Injection of 99mTc-nanocolloid and ICG to identify, retrieve and qualify tumor draining lymph nodes in early-stage lungcancer

Around 14.000 patients are diagnosed with lung cancer in the Netherlands each
year. 85% of these tumors are non-small cell lung cancer (NSCLC), which can be
classified into stages Ia to IVb Current 5-year survival estimates in NSCLC
range from >77% in stage IA disease to <10% in stage IV disease. Approximately
20% of lung cancer patients in the Netherlands are diagnosed at an early-stage
and these tumors are treated with curative intent, receiving surgery or
stereotactic ablative radiation (SABR). If locoregional lymph nodes are
involved, adjuvant treatment is considered, which renders accurate staging of
locoregional lymph nodes a critical step in curation at these early stages of
NSCLC. At present, the recurrence rate at 2-years after intended curative
treatment is 15-22%. Recurrence after surgery is most often the result of
residual disease in the lymph nodes, indicating that, despite guideline
concordant work-up, current methods fail to accurately stage locoregional lymph
nodes and that patients are probably undertreated.
A technique that has been investigated for tumors of several origins
over the past decades is a sentinel lymph nodes (SLN) procedure. During such a
procedure, an intra- and/or peritumoral injection of radioactive, fluorescent,
or paramagnetic particles is administered that subsequently drain via the
lymphatic system to these lymph nodes and can be visualized on imaging before
or during surgery to identify and retrieve them. Indocyanine Green (ICG) and/or
99mTc-nanocolloïd are often used to perform a SLN procedure. Literature on this
procedure in lung cancer suggest identifications rates of SLN by ICG and
radioactive tracers to be around 90%.
The Radboudumc developed the navigation bronchoscopy program to
endobronchially diagnose small peripheral lung lesions. This program provides
an opportunity to inject a tracer in or around the tumor tissue in a minimally
invasive manner directly after diagnosis, enabling us to identify the drainage
path and SLN on SPECT/CT-imaging afterwards. Additionally, injection of ICG
during subsequent surgery will help us identify the SLN on a fluorescent camera
and enable us to more extensively assess these lymph nodes on metastatic
disease.
Therefore, we will investigate the feasibility of sentinel node
procedure using a radioactive tracer (99mTc-nanocolloïd) and fluorescent tracer
(ICG) to improve staging of lung cancer. Furthermore, with developing these new
tools to improve staging, we hope to contribute to a better selection for less
invasive treatments in future patients.

The primary objective is to determine the feasibility of identifying the TDLN
in patients with NSCLC (cT1 to cT2b) on SPECT/CT imaging and during surgical
resection using a radioactive and fluorescent tracer, 99mTc-nanocolloïd and ICG
respectively. The secondary objective is to evaluate, compare and relate tumor
draining lymph nodal contents in terms of pathology and immunology to the
primary tumor.

This is a prospective, single-center intervention study. The feasibility of a
SLN procedure through intra- and/or peri-tumoral administration of a
radiotracer during a navigation bronchoscopy procedure and administration of a
fluorescent tracer during surgery will be assessed.

When malignancy is found on rapid on-site evaluation (ROSE) during the
navigation bronchoscopy, study participants will receive around 4 intra- and/or
peritumoral injections (depending on tumor characteristics) of a radioactive
tracer (99mTc-nanocolloïd). Following, up to 2 SPECT/CT-scans (at two time
points) will be made to assess drainage of the injected tracer to the lymph
nodes.
If patients undergo resection of the lung lesion, a fluorescent tracer
(ICG) will be injected either endobronchially or transthoracic during or
per-procedural and the involved lung tissue will be removed, followed by
routine complete lymph node dissection. The fluorescent lymph nodes will be
more extensively evaluated by the pathologist.

1. Intra- or peritumoral injection of 99mTc-nanocolloid per bronchoscopy:
Anesthesia time (which is 120 for the routine procedure) will be prolonged by
approximately 15 minutes to perform the injections, expecting little to no
additional burdens. The injections will be performed with the Pioneer Plus
catheter, which is CE-marked for intravenous use and has been used by us for
this purpose in an ex-vivo setting. Risks related to these additional
injections are bleeding and a pneumothorax, which are known risks to the
routine procedure as well. The study procedure is not expected to be of risk
for intervening with routine clinical care work-up and will not negatively
affect patient management.

Additional fluoroscopy and CT-scans to safely guide injection could add a
maximum of 6.16 mSv to the procedure, where an average of 5.80 mSv is already
used.
99mTc-nanocolloid has a well-documented safety profile (see SmPC of
99mTc-nanocolloid). Hypersensitivity reactions are reported but very sparsely.
The radiation dose related to the tracer is approximately 100 MBq, equivaling a
total effective dose of 0.5 mSv, which is absorbed by the tissue.

2. SPECT/CT-scan
The expected burden is an additional radiation dose and the patient needing to
be transported to the SPECT/CT-scanner for a scan with a duration of around 20
minutes for a maximum of two times during their hospitalization. The
CT-component of the SPECT/CT-scan is 3.3 mSv per scan. Hospital stay will not
be prolonged by the scans, since patients are still released that same
afternoon.

3. Intra- or peritumoral injection of ICG during surgery:
When a fluorescent tracer is injected, this will be performed under
CBCT-guidance, which will lengthen the procedure with a maximum 45 minutes and
is expected add a maximum of 6.16 mSv to the procedure.

Indocyanine green (ICG) has a well-documented safety profile (see SmPC of ICG).
Side effects are very rare. Reported side effects after intravenous injection
are nausea, an anaphylactic reaction or anaphylactoid.

There is a possibility that malignant or atypical cells seen during ROSE are
not found on histological biopsies that are evaluated after the procedure; a
false-positive malignancy outcome. Patients with a false-positive tumor are
still subjected to the radioactive tracer injection and SPECT/CT-scans, while
not benefiting from more extensive lymph nodal evaluation after surgery.
However, this happens very rarely.

Potential benefits
Study participants that undergo surgery to remove their lung cancer will
receive an injection of ICG that drains to the lymph nodes. Fluorescent lymph
nodes will be separately collected and more extensively evaluated by the
pathologist. If (micro-)metastases are present in these lymph nodes, there is a
higher chance that they will be found, and post-operative staging will possibly
be more accurate. These metastases are taken into account when proposing a
follow-up plan, including additional therapy.