Evaluation of a Clinical Prototype Near-InfraRed Fluorescence (NIRF) Imaging Device for Sentinel Lymph Node (SLN) Detection in Breast Cancer: a Technical Feasibility Study

Breast cancer is the most common form of cancer and second leading cause of
death in women in Europe and the USA, with 450,000 new cases and 120.000 deaths
yearly. Over the last thirty years, wide-spread mammographic screening,
technological developments and raised physicians- and self-awareness have led
to a rapid increase in the diagnosis of small, non-palpable breast cancer.
Surgery of primary breast cancer is dependent on the resection of the primary
tumor and identification of cancer spread to lymph nodes (LNs), both
independent prognostic factors for survival and recurrence of disease. The
mapping of LNs and/or removal of suspicious LNs is a mainstay of minimally
invasive cancer staging. For identification of tumor involvement in axillary
lymph nodes (ALNs), the first-draining node, also denominated as the sentinel
lymph node (SLN) is analyzed by histology. A cancer-free SLN indicates, with
high certainty, absence of spread in the ALNs. Conversely, it is common
practice that a positive SLN is followed by a lymphatic clearance without
knowledge whether there is tumor involvement in the remaining LNs. Currently,
the SLN is the only involved ALN in 57% of breast cancer patients with SLN
metastases. Moreover, in case of an affected ALN, approximately 70% patients
have non-metastatic remaining ALNs as determined after lymphatic clearance.
Therefore, non-affected ALNs are often needlessly removed because the surgeons
lack real-time information about the status of these LNs. In case of a SLN
metastases of >2 mm , an additional axillary lymph node (ALN) dissection is
performed during a secondary procedure, with 57% of the remaining axillary
lymph nodes are negative by definitive histopathological examination . If a SLN
contains a so-called micrometastases, (2mm - 0.2mm, ~25% of all SLN
procedures), this number increases to 70-80% of ALNs negative for metastases.
As such, the SLN procedure, although highly specific and sensitive, leads to
substantial over-treatment in breast conserving therapy. In addition, this
carries the risk of nerve injury, lymphedema, and decreased arm motion and
seroma formation. Since breast sparing lumpectomy combined with radiotherapy is
generally sufficient as a treatment for T1-T2 breast tumours in appropriately
selected patients, breast conserving therapy (BCT) has become the standard
treatment. BCT is considered to be less stressful compared to radical
mastectomy and offers better cosmetic results and reduced wound infection risk.
The most important disadvantage of BCT is the life-long risk for local
recurrence of the primary tumour, in which case additional surgery is
necessary. According to the Dutch guidelines for patients with palpable breast
cancer stage I and II, diagnostics should be aimed at determination of the
disease stage by staging of the locoregional process and if necessary axillary
lymph node status and dissemination studies. In patients with palpable invasive
breast cancer (stage I and II) the current guidelines advise preoperative
imaging with endosonography, mammography or magnetic resonance imaging. In case
of breast conserving treatment the aim of the procedures is to obtain optimal
locoregional control with optimal cosmetic results. In this policy, the
sentinel node (SLN) procedure is the current standard for staging of
locoregional lymph node metastases in breast cancer patient with T1-2N0 status.
Best results for detection of the SLN are obtained by injection of a
radiocolloid and intraoperative injection of Patent Blue. New innovative
imaging modalities like NIRF imaging intend to improve the detection of
remaining axillary lymph nodes to be positive for tumor metastases
simultaneously with the SLN. This may decrease the possibility of
over-treatment in patients with T1-2N0 tumor status, and ultimately leading to
decreased costs .

Ergonomics and function of the imaging system - the NIRF imaging system should
not interfere with the standard Sentinel Lymph Node mapping procedure and used
safely by the surgeon while detection of ICG takes place. Duration: 1,5 hour
clinical procedure.

Interventional study: a phase 0 technical feasibility study / non-randomized,
open label, uncontrolled, single group assignment.
The study will be carried out in collaboration with the Technical University of
Munich, Institute of Biological and Medical Imaging. The actual study will be
carried out at the University Medical Center Groningen, Department of Surgery.

The study protocol is designed as follows:
1. Selection of patients with operable histology proven invasive breast cancer
(T1-2cN0-1) are asked for participation and informed consent at the outpatient
clinic for the proposed study if the apply to the inclusion criteria. Copies of
the proposed study protocol are available at the outpatient clinic. Patients
have at least 24 hours to decide whether they want to participate or not.
2. After approval and documented informed consent, a pregnancy test is
performed and in case of a positive test the patient cannot be included. Next,
the operative procedure is planned together with the NIRF imaging protocol. The
pharmacist of the UMCG is informed of inclusion of the patient together with
the planned date of operation for delivery of ICG.
3. at the day of admission (one day prior to surgery), the standard surgical
procedure for lumpectomy, and the standard SLN procedure combined with ICG
intratumoral injection in the operating room (OR) is again explained to the
patient. The Department of Nuclear Medicine and Molecular Imaging at the UMCG
will deliver the radioactive tracer for detection of the SLN.
4. at the day of surgery, the ICG compound will be delivered by the Hospital
Pharmacy at the OR for intratumoral injection.
5. during anesthesia ICG will be injected with a dose of 0.5 mg (i.e. 1 ml of
volume in a dose of 0.5 mg/ml).

The burden associated with participation consists of an additional injection of
indocyanin green (ICG) intratumoral besides patent blue during anaesthesia for
the detection of the SLN. Additionally, there is a chance of longer operative
procedure by using a NIRF imaging camera (~30 minutes).
1. The possible most serious adverse event for injection of ICG is an allergic
and anaphylactic reaction.
2. The possible effect of prolonged anesthesia because of testing the camera
system and detection of the SLN is limited in itself because of a total time
of no longer than 2 hours.
3. There is no risk or burden of using the intraoperative imaging device, all
necessary test for use of electrical devices in the OR are covered.
4. There is no risk of infection; the imaging device will be covered by special
designed sterile drapes to prevent the risk of infection during a surgical
procedure.