Fluorescence-guided (Minimally Invasive) resections of Colorectal liver metastases - II (MIMIC-II)

Radical surgical resection is still seen as the *gold standard* and the only
potential for cure in patients diagnosed with colorectal liver metastases
(CRLM). Currently, 5-year survival rates are between 35-60% in patients
undergoing surgery with curative intent (1). Hence, achieving a radical
resection (margin of at least 1mm) shows superior survival in patients
undergoing surgery (2, 3). Therefore, improving radical resection rates has the
potential to improve overall survival rates. To improve this rate the LUMC and
the AUMC implemented the use of indocyanine green (ICG) as standard-of-care in
CRLM surgery (Appendix A). After injection, due to the accumulation inside
immature hepatocytes surrounding the metastasis, the specific fluorescent *rim*
of ICG is present around the metastasis during surgery (4). A first
multicentered trial initiated by the LUMC focused to improve the radical
resection rates, the MIMIC-trial including 201 patients, showed improved
radical resection rates by assessing the resection margin using near-infrared
(NIR) imaging with indocyanine green as the imaging agent in minimally invasive
surgery (Manuscript under review). Simultaneously, we performed a retrospective
quantification study including 38 patients with CRLM. In this study we utilized
our in-house developed quantification analysis method, to quantitatively
describe the distribution of ICG around CRLM and to investigate the effect of
several patient and tumor characteristics. This study showed a significantly
lower accumulation of ICG around tumors in patients pretreated with
chemotherapy compared to patients who did not receive chemotherapy. This
finding was supported by difficulties to localize tumors in patients who were
pretreated with chemotherapy. To optimize the contrast between the signal
around the tumor and the background signal in the liver (signal-to-background
ratio (SBR)), optimizing the timing and dose of injection of ICG in these
patients is required. Therefore, this study aims to determine the ideal timing
and dose of the injection of ICG in patients who received neoadjuvant
chemotherapy by optimizing the SBR.

The main objective of this study is to determine the optimal dose and timing of
the ICG injection by optimizing signal-to-background ratios in patients with
colorectal liver metastases pretreated with chemotherapy to improve radical
resection rates in metastasectomies and to improve the identification of
malignant lesions.

This study has a dose escalation study design. The study will start with a
relatively low dose and short interval between injection and surgery.
Thereafter, based on the findings of the first step, the dose or the interval
will be increased. This is executed until the ideal dose and timing of ICG
injections in this specific patient group is found.

Preoperative
Patients will receive a single dose of 10 mg, 20 mg or 0,5 mg/kg of indocyanine
green (ICG) 1 to 7 days prior to surgery.

Intraoperative
The standard surgical procedure will be performed as the use of ICG in CRLM
surgery is standard-of-care in the LUMC and the AUMC. During surgery, a
questionnaire will be filled in per lesion to note its visibility with the
intraoperative fluorescence camera. For robotic surgery, the questionnaire will
also include questions about added value of the sensitive mode of the camera
compared to the normal mode.

Postoperative
After surgery, the resected colorectal liver metastases will be cut into slices
(*bread loaves*) at the Department of Pathology. Thereafter, the loaves will be
imaged with the back-table Pearl fluorescence imaging system. The fluorescence
intensities, background fluorescence intensities, distribution of the ICG, and
the signal-to-background ratios will be determined with our in-house developed
standardized quantification method. Moreover, the microscopic slides will be
used for immunohistochemistry (IHC) staining and Lifetime imaging.

There are no additional risks associated with participation in this study
compared to standard care.

There is no additional burden associated with participation to this study. The
patient will receive indocyanine green during an extra visit to the hospital.
This is not different to standard-of-care.

The direct benefit for patients is that the metastases will potentially be
better visible with higher contrast between background and the signal and a
better assessment of the resection margin can be performed, after optimizing
the timing and dose. Furthermore, the higher contrast can enable the
identification of potential small additional lesions. These lesions, which
would not have been identified without the use of or with low contrast of ICG,
can then be resected during surgery.