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Platelet Aggregation Inhibitors

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Aspirin

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Anti-Inflammatory Agents, Non-Steroidal

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100 mg acetylsalicylic acid per os once daily, starting 1-4 weeks before surgery until 6 months after surgery

Identically looking placebo pill, starting 1-4 weeks before surgery until 6 months after surgery

Acetylsalicylic acid

Placebo

Sebastian Schoelch, MD

Johanna Betzler, MD

This randomized, controlled clinical trial compares the perioperative treatment with acetylsalicylic acid (aspirin) in patients with cancer of the pancreatic head. The main question it aims to answer is: Do patients treated perioperatively with aspirin develop less metastasis after curative resection of pancreatic head tumors?

Participants will be asked to :

* take a daily aspirin tablet starting 1-4 weeks before surgery until 6 months after surgery
* participate in regular follow-up visits.

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.

Approximately 5% of cancer patients are on permanent medication with platelet inhibition (PI), most prominently acetylsalicylic acid (ASA, aspirin) for a cardiac indication. ASA is usually taken orally at a dosage of 100 mg once a day and several studies and meta-analyses have shown that perioperative ASA intake at this standard dosage leads only to a slightly increased risk of bleeding. Therefore, platelet aggregation inhibition with aspirin alone is continued perioperatively nowadays and is classified as safe.

ASA medication leads to increased overall survival in several cancer entities. A meta-analysis of 22 studies evaluating survival of colorectal cancer patients in dependence of ASA treatment revealed a significant survival advantage for patients with continuous ASA treatment in comparison with patients who did not take ASA or terminated ASA intake prior to or at the time point of tumor diagnosis.

So far, despite ample preclinical evidence, only few clinical studies have investigated the effect of ASA treatment on PDAC. Recently published, retrospective data indicates a significantly improved survival after curative resection of PDAC for patients with perioperative low-dose ASA medication, which is directly attributable to a reduced postoperative incidence of distant metastases. A preliminary meta-analysis (incorporating a second study investigating ASA treatment in PDAC) confirms the significantly improved disease-free survival after resection of PDAC in patients under permanent platelet inhibition with ASA. There is also evidence of a reduced incidence of distant metastases under ASA treatment in other tumor entities.

The investigators hypothesize that the reason for the reduced incidence of distant metastases achieved by ASA is the inhibited platelet-mediated protection of CTCs.

In conclusion, perioperative platelet inhibition with ASA may drastically reduce the postoperative incidence of hematogenous metastases with very low toxicity and risk to the patients with PDAC. Despite this favorable benefit-risk ratio, no prospective, randomized-controlled trials investigating this treatment have been conducted. As a result and despite its potential benefits, perioperative ASA treatment in patients undergoing resection of the pancreatic head for malignant indications is currently not generally recommended.

The aim of this multicentric randomized-controlled trial is therefore to investigate the impact of perioperative ASA treatment on the occurrence of hematogenous metastases, survival and perioperative complications in patients undergoing pancreatic head resection (pylorus-preserving pancreaticoduodenectomy / Traverso-Longmire procedure) for PDAC.

Perioperative Platelet Inhibition With Acetylsalicylic Acid in Patients With Resectable Tumors of the Pancreatic Head

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

The primary efficacy endpoint of the study is hematogenous metastases-free survival (HMFS), which is defined as the time from the day of surgery to the date of diagnosis of hematogenous distant metastases (e.g., hepatic or pulmonary metastases) or date of death from any cause, whichever comes first. Peritoneal metastases (peritoneal carcinomatosis) are not regarded hematogenous metastases. The HMFS status is evaluated at regular follow-up examinations for 36 months postoperatively and further recorded during clinical follow-up visits until the end of the trial.

Overall survival (OS) is defined as the time from the day of surgery until death from any cause.

Cancer-specific survival (CSS) is defined as the time from the day of surgery until death due to the treated cancer or a treatment-related complication.

Disease-free survival (DFS) is defined as the time from the day of surgery to the date of diagnosis of tumor recurrence (in any location) or to the date of death from any cause, whichever comes first.

Intraoperative blood loss is documented in milliliters during surgery and subsequently analyzed. Intraoperative transfusions of blood or blood components will also be recorded and analyzed.

The duration of surgery (first incision to wound closure) is recorded and subsequently analyzed.

Surgical complications include postoperative bleeding, anastomotic insufficiencies, pancreatic fistulas, wound infections, fascial dehiscence, delayed gastric emptying (DGE) and gastrointestinal atony.

Medical complications include pneumonia, myocardial infarction, cardiac decompensation, new onset atrial fibrillation, respiratory insufficiency, renal failure, liver failure and sepsis. Other complications include allergic or intolerance reactions, cerebral infarctions, delirium and pain, prolonging the length of hospital stay.

German Cancer Research Center

Jaundice

Hyperbilirubinemia

Jaundice, Obstructive

Head and Neck Neoplasms

Skin Manifestations

Gastrointestinal Agents

Pancrelipase

Pancreatin

endoscopic retrograde cholangiopancreaticography with plastic stent insertion

ultrasound guided percutaneous transhepatic catheter insertion

resection of the head of pancreas and the duodenum followed by triple anastomosis

pancreaticoduodenectomy

Wael N Abdelsalam, doctor

Patients with potentially resectable pancreatic head cancer and high bilirubin level, were stratified into two equal groups according to the method of biliary drainage: endoscopic stenting or percutaneous drainage.

Along with history taking and complete clinical examination, the results of complete blood count, international normalized ratio , renal and liver function tests were obtained. Patients with coagulopathy were corrected by fresh frozen plasma and repeated vitamin K injections to reach an INR of at least 1.4 before the intervention, otherwise, they were excluded. Besides, ultrasound and computed tomography of the abdomen/pelvis (pancreatic protocol) were routinely undertaken. Tumors were staged for resectability according to TNM staging system.

Patients were randomly divided by closed envelope method into two groups; patients were allocated to the first group (ERCP) who underwent Endoscopic Retrograde Cholangio-Pancreatography coupled with placement of a 10-French plastic stent; and to the second group (PTD) who underwent Fluoroscopy-guided Percutaneous Transhepatic Drainage.

Preoperative biliary drainage Parenteral broad spectrum antibiotics were administered prior and after each intervention. ERCP was performed under general anesthesia in the operation room and a 10-french (3.2 mm) covered polyethylene stent with side flaps to prevent migration was placed below the level of biliary bifurcation. Stents were inserted over a guidewire via an Olympus 4.2 mm channel endoscope, by standard techniques.

PTD was placed in the interventional radiology department under local anesthesia via the left duct sub-xiphoid approach, only via the external approach. A 6 french gauge catheter was positioned with its tip above the biliary obstruction. After PTD, patients were instructed to drink a lot of fluids to replace fluid loss or they were given temporary intravenous fluid supplementation.

After either procedure, patients were either discharged home or kept in hospital. Those who were discharged were readmitted for preoperative preparation. Patients were followed up clinically as well as by laboratory results. The total and direct bilirubin level and other liver function tests were repeated after ten days from the procedure to estimate the decline in their levels. Post-intervention complications either PTD-related such as bleeding, cholangitis, bile leak and catheter occlusion/displacement; or ERCP-related such as pancreatitis, cholangitis, bleeding and stent displacement; were recorded.

Surgery After improvement of liver functions, patients were scheduled for PD. All operations were performed through a hockey-stick incision by consultant surgeons experienced in pancreatic surgery. The standard surgical procedure was pancreaticoduodenectomy with pylorus preservation. The effects of pre-operative drainage were evaluated during the operation in terms of operative resection time, blood loss, difficulties of dissection and intra-operative bleeding. While the endoscopic stent is removed intra-operatively after transection of the common hepatic duct, the catheter of PTD is left and inserted in the hepaticojejunostomy (stented anastomosis) to be removed two weeks later. Perioperative complications (\< 30 days) were stratified for each group according to Clavien-Dindo classification.

Endoscopic Versus Percutaneous Biliary Drainage for Resectable Pancreatic Head Cancer

Endoscopic Versus Percutaneous Biliary Drainage for Resectable Pancreatic Head Cancer With Hyperbilirubinemia and Impact on Pancreaticoduodenectomy: A Prospective Cohort Study

to keep the confidentiality of each patient

measuring the difficulty of dissection, number of operative complications encountered

detection of postoperative complications in the early postoperative period

Hani Alhadad

assistant professor

Herbal and Botanical

Cola

The basic principle of the "artery first" approach is the early identification of the SMA at its origin at the aorta with the further resection then being guided by its anatomic course.

The dissection is carried cephalad along the aorta until the origin of the SMA is reached. The posterior and right aspect of the SMA is then dissected over a few centimeters. On the right side of the SMA a replaced or accessory right hepatic artery, if present, will be identified and preserved. This maneuver should be done, if infiltration of the SMA is suspected as the procedure can be terminated at this point. Once the situation at the SMA is assessed and resectability is confirmed resection will be done.

A wide Kocher manoeuver is performed to fully mobilize the duodenum and the head of the pancreas. The colonic mesentery on the right side is separated from the anterior surface of the duodenum and the head of the pancreas. The size of the tumor and its relation to the superior mesenteric artery, the celiac trunk, the mesentery, the portal vein, and the superior mesenteric vein is assessed. If resectability is given a Kausch-Whipple's resection is performed.

early identification of SMA to evaluate infiltration

Artery first procedure

conventional exposure and preparation (Kocher's manoeuvre) before transection of pancreatic parenchyma

No artery first procedure

Nuh N. Rahbari, MD

Heike Elbers

Rahbari

To show whether the artery first approach leads to equal or less rate of positive resection margins in pancreatic head cancer than the standard technique (ppWhipple only with standard Kocher's manoeuvre)

This is a prospective non-randomized trial with two study groups. The trial is designed to show if the ARTERY FIRST approach reduces the rate of R1 resections in patients undergoing surgery for cancer of the pancreatic head.

After the diagnosis of cancer of the pancreatic head by clinical, laboratory and imaging evaluation patients who are scheduled for resection will be screened for inclusion into the trial. Informed consent is obtained at least on the day before surgery and patients meeting the eligibility criteria will be enrolled into the study.

The ARTERY FIRST Approach for Resection of Pancreatic Head Cancer

positive resection margins as described by the pathologists of the University of Heidelberg

Exploratory analyses of frequencies of complications and serious adverse events

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Perioperative Platelet Inhibition With Acetylsalicylic Acid in Patients With Resectable Tumors of the Pancreatic Head	NCT05637567	Pancreatic Canc...	Acetylsalicylic... Placebo	18 Years - 80 Years	German Cancer Research Center
Endoscopic Versus Percutaneous Biliary Drainage for Resectable Pancreatic Head Cancer	NCT04823832	Pancreatic Head... Obstructive Jau...	pancreaticoduod...	18 Years - 80 Years	Alexandria University
Perioperative Platelet Inhibition With Acetylsalicylic Acid in Patients With Resectable Tumors of the Pancreatic Head	NCT05637567	Pancreatic Canc...	Acetylsalicylic... Placebo	18 Years - 80 Years	German Cancer Research Center
The ARTERY FIRST Approach for Resection of Pancreatic Head Cancer	NCT01332773	Pancreatic Head...	Artery first pr... No artery first...	18 Years -	Heidelberg University
Perioperative Platelet Inhibition With Acetylsalicylic Acid in Patients With Resectable Tumors of the Pancreatic Head	NCT05637567	Pancreatic Canc...	Acetylsalicylic... Placebo	18 Years - 80 Years	German Cancer Research Center

Spots Global Cancer Trial Database for pancreatic head cancer