Survival and Axillary Recurrence Following Sentinel Node-positive Breast Cancer Without Completion Axillary Lymph Node Dissection - a Randomized Study of Patients With Macrometastases in the Sentinel Node
Phase: NA
Conditions: Breast Cancer
Sponsor: Karolinska Institutet

1 
 
 
 
 
 
 
 
Survival and axillary recurrence following sentinel node- 
positive breast cancer without completion axillary lymph 
node dissection – the SENOMAC trial. 
 
A randomized study of patients with sentinel node macrometastasis 
 
 
 
 
 
 
 
Revised version 8.2., February 23, 2023 
 
NCT 02240472 (www.clinicaltrials.gov) 

SENOMAC Study Protocol version 8.2, February 23, 2023 
1 
 
 
 
 
Coordinating investigator: 
 
Jana de Boniface, Associate Professor, Department of Molecular Medicine and Surgery, 
Karolinska Institutet, Stockholm, Sweden, and Department of Surgery, Capio S:t Görans 
Hospital, Stockholm Sweden. 
 
 
Trial steering committee: 
 
Leif Bergkvist, Professor, Department of Surgery, Västmanland Hospital, Västerås and 
Center for Clinical Research, Uppsala, Sweden 
 
Jan Frisell, Professor, Department of Breast and Endocrine Surgery and Department of 
Molecular Medicine and Surgery, Karolinska University Hospital and Karolinska Institutet, 
Stockholm, Sweden 
 
Yvette Andersson, PhD, Department of Surgery, Västmanland Hospital, Västerås and Center 
for Clinical Research, Uppsala, Sweden 
 
Malin Sund, Professor, Surgery Center, Norrland University Hospital, Umeå, and the 
Department of Surgical and Perioperative Science, Umeå University 
 
Lisa Rydén, Professor, Department of Surgery, Skåne University Hospital and the 
Department of Clinical Sciences, Lund 
 
Roger Olofsson Bagge, Associate Professor, Department of Surgery, Sahlgrenska 
University Hospital, Gothenburg 
Dan Lundstedt, PhD, Department of Oncology, Sahlgrenska University Hospital, 
Gothenburg 
Sara Alkner, PhD, Lund University Cancer Center, Lund 
 
Statistician: 
 
Robert Szulkin, biostatistician, Scandinavian Development Services (SDS), Stockholm, 
Sweden 
 
Data safety monitoring committee: 
 
Eva Haglind, Professor of Surgery, SSORG, Department of Surgery, Sahlgrenska Academy at 
University of Gothenburg 
 
John Öhrvik, Professor of Clinical Biostatistics, Karolinska Institutet, Stockholm 
 
Beatrice Melin, Professor of Oncology, Umeå University

SENOMAC Study Protocol version 8.2, February 23, 2023 
2 
 
 
Danish trial steering committee 
 
Peer Christiansen, PhD, Professor, Dept. of Surgery, Aarhus University Hospital 
(Danish coordinating investigator) 
 
Tove Filtenborg Tvedskov, PhD, lecturer, Rigshospitalet, Copenhagen 
Birgitte Offersen, PhD, Dept. of Oncology, Aarhus University Hospital  
 
Greek trial coordinating investigator 
Michalis Kontos, Associate Professor, Dept. of Surgery, University of Athens 
 
German trial steering committee 
Thorsten Kühn, PhD, Professor, Dept. of Obstetrics and Gynecology, Klinikum Esslingen 
Toralf Reimer, PhD, Professor, Dept. of Gynecology, University Hospital Rostock 
 
Italian coordinating investigator 
Oreste Gentilini, Head of Breast Surgery and of Breast Unit, Ospedale San Raffaele, Milano 
 
 
 
Sub-committee on Quality of life, arm morbidity and health economy 
 
Jana de Boniface (see above) 
 
Matilda Appelgren, nurse, PhD student, Karolinska Institutet, Stockholm, Sweden 
Yvonne Wengström, professor, nurse, Karolinska Institutet, Stockholm 
 
Helena Ikonomidis Sackey, PhD, Department of Surgery, Karolinska University Hospital, 
Stockholm 
 
Karin Johansson, PhD, associate professor, physiotherapist, Lund University 
Katarina Blom, physiotherapist, PhD, Karolinska University Hospital, Stockholm 
 
 
 
 
 
 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
3 
 
 
Trial Coordinating Center 
 
 
Clinical Trial Office  
Kliniska Prövningsenheten, 
Hotellet Plan 3,  
Karolinska University Hospital  
17176 Stockholm 
 
E-mail: ctokpe@regionstockholm.se 
 
 
 
Data managers and monitors: 
 
Yvonne Larsén 
Phone: 08-5177 0901 
 
Katja Wiklund 
Phone: 08-51772584 
 
Fax: 08-306989 

SENOMAC Study Protocol version 8.2, February 23, 2023 
4 
 
 
 
 
Table of contents 
 
 
 
 
1. Summary 
7 
 
2. Background 
8 
 
3. Purpose 
11 
 
4. Hypothesis 
11 
 
5. Method 
11 
 
Inclusion criteria 
12 
 
Exclusion criteria 
12 
 
Preoperative assessment 
12 
 
Neoadjuvant treatment 
13 
 
Participant identification and inclusion 
13 
 
SENOMAC trial flow chart 
15 
 
Randomization 
16 
 
Injection of isotope and blue dye 
16 
 
Surgical procedure 
16 
 
Pathology 
17 
 
Frozen and paraffin-embedded tissue samples 
18 
 
Adjuvant therapy 
18 
 
Data management 
19 
 
Monitoring and follow-up 
19 
 
Study calendar 
21 
 
 
6. Outcomes 
22 
 
7. Statistics and power calculations 
24 
 
8. Ethics 
27 
 
9. Significance 
28 
 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
5 
 
 
 
10. Withdrawal 
28 
 
11. Publication policy 
28 
 
12. References 
30 
 
 
 
 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
6 
 
 
 
 
1. Summary 
 
 
Sentinel node (SN) biopsy in breast cancer has proven to be a reliable method, and several 
follow-up studies have shown that it is safe to refrain from axillary completion axillary lymph 
node dissection (ALND) in sentinel node-negative breast cancer. Moreover, SN biopsy alone 
is associated with significantly less postoperative arm discomfort. Because of the surprisingly 
low rate of axillary recurrence among patients who have not been subjected to any axillary 
procedure, as well as among SN-positive patients who have not undergone completion 
ALND, the role of ALND has increasingly been called into question even among patients who 
have SN metastases. Two studies have been published in recent years in which SN-positive 
breast cancer patients were randomized either to undergo completion ALND or not. The first 
study (ACOSOG Z0011) included patients with SN macrometastases who had breast- 
conserving surgery. The second study (IBCSG 23-01) included patients with SN 
micrometastasis. The studies did not demonstrate any difference in the rate of axillary 
recurrence, and survival was even slightly better among patients who underwent SN biopsy 
alone, although the difference was not statistically significant. However, these studies had 
several weaknesses, including low power and especially how patients were selected for the 
ACOSOG Z0011 study. 
 
This prospective multicenter study includes patients with 1-2 SN macrometastases. Patients 
are randomized to either undergo ALND or not. The study is designed as a non-inferiority 
study in which we accept a worsening in breast cancer-specific survival in the experimental 
arm (no ALND) of at most 2.5% after 5 years. Previous Swedish results show a 5-year breast 
cancer-specific survival rate of 92% among patients with SN macrometastases. We plan to 
include 3500 patients to achieve 80% power in being able to detect a potential worsening of 
the breast cancer-specific 5-year survival rate from 92% among patients who undergo ALND 
to 89.5% among those who do not. All patients will otherwise primarily be treated according 
to national clinical guidelines and will be clinically followed yearly for 5 years, after 10 years 
and finally after 15 years. 

SENOMAC Study Protocol version 8.2, February 23, 2023 
7 
 
 
 
 
2. Background 
 
 
Lymph node metastasis is one of the factors of greatest prognostic importance in breast cancer 
[1-3]. Lymph node metastases can be classified as isolated tumor cells (≤ 0.2 mm and/or <200 
cells), micrometastasis (> 0.2 but ≤ 2 mm and/or > 200 cells) and macrometastasis (> 2 mm) 
[4]. 
 
Axillary procedures in breast cancer surgery include either axillary lymph node dissection 
(ALND) or sentinel node (SN) biopsy. The purpose of axillary procedures has been viewed in 
part as diagnostic to be able to determine adjuvant therapy, and in part therapeutic to 
diminish/eliminate tumor burden. However, the therapeutic effect has increasingly come into 
question. 
 
Sentinel node (SN) biopsy has proven to be a reliable method [5], and several follow-up 
studies have shown that it is safe to refrain from completion ALND in sentinel node-negative 
breast cancer [6-10]. The greatest advantage to the SN biopsy approach is the significant 
decrease in the frequency and severity of arm problems since fewer lymph nodes are removed 
from the axilla [11-14]. 
 
Refraining from ALND in cases of SN-negative breast cancer is standard treatment in Sweden 
and most other Western countries. Completion ALND is currently carried out in SN-positive 
breast cancer. However, in about 50-65% of patients, no additional metastases are found in the 
remaining lymph nodes [15], in which case a number of nodes have been unnecessarily 
surgically removed. 
 
Interestingly, a surprisingly low rate of axillary recurrence has been noted among patients who 
have not been subjected to any axillary procedure, as well as among SN-positive patients who 
have not undergone completion ALND [16-22]. In addition, follow-up studies have shown that 
the incidence of axillary recurrence among SN-negative patients who were not subjected to 
axillary lymph node dissection is much lower than expected, especially considering the 
approximately 5-10% false-negative SN rate [5, 9, 18]. These findings suggest that not all 
metastatic lymph nodes develop into clinically significant metastases. It may be speculated that 
this is due to the adjuvant therapy, that the body's immune system is fighting the metastases, or 
that not all metastases have the ability to grow without the presence of a primary tumor. 

SENOMAC Study Protocol version 8.2, February 23, 2023 
8 
 
 
 
 
 
Consequently many have begun to question the role of ALND in SN-positive cases, and after 
Giuliano et al. published their ACOSOG Z0011 study in 2011, [23] the strategy of refraining 
from completion ALND in SN-positive cases has gained more advocates and is now also 
beginning to be embraced in many places, especially in the US [24, 25]. The ACOSOG 
Z0011 study randomized SN-positive patients to either undergo ALND or to refrain from the 
procedure. After a median follow-up period of over six years, no difference in the rate of 
axillary recurrence was found, and survival was even slightly better among patients who only 
underwent SN biopsy (disease-free survival 83.9%, compared with 82.2% for patients who 
underwent ALND), although the difference was not statistically significant. The study has 
received some criticism [26, 27]. The main objection is that the patients who were included 
were likely selected. Even though this was an American multicenter study with 177 
participating centers, only half of the initially planned 1800 patients were included over a 5- 
year period. The majority of patients also had favorable prognostic factors, and in regard to 
the size of SN metastases, the distribution was somewhat skewed between the groups, with 
more isolated tumor cells and micrometastases in the group that was randomized to refrain 
from ALND. ACOSOG Z0011 only included patients who underwent breast-conserving 
surgery and who received postoperative radiotherapy to the entire breast and in whom a 
maximum of two SNs with metastases were found. 
 
A different study (IBCSG 23-01), in which SN-positive patients were randomized to either 
undergo completion ALND or not, was published in 2013 [28]. This study included only 
patients with SN micrometastases, but showed, as did the ACOSOG Z0011, slightly better 
disease-free survival in the group operated with SN biopsy alone (87.8% compared with 
84.4% for those who underwent ALND), though the difference was not statistically 
significant here either. Neither the ACOSOG Z0011 study nor the IBCSG 23-01 study 
succeeded in enrolling the planned number of patients and the studies probably do not have 
sufficiently high power to detect small differences. 
 
Besides the ACOSOG Z0011 study and the IBCSG 23-01 study, only a few other randomized 
studies compare patients who have undergone axillary lymph node dissection with patients 
who have not. In the 1970s a total of 1665 women with breast cancer were randomized to 
have either mastectomy plus axillary lymph node dissection (radical mastectomy), 
mastectomy with radiotherapy of regional lymph nodes or mastectomy alone with subsequent 
ALND only in cases of clinical axillary recurrence [20, 21]. No difference in survival was 

SENOMAC Study Protocol version 8.2, February 23, 2023 
9 
 
 
 
 
found after either 10 years or 25 years, but 65 of the 365 patients who received no treatment 
to the axillary region were subsequently reoperated with ALND when they presented with 
clinical lymph node metastases.  The study was criticized because among many of the patients 
who did not undergo ALND, multiple lymph nodes were found in the mastectomy material. 
 
In a somewhat more recent study, between 1993 and 2002, in which 473 women over age 60 
who were randomized to either undergo ALND or to have no axillary procedure [22], there 
was no observed difference in survival either. However, this study also failed to meet the 
enrolment target, and likely included too few patients to be able to find a moderate difference 
in mortality. In 2012 a review of studies was published comparing SN-positive patients who 
underwent axillary lymph node dissection with patients who did not [29]. The study 
concluded that it appears to be safe to refrain from axillary lymph node dissection in selected 
patients. However, most of the studies included were retrospective, and the majority had only 
enrolled limited numbers of patients. 
 
Some studies have also shown a higher rate of distant metastases and other cancers among 
breast cancer patients who underwent ALND, and it has been speculated that lymph node 
removal may put people at an immunological disadvantage. [10]. 
 
There are, however, a few studies that suggest that axillary lymph node dissection may still 
have some therapeutic benefit. A meta-analysis predating consideration of sentinel nodes 
showed that patients who underwent ALND had better survival than those who did not [30]. 
Similar results were found in a retrospective study comparing ALND with axillary lymph 
node sampling combined with radiotherapy [31].  In yet another retrospective study, the rate 
of axillary recurrence among SN-positive patients who did not undergo ALND was a striking 
2.0% after just 30 months, despite otherwise favorable prognostic factors (compared with 
 
0.4% among those who underwent completion ALND) [32].  The results from the Dutch 
MIRROR study [33] also warrant some caution since the rate of axillary recurrence was more 
than twice as high among patients with SN micrometastases who did not undergo ALND 
compared with SN-negative patients (5.6% vs 2.3% after 5 years). 
 
In Sweden, most patients with SN macrometastases receive radiotherapy of the axillary 
region. Several studies have shown that the survival rate among patients who received only 
radiotherapy was as high as among patients who underwent ALND [20, 34, 35]. A large 
European study (AMAROS) randomizing over 1400 SN-positive patients, of whom 861 with 
SN-macrometastases, to either undergo completion ALND or to have axillary radiotherapy 

SENOMAC Study Protocol version 8.2, February 23, 2023 
10 
 
 
 
 
was recently published [36]. No difference in disease-free or overall survival was found. The 
pre-publication data from this trial have already prompted the UK to approve axillary 
radiotherapy in lieu of axillary lymph node dissection. 
 
Although the body of findings suggests that axillary lymph node dissection for SN-positive 
cases is unlikely to significantly improve prognosis, whether there is currently sufficient 
evidence to begin to routinely refrain from ALND remains uncertain. Further studies are 
needed, and this prospective multicenter trial will provide a meaningful contribution to 
answer the question of whether it is safe to refrain from completion ALND. This study will 
also clarify whether patients can forgo ALND even with mastectomy. 
 
 
 
 
3. Purpose 
 
 
The main purpose of this study is to evaluate whether it is safe to refrain from completion 
axillary lymph node dissection in breast cancer cases with SN-macrometastasis. We also want 
to investigate whether the potential risks of refraining from ALND differ among various 
subgroups. A secondary aim is the evaluation of arm morbidity, health economic outcome and 
quality of life in comparison between the two groups. 
 
 
 
 
4. Hypothesis 
 
 
Refraining from axillary lymph node dissection among patients with sentinel node 
macrometastasis will not worsen overall survival by more than a maximum of 
2.5% after 5 years. 
 
 
Refraining from axillary lymph node dissection will improve short- and long-term arm 
morbidity, improve health-related quality of life and reduce health care costs. 
 
 
 
 
5. Method 
 
 
This study randomizes patients with macrometastases in at most two sentinel nodes to either 
undergo completion axillary lymph node dissection or not to have any further axillary 
surgery. 

SENOMAC Study Protocol version 8.2, February 23, 2023 
11 
 
 
 
 
 
 
Patients are registered in a database through an electronic Case Report Form (eCRF) and 
followed prospectively. Frozen tissue samples from the surgery may be saved and stored on a 
voluntary basis for future research. 
 
 
 
 
Inclusion criteria 
 
 
• Patients with primary invasive breast cancer T1-T3 
 
• No palpable lymph node metastases prior to sentinel node biopsy 
 
• Macrometastasis in not more than 2 sentinel lymph nodes (further lymph nodes 
with micrometastasis or ITC do not result in exclusion) 
• Oral and written consent 
 
• Age ≥ 18 years 
 
• Preoperative ultrasound of axilla performed 
 
 
 
 
Exclusion criteria 
 
 
• Regional or distant metastases outside of the ipsilateral axilla 
 
• Prior history of invasive breast cancer 
 
• Pregnancy 
 
• Bilateral invasive breast cancer, if one side meets exclusion criteria. Patients with 
 
bilateral cancers where both sides fulfill all inclusion criteria and no exclusion criteria 
 
may, however, not be included for either side. 
 
• Medical contraindication for radiotherapy 
 
• Medical contraindication for systemic treatment 
 
• Inability to absorb or understand the meaning of the study information; for example, 
through disability, inadequate language skills or dementia. 
 
 
Preoperative assessment 
 
 
Preoperative assessment is carried out in accordance with local practice with triple 
diagnostics. Ultrasound of the axillary region is required and suspected node metastases must 
be biopsied. Patients with non-palpable but 1-2 cytologically and radiologically diagnosed 
axillary metastasis may undergo SN biopsy and be included. Patients may be planned for 

SENOMAC Study Protocol version 8.2, February 23, 2023 
12 
 
 
 
 
partial mastectomy or mastectomy +/- breast reconstruction (including skin-sparing and 
nipple-sparing alternatives) as all types of breast surgery are eligible in this trial. 
 
Neoadjuvant treatment 
Patients planned for neoadjuvant systemic treatment may be included in this trial in case all 
inclusion criteria are met. Thus, patients without palpable lymph node metastases may 
undergo sentinel node biopsy prior to start of their neoadjuvant treatment. In case of up to 
two macrometastases in the sentinel node biopsy, patients may be randomized and included in 
this trial. Randomization is recommended to be performed before start of neoadjuvant therapy 
but must at the very latest take place before the first clinical or radiological response 
evaluation is carried out. In case of disease progression during neoadjuvant treatment and/or 
the appearance of palpable lymph node metastases, participation in the trial is discontinued 
and the reason for study termination recorded in the eCRF. The decision to discontinue 
participation in the trial should always be discussed at a multidisciplinary team conference. 
 
 
Participant identification and inclusion 
 
 
The trial committee recommends that participating centers choose to refrain from perioperative 
sentinel node assessment with frozen section analysis. This recommendation is rooted in both 
logistical and ethical concerns. Diagnostic procedures during ongoing surgery would mean 
that 1) a large number of patients who may potentially be eligible for inclusion would need to 
be informed about the study during presurgical care planning, without subsequently meeting 
the inclusion criteria (i.e., not having macrometastasis in the SN) and 2) patients whose SN 
frozen sections show macrometastasis will ultimately be included and randomized while under 
general anesthesia. However, units that choose for various reasons to proceed with frozen 
section analysis may still participate in the study (see option 2 below). 
Yet another reason to refrain from frozen section analysis involves the currently ongoing 
national cohort study in which patients with SN micrometastasis may be included, and 
thereby refrain from completion axillary lymph node dissection after the SN procedure. 
Preoperative information about inclusion in two possible studies, both of which involve 
patients scheduled for breast cancer surgery with sentinel node biopsy as target groups, may 
be experienced as unreasonably overwhelming for a patient facing cancer surgery. 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
13 
 
 
 
 
Refraining from frozen section analysis may also free up both surgery and pathology 
resources, but is estimated to lead to about a 10-12% reoperation rate among those patients 
who either choose not to participate in the current study, and then undergo completion axillary 
lymph node dissection, or those who are randomized to this procedure. 
 
Thus, there are two options for the inclusion process (see trial flow chart): 
 
 
1.   Units that do not perform SN frozen section analysis: patients who meet all inclusion 
criteria do not receive oral and written information (see enclosed patient information) 
until after sentinel node biopsy, once the final histopathological results become 
available. Patients who agree to participate sign the informed consent form and are 
then randomized. Patients who are randomized to axillary lymph node dissection 
undergo this procedure in a second surgery. In case of neoadjuvant treatment, this 
second axillary surgery is performed at the same time as the breast surgery. 
2.   Units that do perform SN frozen section analysis: patients who meet all other inclusion 
criteria (except for SN macrometastasis) receive oral and written information (see 
enclosed patient information) during the planning phase for the primary surgery. 
Patients who agree to participate sign the informed consent form. If the frozen section 
shows SN macrometastasis the patient is randomized during the ongoing surgery. 
Patients who are randomized to axillary lymph node dissection undergo this procedure 
during the same surgery. In the event that SN macrometastasis is not identified until 
the final histopathology results are received, the patient may be included in accordance 
with option 1. In case of neoadjuvant treatment, frozen section is not encouraged as 
randomization does not lead to an axillary clearance performed at the same session. 
 
 
In the event that the final histopathology results show that a randomized patient does not meet 
all criteria (e.g., additional metastasis identified during SN sectioning), the patient must be 
excluded. In this case, the reason for exclusion is entered in the eCRF to be able to account 
for attrition in a CONSORT diagram. Patients who fulfil all inclusion criteria and receive 
information about the trial but are not randomized are registered in screening logs on site. The 
reasons why these patients were not randomized (declines participation, physician choice, 
other) are recorded without personal identification number.

SENOMAC Study Protocol version 8.2, February 23, 2023 
14 
 
 
 
 
 
 
SENOMAC trial flow chart (pre-and postoperative refers to sentinel node biopsy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breast cancer patients assessed for 
eligibility at postoperative visit (no 
frozen section planned) 
Breast cancer patients assessed for 
eligibility at preoperative visit (frozen 
section planned) 
Meeting all inclusion criteria: 
 
Informed consent, baseline  
assessments and questionnaires  
 
Meeting all preoperative inclusion 
criteria: 
 
Informed consent, baseline 
assessments 
Does not fulfil all criteria at surgery: 
no randomization 
Does not wish to participate: 
screening log 
Randomization 1:1 
No further axillary surgery 
(intervention) 
Completion axillary lymph node 
dissection (standard of care) 
Adjuvant therapy according to MDT 
Baseline questionnaires 
Years 1-5: Annual follow-up 
Questionnaires years 1, 3 and 5 
Year 10: follow-up 
Questionnaires 
Year 15: follow-up 

SENOMAC Study Protocol version 8.2, February 23, 2023 
15 
 
 
 
 
Randomization 
 
 
Randomization may occur on two occasions, see above during “Inclusion”. 
 
 
1.   If frozen section is not used the patient is informed and provides consent at the 
postoperative follow-up visit after sentinel node biopsy/primary surgery, and 
randomization is carried out during that same visit. 
2.   If frozen section is used the patient is informed and provides consent prior to the 
primary surgery. The patient is only randomized during the ongoing surgery if the 
frozen section shows SN macrometastasis. 
 
At the time of inclusion, inclusion and exclusion criteria are entered into the randomization 
application, which is a web-based instrument (ALEA). Username and password are required 
to log in; each researcher authorized to register patients has a personal login user name and 
password. If all criteria are met, patients are randomized and the treatment to which the 
patient is allocated is recorded in the patients’ medical file. Randomization is done 1:1 and 
treatment arms are stratified per country. Randomization is based on permutated block 
technique. 
 
 
Injection of isotope and/or blue dye 
 
 
Injection of isotope and/or blue dye is carried out in accordance with local practice and can be 
administered intracutaneously above the tumor, around the tumor or as a periareolar injection. 
Imaging is optional. New methodologies that may be introduced as routine procedure during 
the course of the study are also permitted, provided that its reliability is proven with a high 
evidence level. Approval of new methods can only be granted by the study steering 
committee, which consists of the principal investigators and the adjunct steering group (see 
title page). Accordingly, the use of Sienna+ and the SentiMag probe, as well as fluorescent 
dye indocyanine green, has been approved by the steering committee in 2015 and 2016, 
respectively. Participating centers cannot on their own authority include patients with a 
sentinel node that was identified by non-approved detection methodology. 
 
 
Surgical procedure 
 
 
Sentinel node biopsy is carried out following injection of isotope and/or blue dye into the 
ipsilateral breast. Sentinel nodes are identified using a Geiger counter and can be defined as 

SENOMAC Study Protocol version 8.2, February 23, 2023 
16 
 
 
 
 
nodes that are blue and/or radioactive. No more than four sentinel nodes should be removed. 
The sentinel node method includes the palpation of axillary lymph nodes during surgery, and 
the removal of clearly suspicious lymph nodes which are included in the sentinel node 
biopsy. Sentinel node frozen section is optional, see under “inclusion” above. In the event 
that extensive axillary metastatic disease is suspected during surgery, it must be verified by 
frozen section and in such cases axillary lymph node dissection must be carried out during 
the same surgical session, and the patient cannot be included in the study. 
 
Patients with failed localization are not eligible for the trial. 
 
 
Axillary lymph node dissection, when necessary, is conducted at levels I and II with the aim 
of removing at least ten lymph nodes in total, i.e. including nodes removed at sentinel node 
biopsy. 
 
Both partial mastectomy and mastectomy are eligible breast surgical interventions, as well as 
primary breast reconstruction (including skin- or nipple-sparing options). Negative surgical 
margins are to be achieved. 
 
 
Pathology 
 
 
The sentinel node and primary tumor should be examined in accordance with the Society of 
Pathology Quality and Standardization Committee guidelines in the Swedish KVAST 
document. These guidelines follow the international classification guidelines by the American 
Joint Committee on Cancer (AJCC) which should be applied in other countries joining this 
trial [37]. Tumor characteristics are documented according to standard procedure and should 
include size, histological type, hormone receptor status, HER2-neu status, proliferation and 
tumor grade. Lymph node metastases, if any, are measured and classified according to AJCC, 
i.e. “the size of a tumor deposit is determined by measuring the largest dimension of any group 
of cells that are touching one another (confluent or contiguous tumor cells), regardless of 
whether the deposit is confined to the lymph node, extends outside the node (extranodal 
extension), is totally present outside the lymph node and invading adipose, or is present within 
a lymphatic channel adjacent to the node. When multiple tumor deposits are present in a lymph 
node, whether ITCs or micrometastases, the size of only the largest contiguous tumor deposit is 
used to classify the node, not the sum of all individual tumor deposits or the area in which the 
deposits are distributed.”  

SENOMAC Study Protocol version 8.2, February 23, 2023 
17 
 
 
 
 
Frozen and paraffin-embedded tissue samples 
 
 
This study will continue for an extended period of time and several years will pass before 
results are available. During this interval, new prognostic and predictive factors will likely 
continue to be discovered. To reserve the possibility of also examining new factors in our 
material, paraffin-embedded tissue from the primary tumor and metastases is stored in local 
biobanks for future investigation.  
 
Frozen tissue samples are prepared from the fresh specimen according to local practices and 
will then be stored in the respective local biobank. Each center wishing to take part in the 
collection of fresh frozen tissue will apply at and register with the own local biobank. 
 
 
 
Adjuvant therapy 
 
 
Adjuvant systemic therapy should be given in accordance with national guidelines of each 
participating country.  
In women who have undergone breast-conserving surgery, the remaining ipsilateral breast 
parenchyma must be irradiated. Boost to the tumor bed should be applied according to each 
country’s national guidelines.  
Post-mastectomy radiotherapy (PMRT) and radiotherapy to the regional lymph node basins 
are based on each country’s national guidelines. It is, however, mandatory, that for those 
participating in this trial, radiotherapy should not be extended or changed based on 
which arm the patient is randomized to, ie, sentinel node biopsy only should be regarded 
as a substitute for axillary clearance. 
In Sweden, radiotherapy to regional lymph node basins follows the recommendations of the 
Swedish National Guidelines available at www.swebcg.se. The regional lymph node target 
(CTV) is composed of axilla level 2 and 3, interpectoral lymph nodes and supraclavicular fossa 
(i.e. axilla level 4) which means that level 1 is omitted from the regional lymph node CTV (in 
practice parts of level 1 will be covered by the tangential beams targeting the breast/thoracic 
wall). For detailed volume description, please see the target definition at ESTRO consensus 
guideline on target volume delineation for elective radiation therapy of early stage breast 
cancer, version 1.1. [38] German radiotherapy guidelines as defined by the 
Arbeitsgemeinschaft Gynäkologische Onkologie e.V. (AGO) are accessible at 
www.agoonline.de. The corresponding references for the Greek [39], Italian and Danish 
guidelines are https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf, 

SENOMAC Study Protocol version 8.2, February 23, 2023 
18 
 
 
 
 
www.radioterapiaitalia.it and www.dbcg.dk, respectively.  
 
The exact regional lymph node target is to be reported in the CRF prospectively throughout the 
trial. Irradiation of internal mammary nodes (IMN) should be handled according to national 
guidelines of each country and treatment of IMN must be recorded in the CRF. 
 
Fractionation schedule is chosen according to local practice, i.e. 2 Gy/f x 25 over 33-35 days 
to the breast and regional lymph nodes. A slightly lower total dose to the nodes (~46 Gy) is 
accepted. Hypofractionated radiotherapy can be chosen, i.e. 2.67 Gy/f x 15-16 over 19 – 22 
days. Dose and fractionation is to be reported prospectively. 
 
 
 
Data management 
 
 
All data are registered using an electronic Case Report Form (eCRF) based on the web 
application Pheedit. Monitoring is performed according to Good Clinical Practice (GCP) 
guidelines. The eCRF provides data on age, completed surgery, tumor and lymph node 
characteristics, as well as neoadjuvant and adjuvant therapy. Data are managed by the 
Clinical Trial Office at Kliniska Prövningsenheten, Karolinska University Hospital, 
Stockholm, Sweden. Security is comparable to bank security with encrypted data. 
 
Recorded information is confidential and the database is privacy-protected; i.e., no data can 
be traced back to the patient in research reports and no unauthorized individuals may have 
access to the data about individuals in the database. The database will be maintained until 
further notice (at least 20 years after inclusion of the last patient) and be reported in 
accordance with the Personal Data Act (PUL, 1998:204). The authority responsible for the 
database is Karolinska Institutet, Stockholm, Sweden. 
 
The SENOMAC trial is registered at www.clinicaltrials.gov (NCT 02240472). 
 
 
 
Monitoring and follow-up 
 
 
This prospective trial is conducted according to GCP guidelines and monitored by the Clinical 
 
Trial Office at Kliniska Prövningsenheten, Karolinska University Hospital. All patients will 
be followed up with yearly clinical examination, comprising recent medical history and 
palpation of breast and regional lymph node basins, and mammography for five years. From 
April 20, 2022, onwards, remote contact was approved by the ethical committee to replace 

SENOMAC Study Protocol version 8.2, February 23, 2023 
19 
 
 
 
 
clinical examination due to restrictions during the covid-19 pandemic and the high safety 
profile and low event rate observed in the safety analysis. 
Each follow-up must take place within +/- two months from the randomization date, and data 
are to be completed in the eCRF within one month from the follow-up date. Additional 
diagnostic measures, e.g. axillary ultrasound, biopsies or other investigations, are carried out 
according to clinical findings and in agreement between the treating oncological and surgical 
departments responsible for routine follow-up. In case of suspected axillary recurrence, a CT 
of the thoracic region is requested in order to define the level of recurrence in the axilla and 
exclude further metastatic spread. Results from follow-up and mammography conducted 
outside the study protocol but within +/- two months of the calculated annual follow-up date 
may be communicated between departments and recorded in the eCRF to avoid unnecessary 
visits and radiological investigations. 
 
Data concerning the most recent follow-up, and any recurrent disease and deaths will be 
reported through the follow-up eCRF. In case of suspected or confirmed recurrence, all data 
on the relapse are to be completed within the recurrence module found in the CRF. 
 
The Clinical Trial Office will be monitoring inclusion and exclusion criteria as well as 
completeness and accuracy of data recorded in the eCRF by regular on-site visits. To this end, 
participating units will grant access to patient medical files in due time on request. Patients 
are informed about monitoring procedures and medical file access in the patient information 
leaflet and grant their consent to these by signing the consent form. 
 
Participating sites that do not adhere to GCP guidelines or to the agreements stated in the 
contract signed between the medical responsible at the individual site and the Clinical Trial 
Office may be excluded from this trial. 

SENOMAC Study Protocol version 8.2, February 23, 2023 
20 
 
 
 
 
Study calendar 
 
 
Time point 
Option 1 
(postop/no frozen section) 
Option 2 
(preop/frozen section) 
Baseline recordings 
(preoperative) 
Surgery 
Baseline recordings 
(postoperative) 
Follow-up 1 year 
Follow-up 2 years 
Follow-up 3 years 
---------------------------------- 
Verify eligibility including 
sentinel node status 
Informed consent 
Randomization 
Record demographics 
Baseline questionnaires: 
Arm morbidity and QoL 
(EORTC QLQ30-BR23, 
Lymph-ICF), health 
economics (EQ-5D) 
Record tumor and lymph 
node characteristics 
Record receptor status 
Report planned radiotherapy 
Verify eligibility except for 
sentinel node status 
Informed consent 
Record demographics 
Randomization 
Record tumor and lymph 
node characteristics 
Record receptor status 
Report planned radiotherapy 
Baseline questionnaires: 
Arm morbidity and QoL 
(EORTC QLQ30-BR23, 
Lymph-ICF), health 
economics (EQ-5D) 
Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. Data on 
received adjuvant treatment. Questionnaires: arm morbidity, 
QoL and health economy 
Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. 
Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. 
Questionnaires: arm morbidity, QoL and health economy 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
21 
 
 
 
 
Follow-up 4 years Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. 
 
Follow-up 5 years Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. 
Questionnaires: arm morbidity, QoL and health economy 
 
Follow-up 10 years Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. 
 
Follow-up 15 years Assessment of disease recurrence; date of mammography 
and date of clinical examination/remote contact. May be 
replaced by register data. 
 
 
 
 
6. Outcomes 
 
 
Primary outcome 
 
 
Overall survival at five years. 
 
 
 
Secondary outcomes 
 
 
• Oncological outcomes at 1, 2, 3, 4, 5, 10 and 15 years: 
 
o local, regional and distant breast cancer recurrence 
 
o survival (recurrence-free and breast cancer-specific) 
 
o contralateral breast cancer 
 
• Arm morbidity at 1, 3, 5 and 10 years 
 
• Quality of life at 1, 3, 5 and 10 years 
 
• Health economic outcomes at 1, 3, 5 and 10 years 
 
 
 
Description and definition of outcomes 
 
 
• Overall survival is measured from the date of randomization until the date of death 
by any cause. Alive participants are censored at the time of last follow-up. 
 
• A local recurrence is a cytologically or histologically proven breast cancer recurrence 
in the ipsilateral breast, breast skin or chest wall. The date of the pathology report 
confirming recurrence is the date of local recurrence. 
• A regional recurrence is a cytologically or histologically proven breast cancer 
recurrence in regional lymph nodes, i.e. in the supra- or infraclavicular basins, the 

SENOMAC Study Protocol version 8.2, February 23, 2023 
22 
 
 
 
 
contralateral axilla, the ipsilateral axilla, interpectoral area or internal mammary 
(parasternal) nodal basin. The date of the pathology report confirming recurrence is 
the date of regional recurrence. 
• A distant recurrence is a recurrence at any other site than above. Here, the date of 
first diagnosis, be it by radiology, cytology or histopathology, is recorded. Cytological 
or histopathological confirmation of the recurrence is encouraged. 
• Recurrence-free survival is measured from the date of randomization until the date 
of first recurrence or death. Recurrence-free and alive participants are censored at 
the time of last follow-up. 
• Breast cancer-specific survival is measured from the date of randomization until 
the date of death by breast cancer recurrence. Participants without a breast cancer 
recurrence will be censored at the date of death by other causes or the date of last 
follow-up if still alive. An isolated ipsilateral in-breast recurrence in a patient who 
dies without further breast cancer recurrences is not included in the definition of 
breast cancer death. 
• Contralateral breast cancer is assessed by mammography or other radiological 
methods and confirmed by cytology or histology. The date of contralateral breast 
cancer is the date of the pathology report confirming the diagnosis. 
• Arm morbidity will be assessed by questionnaire completed by study participants by 
post, online or during the clinic visit preoperatively and after 1, 3, 5 and 10 years. The 
questionnaire used is the Lymphedema Functioning, Disability and Health 
Questionnaire (Lymph-ICF) developed by Devoogdt in 2011. Those sites that wish to 
complement questionnaires with physical measurement of arm volume and/or function 
may do so after separate ethical application (amendment). 
• Quality of life will be assessed by questionnaires completed by study participants by 
post, online or during the clinic visit preoperatively and after 1, 3, 5 and 10 years. 
Questionnaires comprise the EORTC QLQ-30 and BR-23. 
• Health economic outcomes will be assessed at 1, 3, 5 and 10 years by the EQ-5D 
utility scores and by linking trial data to the national registries of Swedish Health 
Insurance (Försäkringskassan) and The National Board of Health and Welfare 
(Socialstyrelsen).

SENOMAC Study Protocol version 8.2, February 23, 2023 
23 
 
 
 
7. Statistics and power calculations 
 
 
Sample size 
The goal of the study is to establish that the intervention (no further axillary surgery) is 
statistically non-inferior to standard of care (completion axillary lymph node dissection, 
ALND) for the primary endpoint overall survival (OS). 
 
Currently, there have only been two studies in which patients with SN metastases were 
randomized to undergo completion axillary lymph node dissection or not [23, 28]. Both 
studies showed a slightly higher 5-year OS among patients who did not undergo axillary 
lymph node dissection (92.5% compared with 91.8%). A previous Swedish publication 
showed a 89% OS after 5 years in patients with SN macrometastasis [40]. Power 
calculations were updated in protocol version 8.1. following the safety interim analysis of 
the SENOMAC Trial in May 2020, estimating a 5-year OS of 94%. Stratification according 
to country of primary treatment is performed. 
 
Clinical non-inferiority is in this study defined as a 5-year OS not worsened by more than 
2.5% when refraining from ALND. To show that the OS at five years is not worsened by 
more than 2.5% (i.e. a 5-year OS of 91.5% in the intervention group compared to 94% in the 
standard of care group - using a one-sided α of 10% and with a power of 80% - a total of 
190 all-cause deaths need to be observed in the study. This corresponds to show that the 
upper one-sided 90% confidence interval for the hazard ratio (HR: Intervention/Standard of 
care) falls below 1.44. For the secondary endpoints of breast-cancer specific survival 
(BCSS) and recurrence-free survival (RFS), 5-year proportions of 97% and 90% are 
estimated. With an unchanged non-inferiority margin of 2.5%, resulting in a HR of 1.86, the 
trial will have sufficient power (80%) to conclude non-inferiority in BCSS once 66 deaths 
due to breast cancer have been observed. With an unchanged HR of 1.44, resulting in a non-
inferiority margin of 4.1%, the trial will have sufficient power (80%) to conclude non-
inferiority in RFS once 190 breast cancer recurrences have been observed. 
 
It is anticipated that the study will be able to recruit up to 3000 patients by the end of 2021. 
With allowance for two extra years of follow-up, the necessary number of events is expected 
to be reached. The total study time will be approximately 7+2 years. 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
24 
 
 
 
A data monitoring committee consisting of independent experts in oncology and surgery, as 
well as a statistician, has performed a safety analysis in May 2020, recommending the trial 
to continue and to change the primary endpoint to OS. A second interim analysis will take 
place in May 2021 with the purpose to assess the recruitment to the study, the rate of overall 
events and to make sure that patients in the intervention group do not appear to fare 
significantly worse than patients in the standard of care group. The committee may 
recommend terminating the study if a significant benefit in favour of standard of care for 
breast-cancer deaths is shown, such that the HR for intervention versus standard of care 
significantly (p=0.001) exceeds 1, or if the recruitment is so low that that the necessary 
number of events is unlikely to be reached. If the committee determines that it is safe to 
proceed with the study, the results of the analysis will remain unknown to everyone except 
the committee members. 
 
 
Statistical methods 
Modified intention-to-treat population 
All participants randomised within the trial constitute the intention-to-treat (ITT) population; 
however, sensitivity analysis will be based on a modified ITT population which includes only 
such participants who did not withdraw their consent within 21 days from randomization, i.e. 
before the potential date of reoperation with ALND in randomization group B. Participants 
who withdrew their consent later than that are instead censured at the date of withdrawal of 
consent. 
Per-protocol population 
 
The per-protocol (PP) population consists of participants who received the surgical axillary 
intervention corresponding to their randomised group assignment. Participants who received 
axillary lymph node dissection despite being assigned sentinel node biopsy only, and 
participants who received sentinel lymph node biopsy only despite being assigned axillary 
lymph node dissection, are excluded from PP analyses. In addition, patients who did at the time 
of randomization not meet all inclusion criteria or met exclusion criteria, even if discovered at 
a later point in time, are excluded from PP analyses. 
For the primary endpoint overall survival (OS), time will be calculated from the date of 
randomization to the date of all-cause death, or for patients still alive to the date of last visit.  

SENOMAC Study Protocol version 8.2, February 23, 2023 
25 
 
 
 
A breast cancer death will be defined as a death with information of a preceding or concurrent 
regional or distant recurrence. Isolated ipsilateral in-breast recurrences will thus not count 
towards BCD. Recurrence-free survival time will be calculated from the date of randomization 
to date of loco-regional recurrence, date of distant recurrence or date of death, whichever 
comes first. For event-free patients time will be calculated from the date of randomization to 
the date of last visit. 
Event-specific cumulative incidence rates - taking competing risks into account - will be 
estimated using non-parametric methods. The effect of the intervention on time to failure will 
be estimated using proportional hazards regression. Both unadjusted analyses and analyses 
adjusting for potential confounding factors will be performed. Results will be presented as HRs 
together with 95% confidence intervals (CI) for all outcomes except for the primary, where a 
two-sided 80% confidence interval will be used to correspond to the primary one-sided test at 
the 10% level. Results from the OS analysis for which non-inferiority was hypothesized will 
also be presented as a figure showing CIs for the hazard ratio, the non-inferiority margin and 
non-inferiority p-value. Both intent-to-treat analyses and per protocol analyses will be 
performed for the primary outcome; per-protocol analysis will be presented as the main 
analysis since it is regarded as the more conservative approach in non-inferiority designs 
(European Medical Agency, ICH, topic E9, Statistical Principles for Clinical Trials). 
Non-inferiority will be concluded if the upper limit of the confidence interval for the hazard 
ratio falls below 1.44. 
Longitudinal health-related quality of life data will be analysed using generalized linear 
models. Results from these analyses will be presented as mean differences and 95% CIs at 1, 3, 
5 and 10 years. Test for interactions between treatment and time – indicating a differential 
effect of treatment over time – will also be performed.  
Pre-specified subgroup analyses will evaluate: 
- 
Differences in chemotherapy rates in randomization groups; this is based on the fact that 
the total number of metastatic lymph nodes is clinically used for recommendations 
regarding systemic treatment including dosage and regimen. For example, pN2 patients 
(more than three metastatic lymph nodes) would typically receive more intense adjuvant 
treatment than pN1 (1-3 metastatic lymph nodes) patients. Thus, omission of ALND could 
potentially under-diagnose a proportion of patients in the intervention group, which should 
be mirrored in lower chemotherapy rates. 

SENOMAC Study Protocol version 8.2, February 23, 2023 
26 
 
 
 
- 
Differences in metastatic nodal burden in lobular versus non-lobular breast cancer and 
associations with oncological outcomes; it is known that lobular breast cancer tends to 
present with higher tumour and nodal stages and yield a higher number of nodal metastases 
at surgery. Omission of ALND, however, routinely does not take the tumour histological 
subtype into consideration. Since lobular breast cancer also shows inferior response rates to 
chemotherapy, it is clinically relevant to assess whether omission of ALND poses a higher 
risk for patients with lobular breast cancer than those with non-lobular breast cancer.  
- 
Differences in nodal burden, proportions of non-sentinel node metastases and oncological 
outcomes in multifocal and multicentric breast cancer. 
- 
Patient experiences of trial participation and axillary surgery and its consequences beyond 
questionnaires; here, a subgroup of patients randomized in Sweden is invited to focus 
group interviews in order to more in detail understand the impact of axillary surgery on 
patients’ lives. 
- 
Patient-reported outcomes (PROs) regarding arm morbidity and quality of life in the 
context of different radiotherapy fields; here, radiotherapy plans of Swedish and Danish 
participants are reviewed in order to obtain exact target volumes and relate these to the 
extent of surgery and PROs. 
- 
Objectively measured arm function, fluid content and volume for the evaluation of 
associations between objectively and subjectively reported outcomes and their association 
with extent of axillary surgery. 
All statistical analyses will be performed using R version 4.1.2 (R Foundation) or SPSS 
version 28.0.0.0. 
 
8. Ethics 
 
 
The original version of this study protocol has been approved by the Ethics Committee of the 
 
Karolinska Institutet, Stockholm (2014/1165-31/1). 
 
 
Based on older studies, a degree of increased risk for axillary recurrence among individual 
patients who do not undergo completion ALND cannot be ruled out. However, newer studies, 
in which patients received adjuvant chemotherapy according to current standards for lymph 
node-positive patients show no reduction in survival or increased risk of axillary recurrence. 
Patients will be closely monitored and receive treatment as needed. 
 

SENOMAC Study Protocol version 8.2, February 23, 2023 
27 
 
 
 
This risk must be weighed against the significant benefit of less arm morbidity associated 
with less aggressive surgery. More and more breast surgeons, in Sweden and abroad, are 
discussing a desire to abandon ALND in the majority of patients with SN metastasis, and in 
many places such discussions have led to action. Nevertheless, there is a risk that this 
approach will be routinely adopted before sufficient evidence is available, for which reason it 
is crucial to first explore this option through a study. 
 
 
 
9. Significance 
 
 
Since most patients with sentinel node metastasis have no additional metastases, and since 
previous studies suggest that even metastases left in place do not have a significant impact on 
prognosis, it is likely that many patients are undergoing an unnecessarily aggressive surgery, 
which in many cases leads to increased arm morbidity. If we are able to show that it is safe to 
refrain from axillary lymph node dissection, then a large number of patients will be spared 
unnecessary suffering. 
 
Refraining from axillary lymph node dissection will also reduce resource needs for surgery, 
pathology assessment and hospitalization. 
 
 
 
10. Withdrawal 
 
 
Patients who wish to withdraw from the study may do so at any time, without providing a 
reason. The patient may request to have completion axillary lymph node dissection during the 
follow-up period. Participants may wish to stop their taking part in the questionnaire part of 
the study which does not exclude them from the overall study. 
 
Data already included in previous eCRFs will be included in the analysis if the participant 
 
does not explicitly wish to have her data excluded from analysis. Ceasing participation will be 
recorded in the eCRF. Long-term follow-up for oncological outcomes, i.e. survival and 
recurrence, will be conducted via national or regional registers for all participants in the 
modified ITT population. 
 
 
 
11. Publication policy 
 
 
Before the collaborative publication of the primary and secondary oncological outcomes from 

SENOMAC Study Protocol version 8.2, February 23, 2023 
28 
 
 
 
the entire cohort, no other publication regarding oncological outcome on parts of the cohort 
can be attempted. Each member of the trial committee of each participating country is to be a 
co-author on any publication reporting on the main findings of the SENOMAC trial, that is, 
any report on oncological outcome and safety issues. Any subanalysis using data from the 
SENOMAC trial, such as radiotherapy quality assurance or quality of life, must first get the 
permission to perform analyses from the trial committee, i.e. all national trial committees if 
international data are used or the respective national committee if only one country’s data are 
used. The overall coordinating investigator is to be informed and applied to for any 
publication, whether it regards national or international data. In such publications, the trial 
committee(s) must be part of the authors’ list as the “SENOMAC Trialists’ Group”; members 
of the trial committee(s) who have taken more active part in any subanalysis and thus fulfil the 
Vancouver criteria for authorship must be included by name in the list of authors. All other 
members must be individually named in Acknowledgements. The Coordinating Investigator 
must be co-author in any publication using data from the SENOMAC trial.

SENOMAC Study Protocol version 8.2, February 23, 2023 
29 
 
 
 
12. References 
1. 
Carter, C.L., C. Allen, and D.E. Henson, Relation of tumor size, lymph node status, and 
survival in 24,740 breast cancer cases. Cancer, 1989. 63(1): p. 181-7. 
2. 
Fisher, B., et al., Relation of number of positive axillary nodes to the prognosis of patients 
with primary breast cancer. An NSABP update. Cancer, 1983. 52(9): p. 1551-7. 
3. 
Soerjomataram, I., et al., An overview of prognostic factors for long-term survivors of 
breast cancer. Breast Cancer Res Treat, 2008. 107(3): p. 309-30. 
4. 
Sobin, L.H., Gospodarowicz, M.K., Wittekind, C., editors. TNM Classification of Malignant 
Tumours, 7th Edition. ISBN: 978-1-4443-3241-4. Wiley-Blackwell 2009. 
5. 
Nieweg, O.E., et al., Lymphatic mapping and sentinel lymph node biopsy in breast cancer. 
Eur J Nucl Med, 1999. 26(4 Suppl): p. S11-6. 
6. 
Andersson, Y., et al., Axillary recurrence rate 5 years after negative sentinel node biopsy for 
breast cancer. Br J Surg, 2012. 99(2): p. 226-31. 
7. 
Krag, D.N., et al., Sentinel-lymph-node resection compared with conventional axillary- 
lymph-node dissection in clinically node-negative patients with breast cancer: overall 
survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol, 2010. 
11(10): p. 927-33. 
8. 
Pepels, M.J., et al., Safety of avoiding routine use of axillary dissection in early stage breast 
cancer: a systematic review. Breast Cancer Res Treat, 2011. 125(2): p. 301-13. 
9. 
van der Ploeg, I.M., et al., Axillary recurrence after a tumour-negative sentinel node biopsy 
in breast cancer patients: A systematic review and meta-analysis of the literature. Eur J 
Surg Oncol, 2008. 34(12): p. 1277-84. 
10. 
Veronesi, U., et al., Sentinel node biopsy in breast cancer: early results in 953 patients with 
negative sentinel node biopsy and no axillary dissection. Eur J Cancer, 2005. 41(2): p. 231-7. 
11. 
Celebioglu, F., et al., Lymph drainage studied by lymphoscintigraphy in the arms after 
sentinel node biopsy compared with axillary lymph node dissection following conservative 
breast cancer surgery. Acta Radiol, 2007. 48(5): p. 488-95. 
12. 
Land, S.R., et al., Patient-reported outcomes in sentinel node-negative adjuvant breast 
cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical 
Adjuvant Breast and Bowel Project phase III protocol B-32. J Clin Oncol, 2010. 28(25): p. 
3929-36. 
13.        Lucci, A., et al., Surgical complications associated with sentinel lymph node dissection 
(SLND) plus axillary lymph node dissection compared with SLND alone in the American 
College of Surgeons Oncology Group Trial Z0011. J Clin Oncol, 2007. 25(24): p. 3657-63. 
14. 
Sackey, H., et al., Arm lymphoedema after axillary surgery in women with invasive breast 
cancer. Br J Surg, 2014. 101(4): p. 390-7. 
15. 
Degnim, A.C., et al., Clinicopathologic features of metastasis in nonsentinel lymph nodes of 
breast carcinoma patients. Cancer, 2003. 98(11): p. 2307-15. 
16. 
Cox, C.E., et al., Significance of sentinel lymph node micrometastases in human breast 
cancer. J Am Coll Surg, 2008. 206(2): p. 261-8. 
17.        Hwang, R.F., 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(4): p. 723-30. 
18. 
Rutgers, E.J., Sentinel node biopsy: interpretation and management of patients with 
immunohistochemistry-positive sentinel nodes and those with micrometastases. J Clin 
Oncol, 2008. 26(5): p. 698-702. 
19. 
Zurrida, S., et al., Axillary radiotherapy instead of axillary dissection: a randomized trial. 
Italian Oncological Senology Group. Ann Surg Oncol, 2002. 9(2): p. 156-60. 
20. 
Fisher, B., et al., Twenty-five-year follow-up of a randomized trial comparing radical 
mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J 
Med, 2002. 347(8): p. 567-75. 
21. 
Fisher, B., et al., Ten-year results of a randomized clinical trial comparing radical 

SENOMAC Study Protocol version 8.2, February 23, 2023 
30 
 
 
 
mastectomy and total mastectomy with or without radiation. N Engl J Med, 1985. 312(11): 
p. 674-81. 
22.        Rudenstam, C.M., et al., Randomized trial comparing axillary clearance versus no axillary 
clearance in older patients with breast cancer: first results of International Breast Cancer 
Study Group Trial 10-93. J Clin Oncol, 2006. 24(3): p. 337-44. 
23. 
Giuliano, A.E., 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(6): 
p. 569-75. 
24. 
Caudle, A.S., et al., American College of Surgeons Oncology Group (ACOSOG) Z0011: Impact 
on Surgeon Practice Patterns. Ann Surg Oncol, 2012. 19(10): p. 3144-51. 
25. 
Gainer, S.M., et al., Changing Behavior in Clinical Practice in Response to the ACOSOG 
Z0011 Trial: A Survey of the American Society of Breast Surgeons. Ann Surg Oncol, 2012. 
19(10): p. 3152-8. 
26. 
Giuliano, A.E., et al., Should ACOSOG Z0011 change practice with respect to axillary lymph 
node dissection for a positive sentinel lymph node biopsy in breast cancer? Clin Exp 
Metastasis, 2012. 
27. 
Latosinsky, S., et al., CAGS and ACS Evidence Based Reviews in Surgery. 40. Axillary 
dissection versus no axillary dissection in women with invasive breast cancer and sentinel 
node metastasis. Can J Surg, 2012. 55(1): p. 66-9. 
28. 
Galimberti, V., et al., Axillary dissection versus no axillary dissection in patients with 
sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised controlled trial. 
Lancet Oncol 2013. 14: 297-305. 
29. 
Francissen, C.M., et al., Axillary Recurrence After a Tumor-Positive Sentinel Lymph Node 
Biopsy Without Axillary Treatment: A Review of the Literature. Ann Surg Oncol, 2012. 
30. 
Orr, R.K., The impact of prophylactic axillary node dissection on breast cancer survival--a 
Bayesian meta-analysis. Ann Surg Oncol, 1999. 6(1): p. 109-16. 
31. 
Shukla, H.S., et al., Does local therapy affect survival rates in breast cancer? Ann Surg 
Oncol, 1999. 6(5): p. 455-60. 
32. 
Park, J., et al., A declining rate of completion axillary dissection in sentinel lymph node- 
positive breast cancer patients is associated with the use of a multivariate nomogram. Ann 
Surg, 2007. 245(3): p. 462-8. 
33. 
Pepels, M.J., et al., Regional recurrence in breast cancer patients with sentinel node 
micrometastases and isolated tumor cells. Ann Surg, 2012. 255(1): p. 116-21. 
34. 
Chetty, U., et al., Management of the axilla in operable breast cancer treated by breast 
conservation: a randomized clinical trial. Edinburgh Breast Unit. Br J Surg, 2000. 87(2): p. 
163-9. 
35. 
Louis-Sylvestre, C., et al., Axillary treatment in conservative management of operable 
breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of 
follow-up. J Clin Oncol, 2004. 22(1): p. 97-101. 
36. 
Donker, M., et al., Radiotherapy or surgery of the axilla after a positive senintel node in 
breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, 
phase 3 non-inferiority trial. Lancet Oncol, 2014. 15: 1303-10. 
37. 
Amin, M., et al. (editors), AJCC Cancer Staging Manual, Eighth Edition. American Joint 
Committee on Cancer, Springer International Publishing, 2017. 
38. 
Offersen, B.V., et al., ESTRO consensus guideline on target volume delineation for 
elective radiation therapy of early stage breast cancer. Radiother Oncol, 2015. 114: 3-10 
39. 
National Guidelines in the Surgical Oncology of Breast. Editor: G Zografos, Publisher: 
Paschalidis Publications, 2013. [“Εθνικές Κατευθυντήριες Οδηγίες (Guidelines) στην 
Χειρουργική Ογκολογία του Μαστού”. Επιμέλεια: Καθ/της Γ. Ζωγράφος. Εκδόσεις 
Πασχαλίδης, 2013] 
40. 
Andersson, Y., et al., Breast cancer survival in relation to the metastatic tumor burden in 
axillary lymph nodes. J Clin Oncol, 2010. 28(17): p. 2868-73.