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Platelet Aggregation Inhibitors

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Aspirin

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Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

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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

Rectal Neoplasms

Neoplastic Processes

Colorectal Neoplasms

Intestinal Neoplasms

Intestinal Diseases

Rectal Diseases

The patients were randomized into a training cohort (n ＝ 211) to train the model. The patients' clinicopathological data were reviewed, including age, sex, obesity, serum carcinoembryonic antigen and cancer antigen 19-9 levels, T- and N-stages evaluated by MRI, yp-T and yp-N stages evaluated by histopathology. The MR-T/N stages of the tumors were assessed by radiologists. The tumor region of interest was manually delineated on high-resolution oblique axial T2WI and generated the VOI using ITK-SNAP. Overall, 1229 features were extracted from each VOI. Biopsy specimens from colonoscopy were sectioned into 5 μm slices and stained with H\&E. Areas with both stromal and tumor cells presented on all four sides were selected to evaluate tumor stroma ratio using an automated scoring method with the highest proportion of stromal components in all measured areas recorded.

The patients were randomized into a validation cohort (n ＝91) to verify the model. The patients' clinicopathological data were reviewed, including age, sex, obesity, serum carcinoembryonic antigen and cancer antigen 19-9 levels, T- and N-stages evaluated by MRI, yp-T and yp-N stages evaluated by histopathology. The MR-T/N stages of the tumors were assessed by radiologists. The tumor region of interest was manually delineated on high-resolution oblique axial T2WI and generated the VOI using ITK-SNAP. Overall, 1229 features were extracted from each VOI. Biopsy specimens from colonoscopy were sectioned into 5 μm slices and stained with H\&E. Areas with both stromal and tumor cells presented on all four sides were selected to evaluate tumor stroma ratio using an automated scoring method with the highest proportion of stromal components in all measured areas recorded.

No intervention was administrated to the two cohorts.

Hongmei Zhang, MD

The goal of this observational study is to construct a multimodal intelligent model to predict the risk of heterochronous metastasis of rectal cancer, which is helpful for individualized diagnosis and treatment and follow-up planning. The main questions it aims to answer are:

* what are the independent risk factors of distant metastasis (DM) in locally advanced rectal cancer (LARC)
* What is the influence weight of the above factors on the heterochronous metastasis of LARC, and how to build a risk-prediction model

This study will not affect or interfere with the routine medical diagnosis and treatment of participants, and will not increase the cost and risk of participants. Participant's information is protected and identified by a unique code.

Data collection process in strict implementation of special management, the full name of quality control. Special personnel are responsible for collecting clinical images and pathological information of patients in the medical record system, and personal identification data will be used to identify and process, in order to protect the privacy of test patients/participants. At the same time, there is a special person responsible for quality control and source data verification. Participants use the project unified number as the unique identification code, personal data and case information by the sample management personnel input and save, the user only see the individual number, no longer show the participants' name and other personal information. Data dictionary that contains detailed descriptions of each variable used by the registry, including the source of the variable, coding information was built. Participants' sample information is stored electronically in a dedicated computer that is not used for other purposes and is provided with a password, which is only available to the person (1 person) who manages the sample. Participants' medical records will be kept at the hospital and will be accessible only to researchers; If necessary, members of the bidding organization, ethics committee or government management department may access the personal data of the participants according to the corresponding authority. The results of the study will be published as statistically analyzed data and will not contain any identifiable participant information.

The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written Standard Operating Procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, good clinical practices (GCP), and the applicable regulatory requirement(s). The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control,data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in use. Noncompliance with the protocol,SOPs,GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.

According to the morbidity of LARC and the risk of distant metastasis, the sample size is 300, and the follow-up interval is at least 3 years.

Plan for missing data: If the proportion of missing data is very large, such as greater than 95%, the investigators can directly remove this field; At 50\~95%, the investigators have two processing methods, one is to remove this field directly; another way is to turn the field into an indicator variable; that is the 0-1 variable. If the field is empty, the field is 0; Otherwise the field is 1. Between 5% and 50% : In this scenario, the investigators need to fill in the missing values. In the process of filling, there are two categories: simple filling and algorithm filling. Simple filling includes: 0 filling, mean filling, median filling, mode filling; Algorithm filling methods such as K Nearest Neighbors (KNN) filling, random forest filling and so on.

Statistics Statistical Product and Service Solutions (SPSS, version 26.0) and R software (version 4.0.5) were used for statistical analyses. Receiver operating characteristic (ROC) curve analysis was used to evaluate the optimum cutoff value of tumor stromal ratio (TSR) in discriminating DM risk based on the maximum Youden index. Heat maps showed the distribution of variables between patients with or without DM within 3 years. The independent DMFS risk factors were determined using Kaplan-Meier (K-M) curves and Cox regression analysis sequentially based on the data of the training cohort. Statistical significance was set at P\<0.05. Inter-observer variability was assessed using κ statistics for categorical and ranked variables, and ICC for continuous variables.

TSR assessment Biopsy specimens from colonoscopy were sectioned into 5 μm slices and stained with H\&E. Areas with both stromal and tumor cells presented on all four sides were selected to evaluate tumor stroma ratio (TSR) using an automated scoring method. The highest proportion of stromal components in all measured areas was recorded as the final TSR value in this study.

Magnetic Resonance analysis Machine-learning method was used to analyze the MR images, which includ image acquisition and reconstruction, image segmentation, feature extraction and qualification, analysis, and model building.

Pretreatment magnetic resonance (MR) examinations were conducted using 3.0 T scanners with an 8-channel phased-array wrap-around surface coil. An intramuscular injection of 10 mg raceanisodamine hydrochloride was administered to minimize bowel movement unless contraindicated. Sequences acquired included T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) with and without fat saturation, and diffusion-weighted imaging (DWI) .

The tumor region of interest (ROI) was manually delineated slice-by-slice on high-resolution oblique axial T2WI (orthogonal to the rectal lumen) by the first radiologist and subsequently confirmed by the second radiologist with more experience on Insight Segmentation and Registration Toolkit-Standford Network Analysis Project (ITK-SNAP), from which the three-dimensional whole tumor volume of interest (VOI) was obtained. Disagreements were resolved through discussions. The radiologists were blinded to the clinicopathological information. Overall, 1229 features were extracted from each VOI, which can be classified into four categories: (1) shape characteristics; (2) first-order statistical characteristics; (3) texture features; and (4) high-order statistical characteristics.

The extracted features' inter- and intraclass correlation coefficients (ICCs) were calculated to assess the reproducibility of the features. Features with \<0.75 ICCs were considered non-stable and were eliminated. Pearson's correlation analysis was used to identify redundant features, and for any two features with a coefficient of 0.9, the one with the larger mean absolute coefficient was eliminated. The least absolute shrinkage and selection operator algorithm (LASSO) was applied to select the most significant predictive parameter from the training cohort, and 5-fold cross-validation was used to perform dimensionality reduction. A signature (i.e. Radscore) was calculated using a linear combination of the final selected features weighted by the respective coefficients.

Model built and validation According to the results of Cox regression, a nomogram (Mr) integrating all independent risk factors except TSR, a TSR nomogram (Mt) integrating all independent risk factors except the Radscore, and a combined model (Mrt) incorporating all the independent risk factors were constructed to predict the 3-year DM risk. The discriminative ability of these models was evaluated and compared using ROC curves. Calibration plots were drawn to explore the calibration ability of the three models. Decision curve analysis was performed to explore the clinical benefits by calculating the net benefit of each decision strategy at each threshold probability.

Constructing a Multimodal Imaging System to Predict the Risk of Heterochronous Metastasis of Rectal Cancer

Role of Microenvironment Analysis and MRI Radiomic Study in the Risk Stratification of Distant Metastases in Rectal Cancer

Defined as cancer recurrence at sites outside the pelvis based on radiological and/or histopathological evidence.

Distant metastasis-free survival (DMFS) was calculated from the date of surgery to the date of the first detection of distant metastasis, death from any cause, or last follow-up.

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
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
Constructing a Multimodal Imaging System to Predict the Risk of Heterochronous Metastasis of Rectal Cancer	NCT06293612	Locally Advance... Distant Metasta...	No intervention...	-	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
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 distant metastases