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Survival and axillary relapse in breast cancer patients with
sentinel node micrometastases who have not undergone
completion axillary clearance - a national cohort study
Principal investigators:
Leif Bergkvist, Professor, Department of Surgery and Centre for Clinical Research, Uppsala
University, Västmanland Central Hospital, Västerås, Sweden
Jan Frisell, Professor, Department of Breast and Endocrine Surgery, Karolinska University
Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet,
Stockholm, Sweden
Jana de Boniface, PhD, Department of Breast and Endocrine Surgery, Karolinska University
Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet,
Stockholm, Sweden
Yvette Andersson, PhD, Department of Surgery and Centre for Clinical Research, Uppsala
University, Västmanland Central Hospital, Västerås, Sweden
Study Protocol Version 2 16 Oct 2013
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Contents
1. Summary
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2. Background
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3. Purpose
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4. Hypothesis
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5. Methods
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Inclusion criteria
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Exclusion criteria
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Performance
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Preoperative examination
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Injection of isotope and blue dye
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Operation
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Pathology
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Frozen tissue samples
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Adjuvant therapy
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Registration
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Follow-up
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6. Participation
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7. Statistics and power calculations
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8. Ethical aspects
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9. Importance
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10. Time plan
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11. Economics
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Estimated costs
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Funding
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12. Withdrawal
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13. References
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1. Summary
Sentinel node (SN) biopsy in breast cancer has been demonstrated to be a reliable method,
and several follow-up studies have shown that it is safe to refrain from completion axillary
clearance (axillary lymph node dissection, ALND) in SN-negative patients. SN biopsy alone
results in significantly less arm discomfort following the operation.
However, as a surprisingly low frequency of axillary relapse has been observed in patients
without any axillary intervention (neither SN biopsy nor axillary clearance), or without
completion ALND after a positive SN biopsy, the importance of ALND is being questioned,
even for patients with SN metastases. A large, randomized study (ISBCG23-1) was not able
to show any differences in 5-year disease-free survival between patients with SN
micrometastases who had undergone ALND and those who had not.
This Swedish multi-center study will include patients with SN micrometastases. These
women will not undergo ALND but will be registered in a study cohort. The patients will
otherwise be treated in accordance with the national guidelines and will be clinically followed
every year for five years, after 10 years and finally after 15 years. As a voluntary part of the
study, frozen material from the primary tumor will also be stored to enable the analysis of
future prognostic factors.
2. Background
The spread of cancer to the lymph nodes is one of the most significant factors in breast cancer
prognosis [1-3]. Lymph node metastases are classified as isolated tumor cells (≤0,2 mm),
micrometastases (>0,2-2 mm) and macrometastases (>2 mm) [4]. Lymph nodes containing
isolated tumor cells are considered, according to TNM classification, to be negative (N0).
Axillary surgery is an integral part of breast cancer surgery either as axillary clearance
(ALND) or sentinel node (SN) biopsy. The purpose of axillary surgery has been regarded to
be partly diagnostic, to be able to make decisions about adjuvant therapy, and partly
therapeutic, to be able to reduce/eliminate the tumor burden. The therapeutic effect is,
however, questioned more and more.
Sentinel node biopsy in breast cancer has been demonstrated to be a reliable method [5], and
several follow-up studies have shown that it is safe to refrain from completion axillary
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clearance (ALND) in SN-negative patients [6-10]. The major advantage of SN biopsy is that
the frequency and severity of arm discomfort is significantly reduced as fewer axillary lymph
nodes are removed [11-13].
To refrain from ALND in SN-negative patients is standard in Sweden and in most Western
countries. In SN-positive patients, a completion ALND is performed (often at the same time
following frozen section results). In around 50-65% of patients no further non-SN metastases
are found [14] and in these cases, lymph nodes have been removed unnecessarily. For patients
with SN micrometastases, the risk of additional metastases is even lower, around 10% [15].
Interestingly, a surprisingly low frequency of axillary recurrence has also been observed in
patients without any axillary intervention and in SN-positive patients without completion
axillary clearance [16-22]. In addition, it has also been observed in follow-up studies that the
incidence of axillary recurrence in SN-negative patients without axillary clearance was much
lower than expected, taking into account that a SN false negative rate of around 5-10% [5, 9,
18]. This indicates that not all metastatic lymph nodes develop into clinically significant
metastases.
Survival for patients with micrometastases has been previously shown to be between that of
node-negative and node-positive patients [23]. Another study, where ALND was performed
on 79.5% of patients with SN micrometastases, demonstrated poorer survival for these
patients than for those without lymph node metastases [16]. Our own group demonstrated a
worse 5-year disease-free survival for patients with micrometastases than for patients without
metastases (94.1% versus 96.9%), although overall survival was not significantly different
[24]. Results from the Dutch MIRROR study [25] also warrants caution, as a more than two
times greater frequency of axillary recurrence in patients with SN micrometastases without
ALND compared with SN-negative patients (5.6% and 2.3%, respectively, after 5 years) was
observed. In the recently published results of the only randomized study thus far, 464 patients
with SN micrometastases who had undergone ALND were compared with 467 patients in
whom ALND had not been performed. There was no significant difference in 5-year diseasefree survival and the authors concluded that ALND does not need to be performed in cases
where there is limited SN metastatic involvement [26].
Another, much debated, randomized study was not able to demonstrate any differences in
survival between SN-positive patients (including macrometastases) who either did or did not
undergo ALND. That study, Z0011, included only patients operated with breast-conserving
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surgery who received whole-breast postoperative radiotherapy, and with a maximum of two
SN metastases [27]. A previous study that randomized 473 women over the age of 60 years
between 1993 and 2002 to receive either ALND or no axillary surgery [22] also did not
observe any differences in survival. Both Z0011 and the previous study, however, failed to
achieve inclusion goals and thus it is likely that there were too few patients for moderate
differences in mortality to be detected. Recently, a review was published of studies comparing
SN-positive patients who had undergone axillary dissection with those who had not [28]. The
conclusion was that it appears to be safe to refrain from axillary clearance for selected
patients. Most of the studies included, however, were retrospective, and the majority included
only small numbers of patients.
3. Purpose
The main purpose of the study is to evaluate the safety of refraining from completion axillary
clearance in breast cancer patients with sentinel node micrometastases.
4. Hypothesis
To refrain from axillary clearance in breast cancer patients with sentinel node
micrometastases does not impair survival.
5. Method
The study is designed as a cohort study for the follow-up of patients with sentinel node
micrometastases in whom no completion axillary clearance has been performed.
The patients will be registered in a database and followed up prospectively. As a voluntary
part of the study, frozen material from the primary tumor may also be stored to enable the
analysis of new factors in the future if such a need should arise.
Inclusion criteria
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
Patients with clinically node-negative, invasive breast cancer ≤ 5 cm (T1-T2) where
histopathology results demonstrate SN micrometastases.

Patients who undergo breast-conserving surgery or mastectomy.

The patient must have given verbal and written consent.
Exclusion criteria

Preoperatively diagnosed lymph node metastases.

Sentinel node metastases > 2 mm.

Metastases beyond the ipsilateral axillary lymph nodes at the time of surgery.

Neoadjuvant therapy.

History of previous breast cancer.

Pregnancy.

Bilateral breast cancer where any of the other exclusion criteria applies to either side.

Medical contraindication for systemic adjuvant therapy.
Performance
There are two alternatives for recruitment of study participants, depending on whether or not
the participating unit performs perioperative SN frozen section analysis.
1. Units where SN frozen section analysis is performed: patients who meet the inclusion
criteria are provided with verbal and written information (see the enclosed patient
information leaflet) when surgery is planned. The reason for the preliminary inclusion
of patients prior to surgery is to enable inclusion of those patients for whom
micrometastases are demonstrated by frozen section. The patients who agree to
participate sign the informed consent form. Final registration in the study occurs after
the final postoperative SN results are known.
2. Units where SN frozen section analysis is not performed: patients who meet the
inclusion criteria are informed about the study after their surgery, when the final
postoperative SN results are known. The patients who agree to participate sign the
informed consent form.
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The patients who meet the inclusion criteria but who for different reasons are not included in
the study will be registered using a code number, along with details of the reason for the
patient not being included, and the other information stated in the protocol (see appendix), so
that drop-outs can be accounted for in a CONSORT report.
Preoperative examination
Preoperative examination will be performed according to local practices, using triple
diagnostics. Ultrasound of the axillary nodes is optional.
Injection of isotope and blue dye
Injection of isotope and blue dye will be performed according to local practices and may be
intracutaneous above the tumor, around the tumor or periareolar. Imaging is optional.
Operation
Sentinel node biopsy will be performed following injection of isotope and blue dye into the
ipsilateral breast. Sentinel nodes will be identified using a Geiger counter and are defined as
nodes that are blue and/or radioactive. No more than four nodes should be removed. Frozen
section of sentinel nodes is optional, see the 'Performance' section above. If extensive axillary
spread is suspected during surgery, this must be verified by frozen section and axillary
dissection is in case of macrometastases performed at the same time.
Pathology
Sentinel nodes and primary tumors should be investigated in accordance with the Swedish
Society of Pathology Quality and Standardization Committee (KVAST) guidelines
(www.svfp.se/node/214). Immunohistochemical SN investigation is optional. Tumor
characteristics are documented in accordance with accepted practice and should include size,
histological type, hormone receptor status, HER2-neu status, proliferation and tumor stage.
Any lymph node metastases are measured and classified.
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Frozen tissue samples
This study will be performed over a prolonged time period and it may be several years before
the results will be known. Over this time period it is likely that new prognostic and predictive
factors will continue to be found. In order to have the possibility of also investigating new
factors in our cohort it is recommended that frozen material from the primary tumor should be
stored for potential future investigation. This part of the study is voluntary, as not all units
may have the resources to do this.
The frozen tissue samples will be prepared from the fresh specimen in accordance with local
procedures and will then be stored in the respective regional biobanks.
Adjuvant therapy
Adjuvant therapy should be administered in accordance with national guidelines. Patients
with micrometastases are considered to be node positive. Radiotherapy should be
administered in accordance with the Swedish Breast Cancer Group (SweBCG) guidelines,
with target definitions in accordance with the Swedish Breast Cancer Radiotherapy Group
(SBRG). Participation in the study does not mean that radiotherapy or any other adjuvant
therapy should be offered more profusely than to corresponding patient categories who are not
participating in the study. The study aims to examine the effects of limited surgery, which is
not to be compensated by increased use of another therapy.
Registration
All participating patients will be registered by an inclusion protocol. Patients eligible for
inclusion but who for some reason are not included in the study will be registered using a
separate protocol (see the appendix). The protocol will record information about age, surgery
performed, tumor and lymph node characteristics and adjuvant therapy details. The protocol
will be sent together with copies of histopathology results to the Centre for Clinical Research,
Västmanland Central Hospital, SE-721 89, Västerås. There the information will be entered in
a data register. All information is confidential and the register is secured, i.e. no information
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can be traced back to individual patients and no unauthorized person can access individual
patient data in the register. The register will be maintained until further notice and will be
managed according to the Swedish Data Protection Act (PUL, 1998:204). The responsible
body for the register is the County of Västmanland Public Health Authority (Landstinget
Västmanland), Västmanland Central Hospital, SE-721 89 Västerås, telephone +46(0)21-17 30
00.
Follow-up
All patients are followed up by annual clinical exam and mammography for five years and
information about the most recent follow-up visit and any recurrence or death is reported to
the study administration via a follow-up protocol (see the appendix).
After ten and fifteen years, a request to attend a follow-up visit will be issued by the
respective regional cancer center; follow-up visits should include clinical exam and
mammography.
6. Participation
The participating units must routinely perform sentinel node biopsy.
7. Statistics and power calculations
The primary endpoint is disease-free survival (DFS). Secondary endpoints are axillary
recurrence, overall and breast cancer-specific survival. Survival and time until axillary
recurrence will be reported using Kaplan-Meier, where the time from the primary operation
and 95% confidence intervals will be calculated.
Based on data from our Swedish cohort and validation studies [6, 24] we know that women
with sentinel node micrometastases had a DFS of 79.6%. Seventy-five percent of these
underwent axillary clearance, but only 22% received chemotherapy. In the recent RCT from
Milan, however, [26] a DFS of as much as 87.8 % was reported for women with SN
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micrometastases who had not undergone axillary lymph node dissection. Our assumption is
that a 5-year DFS of less than 80% is not acceptable. The null hypothesis is therefore H0: the
proportion of DFS = 80% in the population. Note that the clinical question is formulated such
that DFS must be at least 80% (i.e. a one-sided test). In practice, however, a two-sided test is
considered appropriate used in order to be conservative.
452 patients are required to obtain 80% power to demonstrate that DFS is not 80% if the
observed DFS is 85%.
Binary logistic regression is used to compare patients with any type of event to those where
no event has occurred. An interim analysis will be performed after 2 to 3 years.
The cut-off for statistical significance is set at p=0.05.
8. Ethics
The study has been approved by the Ethical Review Board at Karolinska Institutet,
Stockholm, Sweden on 4 September 2013, (2013/1258-31/4). The initial approval includes the
Karolinska University Hospital in Stockholm and the Västmanland Central Hospital in
Västerås, Sweden. All units in Sweden that perform sentinel node biopsy will be asked to
participate and a supplementary application is then sent to the Regional Ethical Review Board
in Stockholm (Regionala etikprövningsnämnden in Stockholm, FE 289, SE-171 77
Stockholm, Sweden).
Based on previous studies, an increased risk of axillary relapse for individual patients who do
not undergo completion ALND cannot be ruled out. More recent studies, where patients have
received adjuvant chemotherapy in accordance with today's standard therapy for nodepositive patients, however, have neither shown poorer survival nor an increased risk of
axillary relapse. Patients will be followed meticulously and will receive treatment as needed.
The risk must be balanced against the significant benefits, with less arm morbidity which is
associated with less extensive surgery. Increasing numbers of breast surgeons, in Sweden and
abroad, are dispensing with ALND for patients with SN micrometastases. The risk is that this
becomes standard practice without there being sufficient evidence, and therefore there is an
urgent need to test and record the question at stake in scientific form.
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9. Importance
As the majority of patients with sentinel node micrometastases do not have any additional
metastases, and as previous studies have found indications that even metastases left in situ do
not have a significantly impaired prognosis, it is likely that many patients have unnecessarily
extensive surgery which in many instances leads to increased arm morbidity. If we can
demonstrate that it is safe to refrain from axillary lymph node dissection then a large number
of patients can be spared unnecessary suffering.
To refrain from an axillary clearance will also reduce the resource requirements for surgery,
pathology and hospital stays.
10. Time plan
Every year almost 8000 women in Sweden develop breast cancer. Around 5-10% (400-800)
of these have micrometastases. If we recruit at least half of these, then recruitment will take
around 2-3 years. The recruitment time could be shortened if centers outside of Sweden also
participate in the study.
11. Economics
Estimated costs
Collecting data, recording data and data analysis will be performed by researchers and
research assistants.
Research assistant (50% for 5 years): SEK 600 000
Researcher (25% for 5 years): SEK 900 000
Statistician: SEK 50 000
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Ethical Board submission fees: SEK 16 000
Meetings: SEK 50 000
Total: SEK 1 616 000
Funding
Funding will be sought from the Swedish Cancer Society (Cancerfonden) and BRO, among
others.
12. Withdrawal
Patients who wish to withdraw from the study are free to do so at any time, without providing
a reason for withdrawing. Patients can request that a completion axillary node clearance is
performed during the follow-up period.
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