Evaluation of Contrast Enhanced Intraoperative Ultrasound (CE-IOUS) as a Clinical Decision-making Tool for Patients With Pancreatic Cancer Undergoing Surgery: A Prospective, Proof-of-concept Trial

1. Introduction Pancreatic cancer is one of the most lethal types of cancer. In fact, is usually detected in an advanced stage, thus being associated with a poor prognosis. Therefore, every surgical intervention has to be precise. Furthermore, the staging of a tumor indicates the resectability of the tumor and the optimal extent of the surgery. In this context, spiral computer tomography (CT) and magnetic resonance tomography (MRI) are employed preoperatively to identify liver metastases but they demonstrate lower sensitivity and specificity than intraoperative ultrasound examination (IOUS) in a number of settings.

IOUS was applied in pancreatic tumors during 1980s for the first time. At liver metastases detection IOUS significantly exceeds CT or MRI in sensitivity, reaching 94-96 % even at small focci with 3-5 mm dimensions. According to Kolesnik, 2015 study IOUS is a convenient method to use and demonstrates superiority over CT and MRI, such as obtaining dynamic image with possibility of correction and new data acquisition at any moment of operation.

Recently, there is a growing trend of implementing contrast-enhanced IOUS (CE-IOUS) in order to identify potential liver metastases intraoperatively. Nonetheless, no real clinical studies on CE-IOUS have been published to evaluate its efficacy in pancreatic surgery. In fact, with CE-IOUS all small vessels and capillaries can be visualized using microbubble-based ultrasound contrast agents. This could benefit by dynamic real-time imaging modality for pancreatic metastases with abnormal vascularization, because isoechoic lesions are underappreciated on IOUS. Additionally, neoadjuvant chemotherapy could induce steatosis (which impairs ultrasound imaging) and cause a certain number of metastases to vanish posing diagnostic and therapeutic challenges, that require the surgeon to adapt the surgical procedure accordingly.

To evaluate the clinical utility of CE-IOUS, we will conduct the first, to the best of our knowledge, prospective trial to evaluate the efficacy and safety of CE-IOUS in the context of pancreatic surgery.

3. Material and methods Following approval by the Ethics Committee, the present study will be performed in the University Hospital of Larissa, Greece. Our primary endpoint is to assess the clinical utility (CU) of CE-IOUS regarding the identification of liver metastases in patients undergoing curative surgery for pancreatic cancer. CU is defined as the justified change in planned surgical strategy (conversion from therapeutic to palliative surgery) using CE-IOUS, based on the identification of new liver metastases that were not described by preoperative imaging modalities. Our secondary objectives are to outline technical modalities of CE-IOUS regarding the dosage and duration of contrast agent administration, compare CE-IOUS with CT, MRI, and IOUS, and to assess the CU of CE-IOUS in the subgroup of patients with missing metastases after neoadjuvant treatment.