Prediction of Surgical Resectability After FOLFIRINOX Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: the Role of Diffusion Weighted Magnetic Resonance Imaging, Radiomics and Liquid Biopsy (PeRFormanCe Trial)

Study Overview
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Brief Summary
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In this prospective study new diagnostic tools are to be explored for the patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma (BR or LAPDA) who undergo neoadjuvant chemotherapy with FOLFIRINOX. The diagnostic work-up and therapy for the study population shall not differ from the gold standard during the study, only extra diagnostic tools will be added and their value is to be analysed post hoc. The 5-year survival rate of pancreatic cancer is 9%, but it can be drastically improved if surgery is possible. With its increasing incidence and dismal prognosis, pancreatic cancer is becoming a global oncologic problem where major breakthroughs are still required to improve outcomes. Patients with BR or LAPDA usually undergo neoadjuvant treatment with FOLFIRINOX chemotherapy, with ulterior referral for surgery in case of response. In these situations, surgical resectability is difficult to predict based on CT because of tumoural desmoplastic reaction, which blurs the tumoural contact with the blood vessels without a clear morphologic change. Consequently, patients without tumoural progression on CT and with a decreased tumour marker (CA 19-9) are considered for surgical exploration, in order not to deny the possibility of a curative path to anyone. However, the unspecific value of CA 19-9 and unreliable spatial changes on CT, do not allow an accurate stratification of the patients. Other diagnostic strategies are necessary for a better prediction of resectability in order to avoid negative laparotomies while not denying a possible curative approach when deemed possible. In this project the investigator will apply diffusion weighted magnetic resonance imaging (DW-MRI) as it has been proven to be useful in the evaluation of tumour response beyond morphologic parameters, with detection of functional tumoural changes, differences in vascularisation or fibrosis without a modification of shape. The statistical evaluation of visual information with radiomics optimises the analysis of data which can be compared in time (before and after chemotherapy) as well as with the operative findings (resectable or unresectable tumour). The investigator will focus on patients with BR and LAPDA and evaluate if a combination of clinical and genetic factors can predict successful surgical resection of tumors. Hereto DW-MRI imaging will be complemented with the evolution of the number of circulating tumour cells (CTC's) in blood samples of patients. Furthermore, the investigator aims to validate in the prospective patient cohort, the predictive value of recently published SNPs (single nucleotide polymorphisms) in genes that regulate cancer progression, invasion, and metastasis and of which some alleles were shown to be associated with an increased risk for tumour-associated death compared with those with protective genotypes.

Detailed Description
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The aim of the study is to assess if the combination of radiomics, of DW-MRI and the evolution of the CTC count in blood before and after neoadjuvant chemotherapy in patients with BR and LAPDA relate to the probability of accomplishing a successful surgical excision of the tumour. Furthermore, a sub-group analysis will be performed whereby the risk alleles of SNPs recently published to be associated with worse survival, will be taken into account. The primary endpoint of this project is to improve the prediction of surgical resectability after neoadjuvant chemotherapy with FOLFIRINOX in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. The focus is to increase the diagnostic specificity in order to better select the group of patients who have an unresectable tumour and therefore surely will not benefit from an explorative laparotomy, delaying further chemotherapy treatment. Secondary endpoints are the evaluation of postoperative complications, cost-minimization, disease free and overall survival. All the factors which shall be evaluated in this study (DW-MRI, radiomics, genetic factors, SNP's, CTC's) are individually promising tools for early diagnosis, assessment of prognosis and show a correlation with tumoral response to chemotherapy in pancreatic cancer. Notwithstanding, they have never been applied in an innovative and original research such as this one, where all parameters are combined to improve clinical decision making. This project applies the available knowledge to have an immediate impact in the therapeutic decision tree, avoiding unnecessary open abdomens and consequently improving the quality of life and making treatment more proficient. Rationale: Patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) usually undergo neoadjuvant treatment with FOLFIRINOX with ulterior referral for surgery in case of response to the chemotherapy. Surgical resectability is difficult to predict based on CT because of tumoral desmoplastic reaction, which blurs the tumoral contact with the blood vessels without a clear morphologic change on imaging. Consequently, patients with a decreased CA 19-9 and without tumoral progression on CT shall be considered for surgical exploration. Other strategies are necessary for a better prediction of resectability in order to avoid negative laparotomies. Diffusion weighted magnetic resonance imaging (DW-MRI) has proven to be useful in the evaluation of tumoral response beyond morphologic parameters and the statistical evaluation of information with radiomics can help to optimise the analysis of data. The sampling of circulating tumor cells (CTC's), 'liquid biopsy', shows a correlation with tumoral response to chemotherapy in pancreatic cancer, but its utility in the neoadjuvant setting is not yet clear. Objective: This single center prospective study aims to assess the utility of diffusion weighted magnetic resonance, radiomics and liquid biopsy in the prediction of resectability after neoadjuvant treatment with FOLFIRINOX for BR and LA PDAC. When there is response to chemotherapy with a decrease in CA 19-9 but without morphologic change on CT, some of these tumors can still undergo R-0 resection. The investigator hypothesize that these cases can be pre-operatively selected if there is a reduction of CTC's together with a reduction in vascularity and cellularity at the tumoral zone with vessel contact on DW-MRI. Study design: A prospective interventional study with one study arm. Study population: Patients with a BR or LA PDAC planned for neoadjuvant chemotherapy with FOLFIRINOX and no contra-indication for pancreatic surgery. A sample size of minimum 45 patients who undergo surgical exploration has been calculated (80% power and α = 0.05 (two-tailed)). Intervention: Patients with BR and LA PADC discussed at the multidisciplinary oncologic meeting will undergo the standard of care in practice. On top of the usual work-up before and after the chemotherapy with clinical evaluation, imaging with CT and assessment of CA19-9, a DWI-MRI and a peripheral blood sample for determination of CTC's shall be performed. In case of no tumoral progression on imaging and a decrease of CA19-9 after chemotherapy, the patients will be considered for surgical exploration. During the surgery a blood sample at the supra-pancreatic portal vein will be retrieved for determination of the CTC's before and after the resection, the latter only in case of a possible R0 resection. The patients will have a peripheral blood sample on their first postoperative consultation to analyse the CTC's and CA 19-9. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Compared with standard care, patients in this study will have two extra DW-MRI's and peripheral blood samples. DW-MRI is a safe widespread imaging method and peripheral blood samples are already taken in the context of oncological treatment.

Official Title
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Prediction of Surgical Resectability After FOLFIRINOX Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: the Role of Diffusion Weighted Magnetic Resonance Imaging, Radiomics and Liquid Biopsy

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Diagnostic Test: Imaging analysis of CT-scan and MRI with radiomics and genetic analysis of peripheral blood samples and questionnaires.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of BR or LA PDAC according to NCCN guidelines 2020 Preoperative pathologic diagnosis of adenocarcinoma No medical or anesthetic contra-indication for surgery Able to understand nature of the study procedures Willing to participate and give written informed consent Exclusion Criteria: Distant metastases Medical or anesthetic contra-indication for surgery Progression after FOLFIRINOX until 12 cycles in clusters of 4 cycles Histologic diagnosis of neuroendocrine tumor or duodenal carcinoma Liver or renal insufficiency Known hypersensitivity for MRI contrast Treatment of PDAC with radiotherapy Pacemaker or prosthesis with incompatibility for MRI Claustrophobia Pregnancy or breastfeeding Not able to understand nature of the study procedure Performance status ECOG score: 0 -2 Impossibility to tolerate at least 4 cycles FOLFIRINOX

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Study arm<br>Imaging with CT-scan and MRI-DWI and peripheral blood samples for liquid biopsy | Diagnostic Test: Imaging analysis of CT-scan and MRI with radiomics and genetic analysis of peripheral blood samples and questionnaires.<br>* The images of CT-scans and MRI with DWI shall be processed with specific software to define the direction of diffusion tensors and indicate the direction (red, green, blue coloring for x,y,z, components of the vector) and intensity (anisotropy, brightness of voxels). Further analysis will be performed by fiber tracking which gives a clear indication of functional connectivity of adjacent tissues. Genetic profilling of liquid biopsies: evolution of the number CTCs in blood samples of patients and subsequent phenotyping of the cells; longitudinal analysis of driver mutations and epigenetic changes in cfDNA; genotyping of germline variations Questionnaires for patient reported outcomes and health economic analysis EQ-5D-5L PAN 26 HADS<br>* Other names: Analysis of imaging with radiomics and genetic analysis of peripheral blood samples (liquid biopsy);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prediciton of surgical resectability | Create an algorithm to predict surgical resectability of BR and LA PDAC after neoadjuvant FOLFIRINOX with radiomics analysis of CT and DW-MRI to determine the tumoral vascular invasion in combination with the evolution of CA19-9 and genetic profilling of liquid biopsies (phenotyping and quantification of the CTCs, longitudinal analysis of driver mutations and epigenetic changes in cfDNA). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prediction of R0 resection | Create an algorithm to predict R0 surgical resectability of BR and LA PDAC after neoadjuvant FOLFIRINOX with radiomics analysis of CT and DW-MRI to determine the tumoral vascular invasion in combination with the evolution of CA19-9 and genetic profilling of liquid biopsies (phenotyping and quantification of the CTCs, longitudinal analysis of driver mutations and epigenetic changes in cfDNA). | 2 years | 
| Perioperative complications | Evaluation according to Clavien-Dindo classification | 2 years | 
| Generic measurement of health status | Questionnaire EQ-5D-5L | 4 years | 
| Overall survival |  | 4 years | 
| Disease free survival |  | 4 years | 
| Measurement of quality of life in patients with pancreatic cancer | Questionnaire PAN 26 | 4 years |