Sentinel node localization in larynx and pharynx cancers after flexible endoscopy-guided tracer injection: a feasibilty study

Head-and-neck (H&N) cancer is worldwide the 6th most common malignacy, with a
mortality of 40*60%. The most important forms of H&N cancer treatment are
surgery and radiotherapy or a combination of the two. Radiotherapy plays a part
in the treatment in 70-75% of the patients.

The first metastases from H&N cancer almost always manifest themselves in the
lymph nodes in the neck. In early stages the metastases can be so small that
even using the most sensitive methods of diagnostic imaging (CT-scan, MRI-scan,
PET-scan, ultrasound examination) they cannot be detected. It has been shown
that of the patients where no metastases were found using modern diagnostics
that 20-30% still appear to have microscopic metastases in the lymph nodes. If
these extremely small metastases remain untreated, the tumor will almost
certainly manifest itself in the neck again, within 2 years. If this occurs
the prognosis is significantly worse.
This is the reason that radiotherapy of a H&N tumor almost always includes the
lymph nodes in the neck region, to prevent the appearance of a recurrence here,
even if standard diagnostics show no metastases. This results in a considerably
larger radiotherapy treatment area than the area where the original tumor was
found. Result is an increase in side-effects and more diverse side-effects. An
example is an inflammatory reaction in the throat which makes swallowing
painful and the patients (temporarily) require painkillers and are limited to
soft food and liquids. By extreme reactions feeding via a tube can become
necessary. Since the salivary glands in the neck are included in the
radiotherapy treatment area the patients also have complaints of a dry mouth
and loss of taste. The irradiated skin becomes red and can sometimes develop
breaks in the skin as occurs with serious sunburn. These side-effects are
mostly temporary but many patients are limited permanently after neck
irradiation such as more diffficulty with swallowing, dry mouth, decrease in
taste. Other long term effects can be: reduced thyroid function, wasting of the
jawbone (infrequent) and arteriosclerosis of the carotid arteries with the risk
of a cerebral infarction.
These side-effects could be limited to a large extent if the area to be
irradiated could be reduced.

The objective of this study is to develop a method whereby reliably can be
determined if there are microscopic metastases in the neck lymph nodes of H&N
cancer patients. In those patients with "clean" nodes the irradiation can be
limited to the original tumor with a significant reduction of the side-effects
whilst maintaining the same chance of cure.

A significantly reliable method to determine the presence of microscopic
metastases in the neck is the so called "sentinel node"procedure. This method
is used for patients with cancer of the oral cavity. Here a radioactive tracer
is injected into the area around the tumor. Via the lymphatic vessels in and
near the tumor this tracer is transported to the nearest lymph nodes. These are
also called the "sentinel nodes". The tracer in fact follows the same path that
the tumor cells travel when they detach from the original tumor and via the
same lymph vessels to reach the lymph nodes where they will nestle and grow to
metastases. With the help of single-photon emission computed tomography
(SPECT-scan) the tracer and therefore the sentinel node(s) can be localised.
These nodes are removed in the operating room and then examined by the
pathologist for the presence of microscopic metastases. If these are not
present in the sentinel nodes the risk that there are metastases in lymph
nodes further away from the tumor extremely small. It is then safe not to
include the neck nodes in the treatment.
In the Radboudumc centre for Head & Neck Oncology this method is succesfully
used for oral cavity tumors. Injection of the tracer in tumors of the oral
cavity is a quick and simple procedure because these tumors are easy to reach.
Tumors in the throat are much less accessible. To be able to take a biopsy but
also for the possible injection of the tracer for the sentinel node procedure
the patient principly has to be anesthetized. First and foremost this is
stressful for the patient but it is also costly and puts pressure on the
capacity of the operating rooms which are already busy.
In this project we therefore want to develop a method where the tracer can be
injected without having to anesthetize and in the out-patient clinic. For this
we use a *flexible scope*. The flexible scope is a thin tube with a small
camera in the tip which is inserted via the nose into the throat and which
enables inspection without anesthesia and is less stressful for the patient.
This method has been in use for years in regular practice and widely used in
the out-patient clinic for examining the throat. Modern scopes are digital and
provide very detailed images. As the cameras become increasingly smaller it is
also possible to insert small instruments into the tube. This can extend the
usability of the scopes.
The H&N department of the Radboudumc is the national and international leader
in the development of new applications of this modern flexible scope. So it is
possible to take biopsies via the flexible scope and since recently the H&N
doctors of our hospital are the only ones in The Netherlands carrying out laser
treatments with this scope. These are procedures which until recently only
could be carried out while the patient was anesthetized.
The plan is to also use the flexible scope in this project for the injection of
the radioactive tracer to track down the sentinel nodes.

Research questions:
a) Are the tracer injections via the flexible scope feasible?
b) How many injections are possible during any one procedure?
c) Does this provide usable SPECT images?
d) How is the correlation with the standard diagnostic CT or MRI?

Application of the radioactive tracer:
In patients who have given permission to take part in the project the H&N
doctor will carry out an inspection of the tumor with the flexible scope such
as is routine in the out-patient clinic. If the tumor is suitably visible, the
tracer will be injected around the tumor via the flexible scope, preferably in
3-4 places if this is feasible.
The procedure can be disrupted if the patient has to cough. The procedure can
also fail if the tracer is not inserted into the tissue but is "spilled" in the
throat. Reliable localisation of the sentinel node can then be hindered. The
whole procedure will be recorded on video and later played back to assess where
possible improvements can be made.
Localisation of the sentinel node(s):
Following injection of the tracer a SPECT-scan is done and the images assessed
by the nuclear medicine doctor for usability.
Assessment SPECT-scan and correlation with other imaging diagnostics:
The study team shall assess the SPECT-images together on the following aspects:
1) Is there enough uptake of the tracer for a reliable localisation of the
lymph nodes?
2) Are there disturbing artefacts? Here thought should be given to for example
*spillage* of the tracer in the throat or a sentinel node which is very close
to the original tumor making it difficult to distinguish separately.
3) Is the localisation of the sentinel node(s) as would be expected by normal
lymph drainage and what is known from scientific literature?
4) Are the localised sentinel nodes also perceived on the routine diagnostic
imaging (CT-scan, MRI-scan, PET-scan, ultrasound)?

The procedure (endoscopy) lasts longer through the application of the
radioactive tracer in the tumor (via flexible scope with inspection of the
tumor as routinely takes place in the outpatient clinic); 2-4 minutes longer
(normally 25-30 minutes).

The procedure can be disrupted if the patient has to cough. The procedure can
also fail if the tracer is not inserted into the tissue and is "spilled" into
the throat. Reliable localisation of the sentinel node can be hinderd. The
whole procedure will be filmed and replayed to assess where possible
improvements can be made.

Exposure to radioactive tracer: hypersensitivity reactions are reported but
very sparsely.

After injection a SPECT-scan is carried out: exposure to external radiation for
low-dose CT scan (SPECT).

There is a low risk of unexpected findings.