The OCEANS II trial: Fluorescence guided surgery with indocyanine green for better visualization of small intestine neuroendocrine tumors: a feasibility study

Neuroendocrine tumors of the small intestine (SI-NETs) are rare tumors.
Patients often do not present until distant metastases are already present in
the abdomen. Curative surgery is no longer possible for these patients. The
clinical problem is that it is often difficult to diagnose these distant
metastases. For this reason, the guidelines state to operate with a laparotomy,
after which it becomes clear that distant metastases are present. It is decided
not to continue the operation.

Near-infrared (NIR) fluorescence imaging (FLI) can be used to improve
visualization of tumors and vital structures during surgery. A previous study
showed that FLI using methylene blue (MB) is an effective method to detect
metastases of SI-NETs. However, primary SI-NETs and multiple primaries could
not be detected with NIR FLI using MB. Indocyanine green (ICG) can be a
possible alternative of MB in detecting both primary SI-NETs and metastases.
Therefore, this study aims to investigate whether a combination of intravenous
indocyanine green and fluorescence imaging can visualize neuroendocrine tumors.
If this is possible, in the future it can be assessed with fluorescence by
means of laparoscopy whether distant metastases are present in the abdomen. In
this way, a group of patients can be sparred from an unnecessary laparotomy.
Moreover occult metastases can be identified for resection when curation is
possible.

The aim of the study is to investigate whether SI-NETs can be visualized with
indocyanine green (ICG) and near-infrared (NIR) fluorescence imaging (FLI).

This is an open-label dose escalation study to investigate whether small
intestine NETs can be visualized with ICG and NIR FLI. A maximum of 31 patients
will be included who are eligible for resection of the SI-NET in the Erasmus
MC. ICG will be administered at least 18 hours prior to surgery. During the
operation standardized pictures of the primary tumor will be taken. The
Tumor-to-Background ratio (TBR) will be measured on each photo. This is a way
to measure the fluorescence intensity. Furthermore, pictures will be taken of
the (lymph node) metastases. Surgical policy will not be changed based on
fluorescent imaging. Biopsies will be taken (if possible) of fluorescence
lesions that are not clinically suspected for tumor.

The first part of the study is the dose finding part. The first 3 patients will
receive the middle dose of 2.5 mg/kg. Standardized fluorescence images will be
taken and the TBR will be determined. In case of a TBR of 2.0 or higher, the
next 3 patients will receive the lowest dose of 1.0 mg/kg. In case of a TBR of
lower then 2.0, the next 3 patients will receive the highest dose of 4.5 mg/kg.
Hereafter, an interim analysis will be performed to assess the optimal dose.
The last 20 patients will receive the optimal dose.

All patients of the first part of de study will first undergo laparoscopy to
investigate whether the primary tumor is visible, followed by the regular
laparotomy. In case of an adequate laparoscopic detection of the primary tumor,
an additional group of 5 laparoscopic patients will be added to the second part
of the study.

Patients will be administered to the hospital a day prior to surgery and will
receive a single intravenous dose of ICG at least 18 hours prior to surgery
(1.0 mg/kg, 2.5 mg/kg or 4.5 mg/kg).
The abdomen of the first 6 patients will first be inspected using the
laparoscope via the laparotomy wound to visualize the primary tumor. No extra
incisions will be made. Hereafter, laparotomy will be performed an standardized
pictures with the NIR camera will be made of the primary tumor(s) and (lymph
node) metastases.

Indocyanine green is a near-infrared fluorescence imaging reagent approved by
the European Medicines Agency (EMA) in doses of max. 5.0 mg/kg. In this study,
the maximum dose will be 4.5 mg/kg and therefor the risks of side effects will
be minimal. Possible side effects will be, among others, hypersensitivity
reactions. For this reason, we excluded patients known with clinically
significant allergy or anaphylactic reactions to any of the components of the
agent, including iodine. In addition, precautionary measures were taken,
including supervised administration by qualified staff and availability of
adequate medications in case of a hypersensitivity reaction. Regardless of the
findings during surgery, the surgical plan will not be altered and therefore
the patient risks are minimal and the patients benefits are none.