Detection of sentinel lymph nodes in laryngeal cancer by injection of patent blue dye via flexible laryngoscopy as a new technique

Worldwide laryngeal carcinoma (LC) is in the top 25 most common cancers with an
annual incidence of more than 175.000 and around 90.000 deaths each year (13).
In the Netherlands each year around 700 patients will develop LC. Five years
overall survival is 60% and in advanced stage supraglottic LC, this is
approximately 30%. The recurrence rate of LC increases with an advanced
T-stage: patients with T1-T2 stage have a recurrence rate of up to 30%, while
in T3-T4 this is 50% (1). The treatment consists of nonsurgical, surgical,
radiation or chemoradiation modalities. The presence of lymph node metastases
or the likelihood of a tumor spread to the lymph nodes are important for the
treatment selection (2). According to international guidelines, elective
treatment of clinically and radiologically confirmed N0 regional lymph nodes is
indicated in cT1-T3 supraglottic and T2b-T4b glottic cancer (i.e. without
clinical signs of lymph node metastases).

Improving the detection of the SLN in LC
In general, the sentinel lymph node (SLN) is the primary site which receives
lymphatic drainage from metastasizing tumor tissue. Previous treatment in
second primary tumors or recurrent LC could possibly influence the lymphatic
drainage and metastatic behavior (14). With the identification of the SLN due
to BD injection around tumor tissue the individual tumors drainage pattern gets
visible (14). This SLN sampling technique turned into the standard care in
malignant breast cancer and melanoma (3-6). In the UMCG, the SLN procedure
using BD is applied for breast cancer and melanoma (7). Also, the SLN procedure
using BD has been studied in vulva cancer and colon cancer in the UMCG (8, 9).
A confirmed negative SLN could lead to avoid unnecessary treatment of the neck
and decrease swallowing problems, fibrosis or lymphedema as complications of
treatment of the neck. After an ex vivo first pilot study, the aim of this
second in vivo part of this pilot study (feasibility and validation) is to
analyze [*] the applicability and diagnostic accuracy of BD for detection of
the SLN in LC in vivo by injection via the working channel of a flexible
laryngoscope around the tumor (in vivo). The flexible laryngoscope with the
working channel is routinely used in patient care in the UMCG since 2017 and
has received the European certification mark (CE) which shows that the product
meets the safety, health and environmental requirement for selling and using in
the European Union (10). The injection by using the working channel is conform
the intended use (11). For injection of BD we will use the single use injector
needle (injector force max. model number NM-401L-0425, Olympus). We hypothesize
that BD locates accurately at SLN by injecting BD around tumor tissue. This
could result in a prevention of patients receiving an unnecessary treatment of
the neck.

Primary Objective: After ex vivo confirmation that BD injected around LC in a
laryngeal surgical specimen is not spreading into tissues beyond the tumor, the
detection of SLN by a technique of injecting BD via a flexible laryngoscope
using a working channel has to be tested.

Secondary Objective: We want to analyze the difference in BD spreading for
detection of SLN in primary TL and salvage TL.

After previously tested spreading of BD around the LC ex vivo in prospectively
collected laryngeal surgical specimens, we will prospectively include ten
patients who will undergo a TL with planned neck dissection to inject BD in
vivo.
Duration: Study period of 18 months
Setting: In total, around 20 total laryngectomies are performed at the
department of Otolaryngology / Head and Neck Surgery of the University Medical
Center Groningen each year.

In this study we will analyze if BD distributes accurately to the SLN in vivo
in ten patients who will undergo a TL with planned neck dissection. Secondary,
we want to analyze the difference in BD spreading in primary TL and salvage TL.
Therefore, 0.5-1 ml BD will be injected around laryngeal tumor tissue at the
beginning of the planned TL under general anaesthesia by using a standard
injection needle via the working channel of a routinely used flexible
laryngoscope. Applicability and diagnostic accuracy (sensitivity, specificity,
positive and negative predictive value and diagnostic accuracy) for detection
of SLN will be calculated by using histopathological results as gold standard.

BD is widely used in several medical studies and turned into standard care for
SLN sampling technique in malignant breast cancer and melanoma (3-6). Adverse
reactions reported to BD subcutaneous administration are allergic reactions (3,
12). In approximately 1% of the patients it causes hypersensitivity reactions
and the risk of anaphylactic shock is the highest within the first 30 minutes
(3, 16). The risk of the side effects is higher in patients with
hypersensitivity reactions to BD earlier and to trifenylmethan pigment.
Therefore, we will exclude patients with this hypersensitivity in medical
history. Also, we will administer BD during general anaesthesia in the
operation theatre. The patient is under constant supervision and the vital
parameters are controlled. In the rare case of (the first signs of an
anaphylactic allergic reaction medical support is given instantly. Next to
this, the urine of the patient can be coloured blue within the next 24-48 hours
after injection (3). Adverse effects reported by using BD intravenously are
next to allergically reactions and anaphylaxis also oedema of the larynx and
angio-oedema (4). Other side effects are urticaria, erythema, itching and skin
rash (4). At the side of injection, BD can colour the skin blue. We will not
inject BD intravenously but subcutaneously. Therefore, we do not expect these
side effects in our study. Due to staining lymphatics we are able to localize
the spreading of BD. We will exclude pregnant woman because it is advised to
only use BD in strict indications during pregnancy (3).