More than fifteen years ago, the sentinel lymph node biopsy (SLNB) was introduced in clinically node negative breast cancer patients to evaluate their lymph node status for diagnostic purposes. In case of a negative sentinel lymph node (SLN) an axillary lymph node dissection (ALND) was omitted. The SLN is negative in approximately 74% of patients in a general breast cancer population [
]. Although SLNB is less invasive compared to ALND, short-term complications still occur in 25% of the patients. Most reported complications are axillary seroma, wound infections, hematoma, anaphylactic reaction, axillary paresthesia, and lymphedema, which is described in 8% of patients after a follow-up of only 3 years, resulting in significant reduction of quality of life (QoL) of breast cancer survivors [
Ever since the National Surgical Adjuvant Breast and Bowel Project (NSABP B-04) trial, the need for completion axillary treatment for clinically node negative patients has been questioned. This trial revealed that omitting ALND in clinically node negative patients did not affect disease-free survival (DFS) and overall survival (OS) [
]. Patients were randomized for mastectomy-only, mastectomy with ALND or mastectomy with axillary radiotherapy (RT). About 40% of the patients who underwent mastectomy-only had lymph node metastases that were not removed at the time of initial surgery. During follow-up, ipsilateral lymph nodes became clinically apparent in less than half of these patients (18.6%). Nevertheless, omitting ALND in clinically node negative patients did not affect DFS and OS, even after 25 years of follow-up and without adjuvant RT or systemic therapy.
The more recent American College of Surgeons Oncology Group (ACOSOG) Z0011 and International Breast Cancer Study Group (IBCSG) 23–01 trials investigated whether completion ALND can be safely omitted in patients with a metastasis in the SLN. The ACOSOG Z0011 trial included patients with 1–2 macrometastatic SLN(s) who were treated with breast conserving therapy (BCT) [
]. The IBCSG 23–01 trial only included patients with a micrometastasis in the SLN, but gave no restriction on type of breast surgery [
]. Most patients were treated with adjuvant systemic treatment (both 97%). Patients in these trials were randomized to completion ALND or watchful waiting. Additional lymph node metastases beyond the SLN were detected in 27% (ACOSOG Z0011) and 11% (IBCSG 23–01) in the ALND groups [
]. Despite the fact that nodal metastases remained in situ in a considerable percentage of patients in the ‘watchful waiting’ groups, omitting completion ALND did not result in inferior regional recurrence (RR) rates, DFS and OS after 5-years of follow-up. These studies indicated that completion ALND can be safely omitted in presence of positive SLN(s) in patients treated with BCT and adjuvant systemic treatment. Since the outcome of the SLNB has no clinical consequence, the value of the SLNB itself is being questioned.
Clinically node negative status in the NSABP B-04, ACOSOG Z0011 and IBCSG 23–01 trials was based on negative physical examination of the axilla. Preoperative nodal staging with physical examination has a low accuracy, with a sensitivity of only 32% [
]. In the Netherlands, axillary ultrasound is part of standard preoperative axillary work-up. The sensitivity of axillary ultrasound (in combination with tissue sampling where deemed necessary) is approximately 80% [
]. Furthermore, a negative axillary ultrasound excludes the presence of four or more lymph node metastases, with a negative predictive value of 93–96% in the general breast cancer population [
]. Therefore, axillary ultrasound improves preoperative selection of node negative patients, as it selects patients with a more favourable tumour load and confidently excludes advanced nodal disease.
Several factors besides surgery have proven to decrease RR rates. For instance, it is assumed that biology plays an important role in dormancy of nodal metastases. Less than half of the patients with occult nodal metastases in the NSABP B-04 trial, developed clinically detectable lymph nodes during follow-up, none of these patients received adjuvant systemic or RT [
]. Adjuvant systemic therapy is known to decrease RR rates [
]. Primary systemic therapy can eradicate lymph node metastases with a reported pathologic complete response rates of 20–40% [
]. Lack of knowledge on the pathological lymph node status is nowadays hardly influencing systemic therapy indication [
]. Low RR rates in the ACOSOG Z0011 (and IBCSG 23–01) trial might be due to whole breast irradiation (WBI) following lumpectomy [
]. RT of the breast may contribute to the elimination of (occult) lymph node metastases by including part of the axilla [
]. A recent study has shown that, even with contemporary 3D radiation techniques, the SLN receives an elective radiation dose in 76% of patients [
]. Biology, adjuvant systemic and RT most likely diminish the risk that possible lymph node metastases left in situ develop into clinically detectable lymph nodes.
This randomized controlled BOOG 2013–08 trial proposes to demonstrate that the SLNB can be safely omitted in breast cancer patients with a clinically node negative T1–2 status undergoing BCT. This trial aims to decrease the number of breast cancer patients receiving an invasive axillary procedure, to decrease the axillary morbidity rate, thereby improving QoL and reducing the costs of SLNB without affecting regional control and survival.
Main study objectives
Primary objective of this study is to investigate whether watchful waiting (i.e. no SLNB) is not inferior in terms of 5 and 10-year RR rate to the current axillary staging regimen in breast cancer patients with a clinically node negative T1–2 status undergoing BCT. Secondary objectives are distant-DFS, OS, local recurrence (LR) rate, contralateral breast cancer, number of delayed axillary treatment, adjuvant RT, QoL, axillary morbidity rate, and cost-effectiveness after 5- and 10-years of follow-up.
The authors gratefully acknowledge the contributions of Elise van Leeuwen from the Dutch Breast Cancer Research Group (Borstkanker Onderzoek Groep; BOOG) and Astrid Swinkels, Mariska Stals, Saskia van Gastel, Steffen de Groot, Baukje Hermans, Ria de Peuter and Wendy Dontje from IKNL clinical research department.
The BOOG 2013–08 study received grant support from the Dutch Cancer Society for independent data management performed by IKNL clinical research department (KWF-UM 2014–6679), Central Health Insurance (CZ 201400316) and the Netherlands Organization for Health Research and Development (ZONMW 843002624) for salary of independent PhD-students and quality of life questionnaires.
Availability of data and materials
LvR is surgeon in training and received her PhD degree in surgical oncology at Maastricht University Medical Centre, MV is PhD candidate in surgical oncology at Maastricht University Medical Centre, AK is statistician at Maastricht University Medical Centre, TvD is surgical oncologist at Diakonessenhuis Hospital, JvdH is surgical oncologist at Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, LS is surgical oncologist at Canisius-Wilhelmina Hospital, LB is radiation oncologist at Maastricht University Medical Centre (MAASTRO clinic), SL is professor in medical oncology at Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, ML is breast radiologist at Maastricht University Medical Centre, PP is professor in radiation oncology at Radboud university medical centre, VTH is professor in medical oncology at Maastricht University Medical Centre, KVdV is pathologist at Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, JdV is professor in quality of life in the medical setting at Tilburg University, AW is radiation oncologist at Arnhem Institute for Radiation Oncology, JdW is professor of surgical oncology at Radboud university medical centre, MS is surgical oncologist at Maastricht University Medical Centre.
Ethics approval and consent to participate
The study is conducted in accordance to the standards of Good Clinical Practice, in agreement with the Declaration of Helsinki and with Dutch law in general and with the Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-wetenschappelijk Onderzoek met mensen) in particular.
This study was approved by the medical ethics committee Stichting het Nederlands Kanker Instituut – Antoni van Leeuwenhoek ziekenhuis Amsterdam, the Netherlands (PTC15.0111/M14CNB).
The study will be performed in 35 participating centres, including 4 university medical centres. The Board of Directors approved initiation of the study in current participating centres that are open for accrual. The BOOG 2013–08 trial is registered at
All patients will be provided with written information in the form of a Patient Information Folder, including the study aims, randomization procedure, possible AEs, and their rights and responsibilities. Written informed consent must be obtained for all patients included in the study before they are randomized in the study.
Consent for publication
The authors declare that they have no competing interests.