Clinically node negative breast cancer patients undergoing breast conserving therapy: Sentinel lymph node procedure versus follow-up. A Dutch randomized controlled multicentre trial.

The NSABP B-04 trial revealed that omitting primary axillary treatment of
occult positive lymph nodes in clinically node negative breast cancer patients
does not affect survival, even after 25 years of follow-up and without the use
of adjuvant systemic or radiation therapy. A delayed axillary dissection in
case lymph nodes become clinically positive does not affect survival and
prevents axillary overtreatment in the majority of patients. The ACOSOG Z0011
and IBCSG 23-01 trials revealed that completion axillary dissection can be
safely omitted in clinically node negative patients with metastatic sentinel
nodes. Patients randomized for watchful waiting were likely to have residual
nodal disease (13-27%) that was not surgically removed. Nevertheless, survival
rates were not affected and regional recurrence rates low. Use of axillary
ultrasound will improve the preoperative selection of node negative patients,
as it selects patients with a more favourable tumour load and accurately
excludes advanced nodal disease (>=4 metastatic nodes). Biology and adjuvant
systemic and radiation therapy are all factors that most likely diminish the
risk that possible metastases left in situ develop into clinically detectable
lymph nodes. Patients treated with breast conserving therapy are significantly
more often diagnosed with pathologic node negative disease or with
micrometastatic disease, compared to patients treated with mastectomy. The risk
for occult (macro)metastases in cT1-2N0 breast cancer patients treated with
breast conserving therapy is low: about 88% will be node negative and about 95%
of node positive patients will have no lymph node metastases beyond the
sentinel node. Reflected by the low regional recurrence rate after a (false)
negative sentinel node, only a small amount of patients (0.8%) with node
positive disease is expected to develop clinically detectable nodal disease.

The objective of this study is to decrease the number of breast cancer patients
receiving overtreatment of the axilla, in order to positively influence the
axillary morbidity rate and quality of life. Therefore, we investigate whether
the sentinel lymph node procedure can be safely omitted in clinically node
negative breast cancer patients undergoing breast conserving therapy, in terms
of non-inferior regional control, distant-disease free and overall survival.
All objectives are measured during a follow-up of 5 years.

A randomized controlled non-inferiority multicenter study. Patients who meet
the in- and exclusioncriteria will be randomized after informed consent for one
of the two treatment methods: - Arm A (control arm): lumpectomy with sentinel
lymph node procedure, followed by radiotherapy of the breast with or without
completion axillary treatment according to the Dutch breast cancer guideline. -
Arm B (experimental arm): lumpectomy without further axillary staging, followed
by radiotherapy of the breast. Stratification: age (<=50, 50<=75, >75 years old),
oestrogen receptor status (positive vs. negative), HER2neu status (amplified
vs. not amplified), clinical tumour stage prior to any treatment (<3 cm vs. >=3
cm), grading (grade I-II vs. III - according to Bloom-Richardson grading
system), is or will be treated with primary systemic therapy (yes/no) and
participating centre. Adjuvant systemic treatment is administered if indicated
according to the Dutch breast cancer guideline. Primary systemic therapy is
allowed if the patient has a clinical T1-2N0 status (initial stage) that is
amenable to lumpectomy pre-systemic therapy. Yearly follow-up with physical
examination of the axilla for 5 years. Axillary ultrasound (+/- tissue
sampling) on indication. Staging for distant metastases and/or a delayed
axillary lymph node dissection if indicated by the multidisciplinary team.
Validated questionnaires are used to assess axillary morbidity rate and quality
of life (Lymph-ICF, QLQ-C30, QLQ-BR23) and to measure if anxiety and
personality traits influence the outcome of quality of life (STAI-trait,
NEO-FFI) in 1056 of 1730 patients. These questionnaires are provided before
randomization and sequentially post randomization at 6 months, 1, 2, 3 and 5
years. Cost-effectiveness questionnaires are provided before randomization and
sequentially post randomization at 6 months, 1, 2 and 3 years.

Patients in the control arm will be treated with the sentinel lymph node
procedure according to the Dutch breast cancer guideline. Patients in the
experimental arm will not be treated with the sentinel lymph node procedure.

There is no extra burden for participating patients as regard to additional
diagnostic tests/interventions and follow-up. Any additional burden for the
patient will only consist of completing quality of life questionnaires in 1056
of 1644 study patients. These questionnaires are provided before randomization
and sequentially post randomization at 6 months, 1, 2, 3 and 5 years. The
cost-effectiveness analysis study (CEA) was set up later and added to the
Qol-study. The inclusion rate of the CEA was 66%. Since this sub-study needed
to include 474 patients, still another 74 patients need to be approached until
a total of 1056 patients.
If patients do not return the questionnaires or only one out of the first two,
a letter to thank the patient for taking part in the study. They will not be
bothered with further questionnaires. After patient 1056 no questionnaires will
be sent out.
We hypothesize that omitting the sentinel lymph node procedure is not inferior
to the standard treatment. Nevertheless, possible disadvantages are a worse
regional recurrence rate, and delayed axillary treatment if indicated. Patients
in the experimental arm have the possible advantages of less morbidity, fewer
operations and hospitalizations and improved quality of life, compared to
patients treated with the sentinel lymph node procedure.
No patient will encounter any delay in their treatment as a result of
inclusion.