Delayed Sentinel Lymph Node Biopsy in Ductal Cancer in Situ

The SentiNot 2.0 protocol aims to elucidate the effectivity and accuracy of the delayed

sentinel lymph node dissection concept (dSLND) when upfront SLND is considered

unnecessary, such as in the setting of a preoperative diagnosis of DCIS, in cases of

unclear BIRADS 4 or 5 lesions that are planned for diagnostic excisional biopsy or in

selected cases of risk reducing mastectomy. Acknowledging the large variance of practice

in this setting, the study aims to address pragmatism to allow for inclusion. For this

reason, the trial is designed separately and independently for mastectomy and breast

conserving surgery, so that participating sites can recruit as fitting in their practice.

In patients included in the SentiNot 2.0 trial, SPIO (MagTrace,2.0 ml) is injected up to

24 hours preoperatively or perioperatively during primary breast surgery on patients with

a preoperative diagnosis of DCIS (or suspicious lesions with no clear diagnosis of

invasive cancer but, considered for SLND). The SPIO is injected close to the lesion. If

injected less than 24 hours before the operation, a 5 minute massage should be performed.

Planned breast surgery is performed. The transcutaneous magnetic counts by SentiMag in

the axilla is measured at the end of the breast procedure, so as to allow for

confirmation that SLND may be identified. Thus,the SLN is consequently marked with SPIO,

but not excised.

In this manner, women that have pure DCIS on final histopathological examination have

avoided unnecessary upfront SLND.

If there is underlying invasive breast cancer on final histopathological examination,

SLND will be performed at a second operation (d-SLND). A preoperative injection of

radioisotope (RI) RI will be added to maximize the chance to detect the SLN. SLND will

start with a registration of the magnetic and isotope signal in the axilla, and the

incision will be placed in relation to the signal. In patients that have undergone

mastectomy, tracers are to be injected intracutaneously in the lateral part of the

mastectomy scar. The routine use of blue dye (BD) is strongly advised, but is not

compulsory. However, if no transcutaneous signal for SPIO and RI is measured in the

axilla pre-incision, an injection of BD according local routines will be administered.

Subsequently, SLND will be performed. Patients with upgrade to invasive cancer will

undergo SLND, but will be randomized with an allocation ratio of 1:1 to SentiMag first or

Radioactive probe first. This will mandate the "principal modality" to perform SLND.

Every step of the procedure will be controlled; if the principal modality fails, then the

surgeon will use the "secondary". If the principal modality succeeds, the secondary will

be registered and documented.

The procedure will be divided to the following steps:

- Transcutaneous axillary signal detection

- Subcutaneous axillary detection, after the incision has been performed.

- In situ SLN identification.

- SLN retrieval ex vivo.

- Residual axillary signal ("Background counts"). If a SLND is successfully completed

with the primary modality and no residual axillary signal is detected, before

completing the procedure, the secondary modality will be undertaken to allow for the

detection of "discordance".

Principle modalities maybe either RI or SPIO. If BD is used, dyed lymphatics should be

ignored until failure with both modalities has been reached. The success of each

modality, principal and secondary, will be controlled per step. If the surgeon documents

principle modality failure for a given step, this is to be documented. The

intention-to-treat principle will apply, but if there is failure of the modality

randomized as principle, then the per-protocol-analysis principle will apply. All SLNs

(magnetic, brown, radioactive, blue) will be removed. Palpable nodes may be removed

according to surgeon discretion, but should be reported as such. Total technique failure

has to be discussed with the patient in advance, and a plan with patient consent

consisting of no-surgery, sampling, axillary dissection or treatment according to

intraoperative decision has to be available. If no SLN is found, the procedure performed

(axillary clearance, sampling. etc) should be discussed in advance with the patient. The

SLN may be sent for frozen section in order to avoid a third operation, if SLN metastases

are present.

Standard of care patients (SLND performed upfront for diagnoses included in the inclusion

criteria or patients going to l-SLND without SPIO) may also be enrolled in the study

prospectively as a control arm.Additionally, patient preference will be tolerated and

results will be reported for study secondary and other pre-specified endpoints. Patients

in the control group has to be informed that their un-identified data will be used as a

comparison and, an oral consent has to be given before surgery regardless whether SLND is

planned or not. This will allow for controlled real world data from a prospective control

arm in fashion of a cohort.