): 1303-1310.

18. Louis-Sylvestre C, Clough K, Asselain B, et al. Axillary treatment in conservative

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management of operable breast cancer: dissection or radiotherapy? Results of a
randomized study with 15 years of follow-up. J ClinOncol 2004; 22: 97–101.

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19. Hoebers FJ, Borger JH, Hart AA, Peterse JL, Th EJ, Lebesque JV. Primary axillary
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radiotherapy as axillary treatment in breast-conserving therapy for patients with breast
carcinoma and clinically negative axillary lymph nodes. Cancer 2000; 88: 1633–42
M

20. Savolt A, Musonda P, Matrai Z et al. Optimal treatment of the axilla after positive
sentinel lymph node biopsy in early invasive breast cancer. Early results of the
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OTOASOR trial. Orvosihetilap, 2013, 154.49: 1934-1942.

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21. Savolt A, Polgar C, Matrai Z et al. Does the Result of Completion Axillary Lymph
Node Dissection Influence the Recommendation for Adjuvant Treatment in Sentinel
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Lymph Node–Positive Patients? Clinical breast cancer, 2013, 13.5: 364-370.

22. Whelan TJ, Olivotto IA et al. Regional nodal irradiation in early-stage breast
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cancer. New England Journal of Medicine, 2015, 373.4: 307-316.

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23. Dengel LT, Van Zee KJ, King TA et al. Axillary dissection can be avoided in the
majority of clinically node-negative patients undergoing breast-conserving
therapy. Annals of surgical oncology, 2014, 21.1: 22-27.

24. Lyman GH, Temin S, Edge SB et al. Sentinel lymph node biopsy for patients with
early-stage breast cancer: American Society of Clinical Oncology clinical practice
guideline update. Journal of Clinical Oncology, 2014, 32.13: 1365-1383.

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25. Colleoni M, Rotmensz N, Peruzzotti G, et al. Size of breast cancer metastases in
axillary lymph nodes: clinical relevance of minimal lymph node involvement. J
ClinOncol. 2005; 23:1379–89.

26. Coates AS, Winer EP, GoldhirschA et al. Tailoring therapies—improving the
management of early breast cancer: St Gallen International Expert Consensus on the
Primary Therapy of Early Breast Cancer 2015. Annals of Oncology, 2015, 26.8: 1533-

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1546.

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Figure 1. Patients flow chart of study protocol and number of enrolled cases SLNB –
sentinel lymph node biopsy, cALND – completion axillary lymph node dissection, RNI –
regional nodal irradiation.
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2,106 pts. eligible

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Randomization

n=2,073 SLNB done Excluded (n=33)

SN not identified

n=526 SN positive Excluded

(n=1,547)SN negative
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SLN positive
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Lost to follow-up (n=0)

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Analyzed as randomized (n=244) Analyzed as randomized (n=230)

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Figure 2. The Kaplan-Meier survival curves (DFS - disease-free survial, OS - overall

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survival)
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0.8
Probability

0.6

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0.4

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Censors

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0.2 1A - cALND
2B - RNI
p=0.51
0

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0 50 100 150

DFS time (months)

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0.8
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Probability

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0.4
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0.2 1A - cALND
2B - RNI p=0.060, HR=0.59
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0
0 50 100 150
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OS time (months)

Figure 3. The Kaplan-Meier survival curve (PPS - post progression survival)

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1A - cALND
0.8 2B - RNI
Probability

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0.4

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0.2

p=0.0197, HR=0.52
0

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0 20 40 60 80 100 120 140

PPS time (months)

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Table 1. Patient and treatment characteristics according to treatment arms.

Characteristic Arm A (cALND) Arm B (RNI)

(n=244) (n=230)

No (%) No (%) p-value

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Age (years) Mean (Range) 54.7 (26-74 ) 55.2 (27-74)
0.602*

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Menopausal Pre 83 (34) 62 (27) 0.095

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status Post 161 (66) 168 (73)

Surgery Breast-conserving 200 (82) 200 (84) 0.164

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ROLL(non-palpable) 71 (29) 76 (33)
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Mastectomy 44 (18) 30 (16)

cTcategory cT1 152 (62) 157 (68) 0.173

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cT2 (<3 cm) 92 (38) 73 (32)

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pTcategory pT1 105 (44) 138 (60) 0.003

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pT2 123 (50) 87 (38)

pT3 16 (6) 5 (2)

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Histology Ductal 193 (79) 188 (82) 0.397

Lobular 40 (16) 28 (12)

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Other 11 (5) 14 (6)

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Histologic grade I 38 (16) 50 (22) 0.221

II 125 (51) 111 (48)

III 81 (33) 69 (30)

Multifocality Yes 26 (10) 27 (12) 0.708

No 218 (90) 203 (88)

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Hormone receptor status

ER status Positive 203 (83) 194 (84) 0.734

Negative 41 (17) 36 (16)

PR status Positive 178 (73) 168 (73) 0.982

Negative 66 (27) 62 (27)

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HER-2 status Positive 28 (12) 40 (17) 0.066

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Negative/UK 216 (88) 190 (83)

cALND – completion axillary lymph node dissection, RNI – regional nodal irradiation, ROLL

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– radio-guided occult laesion localization, cT – clinical tumor size, pT – pathological tumor
size, ER – estrogen receptor, PR – progesterone receptor; UK = unknown. Data presented as
number of patients and percentage in parentheses, unless otherwise noted. *Mann-Whitney
two sample test (all other variables were tested with the chi-square test)

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Table 2. Lymph node characteristics according to treatment arms.

Characteristic Arm A (cALND) Arm B (RNI)

(n=244) (n=230)

No (%) No (%) p-value

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Mean no. of SN removed (range) 1.83 (1-5) 1.95 (1-5) 0.674

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Mean no. of SN+ (range) 1.36 (1-4) 1.17 (1-4) 0.001

Mean no. of non-SN removed (range) 12.5 (5-31) NA

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Mean no. of non-SN+ (range) 1.4 (0-23) NA

Mean no. of total LN removed (range) 14.31 (7-32) 1.95 (1-5) NA

Mean no. of total LN+ (range)

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2.77 (1-24) 1.17 (1-4) NA
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pN category pN1mi 61 (25) NA
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pN1a 129 (53) NA

pN2a 41 (17) NA
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pN3a 13 (5) NA
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cALND – completion axillary lymph node dissection, RNI – regional nodal irradiation. LN –
lymph node, SN – sentinel node, NA – not applicable. Data presented as number of patients
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and percentage in parentheses, unless otherwise noted. *Mann-Whitney two sample test (all
other variables were tested with the chi-square test)
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Table 3. Axillary recurrence and survival

Treatment arm Arm A Arm B p

Axillary recurrence

Total number (%) 5 (2.0) 4 (1.7) 1.00

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Isolated number (%) 1 (0.4) 2 (0.8) 0.61

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Survival at 8 years

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Overall survival number (%) 190 (77.9) 195 (84.8) 0.060

Disease-free survival number (%) 176 (72.1) 178 (77.4) 0.51

Alive with recurrence number (%)

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Died of breast cancer number (%) 34 (13.9) 20 (8.7)
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Died of other cause number (%) 20 (8.2) 15 (6.5)

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