Near-infrared fluorescence imaging with IndoCyanine Green for the intraoperative identification of Gastrointestinal stromal cell tumours: a pilot study

1.1 General
Gastrointestinal stromal cell tumours (GIST) are the most common mesenchymal
neoplasms and account for 1% of primary gastrointestinal tumours. Estimations
of the incidence range from 6.8 to 14.5 per million. The mean age of diagnoses
is 64 years. In 85% GISTs are discovered after symptomatic clinical
presentation (i.e. bleeding, pain). However, GISTs can be asymptomatic and
found by chance.

Although disagreement persists about the treatment of GISTs <2cm, consensus
exists that GISTs >2cm require treatment. Surgical resection is the preferred
treatment modality if no sequalae is expected. Adjuvant therapy with Imatinib
is indicated when sequalae are expected after surgery, to significantly improve
survival. GISTs arise as a result of mutations in proto-oncogenes C-kit and
PDGFR and are frequently identified by expression of the KIT protein. Imatinib
is an inhibitor of receptor tyrosine kinase, product of the KIT proto-oncogene.

Secondary progression of the disease is usually observed after 24-30 months
after resection, whereupon second-line treatment with Sunitinib is recommended.
Surgery could be an alternative for switching to second-line treatment, since
it has been shown that cytoreductive surgeries, including peritoneal lesions
and liver resections, can provide survival benefit12.

Since resectability of GISTs depends upon tumour location, size and extent of
spread, optimal staging and tumour identification are to be pursued. We suspect
intraoperative imaging of GISTs to be useful to achieve optimal margin status
in resection and cytoreductive surgery.

1.2 Intraoperative imaging
Intraoperative imaging leads to better intraoperative tumour identification and
tumour demarcation in various types of tumours resulting in more radical
resections and less iatrogenic harm13. Yet more progress is to be made as
intraoperative imaging in gastrointestinal stromal tumours (GIST) has not been
researched. Especially imaging of endoluminal GISTs is expected to contribute
to improve intraoperative tumour localization. Given that GISTs frequently
metastasize to liver and peritoneum, intraoperative imaging could improve
staging and cytoreductive surgery of GISTs.

With the use of indocyanine green (ICG) (a well-known NIR fluorophore) and
near-infrared (NIR) fluorescence imaging systems, tumours can be identified
intraoperatively14. The exogenous light penetrates several millimetres in
tissue and therefore has the possibility to make non-superficial structures
visible. This technique could possibly also enable fluorescence imaging of
GISTs.

1.3 Purpose of the study
It is necessary to demonstrate in a pilot study that primary GISTs and
metastasis can be visualized with ICG and NIR fluorescence camera systems. The
ultimate aim is to optimize surgery and the treatment of GISTs to improve
patient outcomes (i.e. survival).

The primary objective is to achieve intraoperative detection of histologically
or cytologically proven GIST and metastases with ICG and NIR fluorescence
imaging. The primary end-point is the diagnostic value of ICG in detecting GIST
with NIR fluorescence imaging.
Furthermore, the signal in tumour tissue compared to the signal of the
surrounding tissue, i.e. tumour-to-backgroundratio (TBR) will be determined.
* Primary objective: to assess the diagnostic value of ICG in intraoperative
GIST and metastases detection

* Efficacy endpoint: tumor to background ratio will be determined, which is
defined as the fluorescence signal in the tumor compared to the fluorescence
signal of the surrounding tissue

This is an open-label pilot study consisting of 10 patients diagnosed with
GIST, locally or metastasized, and scheduled to undergo an elective open or
laparoscopic resection in Leiden University Medical Center (LUMC) and Erasmus
Medical Center (EMC). Screening will coincide with routine pre-operative
screening. Patients will receive a single dose injection of 10mg ICG at an
given moment during the hospitilisation prior to surgery or during surgery. The
timing of administration will be determined according to a step-up, step-down
procedure. The first administration will be given intra-operatively since this
has proven to be most effective for peritoneal metastasis in other tumours.
During surgery the surgeon will perform standard of care surgery and a NIR
fluorescence imaging system will be used to record the GIST under fluorescence.

Patients will receive a single dose injection of 10mg ICG at an given moment
during hospitalization and prior to surgery or during surgery. This will be
done on the surgical ward at the LUMC. During surgery the surgeon will perform
standard of care surgery and a NIR fluorescence imaging system will be used to
record the GIST under fluorescence.

The use of ICG for diagnostic purposes is very safe. Within the LUMC ICG is
frequently used by the departments of anaesthesiology, ophthalmology and
surgery. However, it cannot be excluded that hypersensitivity reactions may
occur. Such reactions are generally mild and transient in nature and can be
treated effectively.
Adverse events can be: headache, pruritus, urticarial, faeces discoloration
(green), diaphoresis and anaphylactic reaction have been registered as adverse
events of intravenous ICG. These events are uncommon. In two studies a
treatment for adverse event was necessary in <0,01%.