Perioperative Platelet Inhibition With Acetylsalicylic Acid Targeting Intraoperative Tumor Cell Seeding in Patients With Resectable Tumors of the Pancreatic Head - a Randomized, Controlled Multicenter Study

With few symptoms, rapid progression and early metastasis pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is the third leading cause of cancer death worldwide. In early stages of PDAC, surgical resection followed by adjuvant chemotherapy is the mainstay of treatment. Unfortunately, the majority of patients develop tumor recurrence (most frequently in the liver) despite complete resection and adjuvant treatment. This early postoperative recurrence is a result of preoperatively present, undetected micrometastases, and, most importantly, iatrogenic dissemination of circulating tumor cells (CTCs) by surgical manipulation of the tumor during resection. CTCs can be detected in the majority of PDAC patients and correlate with worse overall survival.

Survival of CTCs in the hostile environment of circulation requires resistance to physical forces (i.e., turbulence, shear stress), but also immune escape mechanisms to avoid clearance by immune cells such as natural killer (NK) cells. CTCs are highly heterogeneous and, by the majority, non-tumorigenic. The number of other nucleated blood cells such as leukocytes greatly exceeds the number of CTCs; in many solid tumors including PDAC, the average number of (detectable) CTCs is less than 10 cells / mL of whole blood. This demonstrates the inefficiency of the metastatic process, which is at least partially a result of early clearance of CTCs after entering the blood stream.

After entering circulation, the first cells that CTCs come in direct contact with are platelets. This leads to activation of platelets and aggregation on the CTCs, which are thus enveloped and protected from the hostile environment in the circulation. This effect is seen in many, but not all CTCs, the underlying molecular mechanisms are currently being investigated. It is conceivable that not only shear forces and turbulence have less influence on CTCs enveloped by platelets, but also that immune cells (e.g. NK cells) in the bloodstream are less likely to detect and eliminate CTCs and therapeutic antibodies have fewer binding sites.

Arguably the most decisive days in the lives of cancer patients are when they undergo surgery for tumor resection. For most solid tumors, surgery is part of all curative treatment regimens. However, the occurrence of distant metastases often brings surgery to its limits, either because not all metastatic lesions are resectable, or due to rapidly recurring metastatic disease after surgery. Many patients develop disseminated disease early after curative resection of an initially non-metastatic tumor. There are several potential reasons behind this phenomenon, most prominently the immunosuppression resulting from major surgery and the iatrogenic dissemination of CTCs during surgery. Surgery-related immunosuppression is addressed by continuous improvement of perioperative medicine such as prehabilitation or early recovery / fast-track programs as well as minimally invasive surgical procedures, whenever possible. However, only few measures have been taken so far to reduce iatrogenic dissemination of tumor cells during PDAC surgery.

During cancer surgery, the tumor is inevitably touched, manipulated or even squeezed as it has to be mobilized from its surroundings while limiting the damage to neighboring structures. This manipulation of the tumor leads to iatrogenic CTC dissemination. The only clinically used measure to reduce tumor cell dissemination during surgery is currently an early ligation of tumor-draining veins prior to manipulation and mobilization of the tumor mass. This method can only be employed in tumor entities that are drained by one or few well-defined veins such as lung cancer or colorectal cancer, in which this method is successfully applied. In other tumors, which are drained by multiple small and/or initially inaccessible vessels (e.g., hepatic tumors) or in which the tumor-draining vein cannot be occluded for prolonged periods of time (e.g., the portal vein draining tumors of the pancreatic head), this "vein first" or "no touch" approach is not applicable. Since especially in pancreatic tumors, hepatic recurrence often occurs after curative resection and inevitably leads to the death of the patient, this represents a major clinical problem.