Intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus chemotherapy alone: a randomized controlled trial (METAPANC)

Intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus chemotherapy alone: a randomized controlled trial (METAPANC) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus chemotherapy alone: a randomized controlled trial (METAPANC) Michael Ghadimi, Uwe Pelzer, Marc G. Besselink, Jens Siveke, Ralph Telgmann, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5815668/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Feb, 2025 Read the published version in BMC Cancer → Version 1 posted 4 You are reading this latest preprint version Abstract Background Based on current guidelines, surgical treatment of hepatic oligometastases in patients with pancreatic ductal adenocarcinoma (PDAC) is not primarily recommended. Systematic chemotherapy is the therapy of choice for these patients. The relevance of subsequent surgical resection after chemotherapy remains unclear. This multicentre, randomized, controlled phase III trial is planned to evaluate whether resection of the primary tumor and liver metastases can improve overall survival in patients with PDAC with hepatic oligometastases in a multimodal treatment setting. Methods After an induction therapy with eight cyles of mFOLFIRINOX and a response assessment after four and eight cycles, patients will be randomized to either Arm 1 (perioperative mFOFIRINOX plus resection of the primary tumor with resection or ablation of all hepatic metastases) or Arm 2 (continuation of 4 cycles of the standard-of-care mFOLFIRINOX chemotherapy). This clinical trial will focus on a well-defined patient group with metastatic disease limited to the liver as the target organ, with a maximum of three metastases. Discussion METAPANC is the first international, randomized, controlled, open-label, multicentre, phase III clinical trial for curative intended surgical therapy of oligometastatic pancreatic cancer in Europe and America. The multimodal surgical treatment of patients with oligometastatic pancreatic cancer could significantly extend the overall survival of this patient group. A possible recommendation of this multimodal treatment regimen outside of clinical trials requires data from randomized controlled trials first. To identify patient subgroups that might benefit from multimodal surgical therapy, additional information on tumor genetics could supplement valid parameters. Trial registration: EU Clinical Trials No. 2023-503558-10-00 Oligometastasis Pancreatic Ductal Carcinoma (PDAC) Oligometastatic Pancreatic Cancer Liver Metastasis Multimodal Treatment Chemotherapy Pancreatic Surgery Clinical Trials Figures Figure 1 Figure 2 Background Pancreatic ductal adenocarcinoma (PDAC) has a poor overall survival rate of 8% due to early metastasis and therapy resistance. The successful introduction of intensified chemotherapeutic regimens, such as FOLFIRINOX and gemcitabine/nab-paclitaxel, has led to a significant, though still moderate, improvement in response rates, disease control, and overall survival. Current standards recommend systemic chemotherapy but no surgical approach in metastatic (stage IV) PDAC. FOLFIRINOX has the highest rates of response and overall survival and is a current standard-of-care chemotherapy regimen in patients with metastatic PDAC and good performance status [ 1 ]. Given the high rates of recurrence, and without available biomarkers for potential target populations that may benefit from extensive and complex surgical interventions, synchronous or metachronous metastasectomy is not recommended and only rarely performed in individual cases However, pancreatic resections, including pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy, resection of metastases have reached a high-quality level with considerably low morbidity and < 5% mortality in high-volume centres. Several case studies have reported favorable outcomes for selected patients with PDAC undergoing resection of metastases [ 2 ] [ 3 ] and highly selected patients with oligometastatic PDAC and good response to intensified chemotherapy may potentially benefit from multimodal approaches. Recently, the Chinese Study Group for Pancreatic Cancer (CSPAC) reported on a multicentre, randomized, controlled phase III trial [ 4 ], using a similar definition as used in the here proposed METAPANC trial design. In CSPAC-1, various first-line chemotherapeutic regimen are used, and time of treatment and randomization prior to the surgery or control arm is variable. CSPAC-1 aims is to establish a treatment strategy to select patients who might benefit from simultaneous resection of primary pancreatic cancer and liver metastatic sites. The trial is expected to run for at least 7 years. METAPANC uses a similar yet distinct study protocol and is the first international, randomized, controlled, open-label, multicentre, phase III clinical trial for curative intended surgical therapy of oligometastatic pancreatic cancer in Western Europe. Objectives and endpoints Objectives The primary objective of the METAPANC trial is to evaluate the efficacy of neoadjuvant multimodal chemotherapy followed by complete tumor and metastases resection in patients with hepatic oligometastatic PDAC. The principal research question is whether overall survival in patients with oligometastatic pancreatic cancer is superior in patients treated with perioperative modified FOLFIRINOX (mFOLFIRINOX) followed by complete surgical resection compared to standard-of-care mFOLFIRINOX first-line chemotherapy alone. In a prospective randomized trial design, we aim to evaluate survival and quality of life after multimodal therapy with perioperative mFOLFIRINOX chemotherapy (two times 4 cycles prior to resection of the primary tumor and resection / ablation of the metastases), followed by 4 cycles of adjuvant mFOLFIRINOX chemotherapy (total of 12 cycles) vs. mFOLFIRINOX without surgery / ablation (total of 12 cycles) as standard of care first-line treatment (Fig. 1). All patients will be followed-up for at least 2 years. Secondary objectives are to determine the safety of the treatment concept and health-related quality of life. Hereby we explore procedure-related complications and mortality. Furthermore, we seek to evaluate biomarkers and imaging data for better identification of a potential target population which may benefit from intensified multimodal treatment strategies. Endpoints The primary endpoint is overall survival (OS) as the time from randomization to death of any cause. Secondary endpoints include progression-free survival (PFS), quality of life (EORTC QLQ-C30, PAN-26, Q-TWIST) and translational endpoints. PFS is defined as the time from randomization to death or progression whatever occurs first. During the induction phase of the study, response will be assessed according to RECIST v1.1. Progression is based on radiological assessment according to RECIST v1.1. For translational research purposes, tissue from the initial diagnostic biopsy and the resection specimen will be collected, if possible from both tumor tissue from the primary tumor and from metastases (this should be feasible at least for patients that were surgically explored). Aims are to identify predisposing factors for metastasis, response to mFOLFIRINOX treatment and adaptive molecular changes under chemotherapy. Characterization will address the molecular subtype and clonal evolution to better understand mechanisms of metastasis and to identify chemotherapy response / resistance patterns. Blood samples are taken before each chemotherapeutic cycle, before surgical resection and during maintenance therapy and surveillance. Analysis will focus on circulating tumor DNA, analysis for monitoring of mutational patterns of pancreatic cancer during cancer therapy (prognostic for disease survival, predictive for primary or secondary drug resistance) in comparison to currently used tumor markers (CA19- 9) using e.g. a multiplex amplicon-based sequencing approach. Table 1 Objectives and endpoints of the METAPANC trial Methods/study design METAPANC is an international, randomized, controlled, open-label, multicentre, phase III clinical trial. This trial is composed of two arms, and patients will be randomized to either Arm 1 (perioperative mFOLFIRINOX plus resection of all cancer lesions) or Arm 2 (standard-of-care mFOLFIRINOX chemotherapy). Prior to randomization, all patients will undergo 8 cycles of mFOLFIRINOX induction therapy with response assessment after the fourth and eighth cycles. Patients in Arm 1 will be treated for approximately 12 months (induction chemotherapy with mFOLFIRINOX) followed by surgery and adjuvant of 4 cycles of mFOLFIRINOX-chemotherapy. Patients in Arm 2 will be treated for approximately 6 months with 12 cycles of mFOLFIRINOX-chemotherapy. Follow-up visits will be performed for all patients for a minimum of two years. Fig. 1 Flow chart of the entire study including the optional percutaneous interventional ablation of metastases in Arm 1. In these cases the liver ablation of selected metastatic lesion(s) can be planned 1-3 weeks after the last mFOLFIRINOX cycle, but within six weeks between the last cycle of chemotherapy and surgery. Alternatively, the ablation can be conducted intraoperatively. Trial population Patients with hepatic oligometastatic pancreatic ductal adenocarcinoma with a maximum of 3 liver metastases who meet the inclusion criteria and do not meet the exclusion criteria will be eligible to participate in this clinical trial. Inclusion criteria Patients eligible for inclusion in this trial must meet all the following criteria: 1. Age ≥ 18 years and ≤ 80 years 2. histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas 3. medical and technical operability of the primary tumor 4. limited synchronous liver metastatic status (≤3 resectable/ ablatively treatable liver metastases) OR limited metachronous liver metastatic status (≤3 resectable/ ablatively treatable liver metastases), but must have completed adjuvant chemotherapy at least 6 months before start of study treatment 5. previous neo-/adjuvant anti-cancer therapy for non-metastatic PDAC with last dose administered ≥6 months before the start of study treatment are allowed 6. adequate hematological (WBC ≥3000/μl, platelets ≥100.000/μl, hemoglobin ≥8 g/dl), hepatic (bilirubin ≤2.5 x mg/dl) and renal function (creatinine clearance >50 ml/min) parameters 7. ECOG performance status ≤1 8. written informed consent obtained according to international guidelines and local laws 9. measurable disease according to RECIST v1.1. prior to induction therapy Exclusion criteria Patients eligible for this trial must not meet any of the following criteria: 1. Unresectable pancreatic cancer 2. Prior chemotherapy within 6 months or prior radiation therapy within 28 days (e.g. in adjuvant settings). 3. Exception for previous systemic anti-cancer treatment for metastatic PDAC: Patients with need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFIRINOX or modified FOLFIRINOX prior to study entry (Cycle 0) and may be enrolled. 4. Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively and has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible 5. Patients with either peritoneal carcinomatosis or >3 liver metastases or extrahepatic metastasis) 6. Known hypersensitivity to the active substances or any of the excipients 7. Impaired cardiac function or clinically significant cardio-vascular disease, such as: – Congestive heart failure requiring treatment (NYHA grade >2), or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation) – Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery < 3 months prior to study entry 8. Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registries and diagnostic trials is allowed 9. Inability to understand the study and/or comply with the protocol procedures 10. Subject pregnant or breast feeding, or planning to become pregnant within 6 months 11. Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly) 12. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. These conditions should be discussed with the patient prior to registration in the trial Trial design Patients with locally resectable but oligometastatic PDAC will be screened for study enrollment (approximately n= 400) according to the inclusion and exclusion criteria. If enrolled and registered for the study, patients will receive 2 x 4 cycles mFOLFIRINOX with response assessment after 4 and 8 cycles. Patients with progressive disease (PD) will be excluded from the trial. 272 patients with complete response (CR), partial response (PR) or stable disease (SD) according to RECIST v1.1 will be randomized (1:1) into Arm 1 (experimental arm) or Arm 2 (control arm). In the experimental arm patients will receive at least eight cycles of mFOLFIRINOX followed by resection of the primary tumor and metastatic lesions, preferably in one procedure. Local ablation of liver metastases is allowed. After resection, patients receive adjuvant chemotherapy of 4 cycles of mFOLFIRINOX followed by surveillance / follow-up. In the control arm patients will receive at least 8 cycles of mFOLFIRINOX followed by adjuvant chemotherapy (mFOLFIRINOX for 4 cycles) followed by surveillance / follow-up. All Patients will undergo a follow up of 2 years. Figure 2 shows the study design as flow chart. Fig. 2 Flow chart of the METAPANC trial Tumor imaging/laparoscopy CT or MRI of abdomen with intravenous contrast agents according to specific protocols for imaging of the pancreas and local institutional practice as a standard-of-care procedure. CT/MRI may be used for imaging of the abdomen, Chest imaging by CT for detection of lung metastases. In patients, who have not been surgically explored before application of mFOLFIRNOX chemotherapy, a diagnostic laparoscopy is optional but recommended under certain conditions. The aim of the diagnostic laparoscopy is to exclude patients with peritoneal carcinomatosis or more than three visible liver metastases. In general, a diagnostic laparoscopy should be performed in cases of resectable pancreatic cancer under the following conditions: when imaging shows a large tumor (>3 cm), or if ascites is present, or if there is an elevated tumor marker value of CA 19-9 > 500 U/ml, without cholestasis. In these situations, there is suspicion of occult organ metastasis (liver metastasis and/or peritoneal carcinomatosis). Intraoperative ultrasound, if available, of the liver during the diagnostic laparoscopy procedure is optional. MRI liver assessment at Response Assessment II is mandatory prior to randomization. Treatment regimen Modified FOLFIRINOX (mFOLFIRNOX) is a combination of systemic chemotherapy agents. It consists of: Oxaliplatin at a dose of 85 mg/m2 given as a 2-hour intravenous infusion Leucovorin at a dose of 400 mg/m2 given as a 30 min to 2-hour intravenous infusion Irinotecan at a dose of 150 mg/m2 given as a 90-minute intravenous infusion 5-FU at 2400 mg/m2 administrated as an intravenous infusion of over a 46-hour period Table 2 Treatment regimen mFOLFIRINOX Drugs will be used in its commercially available form and will be provided by the local pharmacies, all brands allowed and identified by the ACT code generic versions of oxaliplatin, irinotecan, leucovorin, and 5-FU if commercially available can be used according to local practice and local regulation. Preparation, doses and administration of the mFOLFIRINOX regimen will follow the institutional practice of the study site and instructions given in the local SmPCs. Regimen will be repeated every two weeks. Primary prophylaxis with G-CSF after every cycle of mFOLFIRINOX will follow the institutional practice of the study site. Dose modifications and prerequisites for the start of a new cycle A dose modified regimen starting at the first cycle is also allowed at the discretion of the treating physician: irinotecan and oxaliplatin starting dose may be reduced to 80% [1][5][6]. Dose adjustments during treatment should be based on the maximum graded toxicity within the previous cycle, graded using the National Cancer Institute Common Toxicity Criteria (version 5.0). Any toxicity associated with or possibly associated with study drug treatment should be managed with symptomatic treatment and dose modifications. Dose modifications may include dose reduction, dose interruption, and/or dose discontinuation. In case of non recovery after more than 2 weeks delay, stop treatment and refer to sponsor for decision on continuation. If mFOLFIRINOX is interrupted or delayed for > 4 weeks due to toxicity that is suspected to be related to treatment, study treatment should be permanently discontinued. After treatment interruption because of toxicity, the dose of one or more agents of the mFOLFIRINOX regimen may be modified according to maximum graded toxicity within the previous cycle as described below. Dose modifications will be at the discretion of the investigator per medical judgment. Prerequisites and surgical procedures after randomization into Arm 1 It is requested that the surgical procedures should be performed by the most experienced senior surgeons available in the individual centre. Selection of patients according to the inclusion criteria and eligibility of resectability will be performed in certified tumor boards in each participating centre. Simultaneous resection is performed when the following criteria are met: 1. No peritoneal carcinomatosis or other organ metastases (except liver metastases) 2. No more than 3 liver metastases 3. Both primary tumor and liver metastases must be considered resectable. Judgement of resectability of the primary tumor Multidisciplinary participation is required for resectability judgement. The resectability of the primary tumor will be judged based on the “Resectability criteria pancreatic adenocarcinoma” of the Dutch Pancreatic Cancer Group (DPCG), 2012, http://www.dpcg.nl. Resectability is determined on preoperative imaging and defined by the DPCG. Resectable disease is defined as no arterial (hepatic artery, superior mesenteric artery, or coeliac trunk) tumor contact and venous (portal vein or superior mesenteric vein) tumor contact of 90 degrees or less. Borderline resectable disease is defined as arterial tumor contact 90 degrees or less and venous contact of 90 to 270 degrees without occlusion. Table 3 Resectability criteria for pancreatic adenocarcinoma according to the Dutch Pancreatic Cancer Group, 2012, http://www.dpcg.nl Sequence of surgical interventions 1. Resection of one liver metastasis during the first explorative laparotomy or diagnostic laparoscopy is allowed for histological confirmation, preferably an atypical small resection of one peripheral liver metastasis. Macroscopic R0 resection should be achievable for the metastatic lesion. In this situation, the primary tumor will be resected after application of 8 cylces of mFOLFIRINOX chemotherapy in combination with the remaining liver metastases (if more than one but less than 3 liver metastases existed). 2. Explorative laparotomy and resection should be performed within 2-6 weeks after the last mFOLFIRNOX administration according to local institutional practice. Explorative laparoscopy to exclude peritoneal carcinomatosis immediately before laparotomy is optional. All procedures necessary to prepare for surgery, perioperative and postoperative that are standard-of-care, will also follow local institutional practice. 3. Based on the intraoperative findings during explorative laparotomy, the surgeon will evaluate and decide whether resection of the primary tumor in curative intent can be performed. Intraoperative rapid section analyses are obligatory for the pancreatic transection margin to ensure safe and margin-free resection. 4. The resection of the primary pancreatic tumor and the liver metastases can be conducted in the open laparotomy or minimally invasive technique. It is up to the surgeon, to conduct the sequence, first the resection of the metastases and secondly the resection of the pancreatic adenocarcinoma, or vice versa. In this decision, also the role of ablation is relevant which may lead to necrotic parts in the liver which could be infected by a subsequent hepaticojejunostomy. Surgical procedures for the liver metastases 1. We have restricted the extent of liver surgery within the trial up to atypical liver resections of a maximum of three metastases. 2. Macroscopic R0 resection or ablation must be achievable for the metastatic lesion(s). 3. A bisegmentectomy of segment II/III can be considered in individual cases. 4. In patients with metastatic lesions located in the center of the liver, requiring major resections, locally ablative techniques (e.g. radiofrequency or techniques available in the respective local study site) can be combined intraoperatively with surgical removal of resectable metastases. We recommend to conduct the ablation sonoguided intraoperatively according to local institutional practice. 5. Alternatively, the ablation can be conducted interventionally (e.g. percutaneous ct-guided) according to local institutional practice. In these cases the liver ablation of selected metastatic lesion(s) can be planned 1-3 weeks after the last mFOLFIRINOX cycle, but within six weeks between the last cycle of chemotherapy and surgery. Statistical considerations Sample size calculation The sample size calculation is driven by the primary endpoint overall survival. Recruitment will be over 5 years and all patients will be followed up for at least 2 additional years, unless the patient dies beforehand, resulting in a maximum follow-up of 7 years. Assuming two-year survival probabilities of 15% in the control arm [7] Figure 1A mFOLFIRINOX arm) and 30% in the experimental arm a sample size of 109 patients per group will yield a power of 90% at the usual two-sided significance level of 5%. The assumed two-year survival probability of 30% in the experimental treatment arm corresponds to a hazard ratio of 0.635, which is considered clinically relevant. Adjusting conservatively for about 20% dropout (i.e. study discontinuations following randomization) we aim to randomize a total of 272 patients. The sample size calculation was carried out using nQuery (version 8.2.0.0). Assuming that about two thirds of the screened patients will be eligible for randomization we plan to screen about 400 patients. We will use an adaptive design in METAPANC. Towards the end of the recruitment period, we will conduct a sample size review verifying planning assumptions such as the overall event and dropout rate, i.e. based on non-comparative data (also referred to as blinded sample size re-estimation); the randomization code will be kept confidential and not be used in the sample size review. Furthermore, a futility analysis will be carried out; futility criteria will be based on the overall event rate and recruitment considerations. Efficacy The primary analysis will follow the intention-to-treat (ITT) principle. The primary outcome survival will be analyzed by a Cox proportional hazards regression. The treatment effect will be reported as hazard ratio with 95% confidence intervals and p-value testing the null hypothesis of no effect (i.e. a hazard ratio of 1). Patients withdrawing from study treatment will be followed up for endpoints. Withdrawal from the study will be dealt with as independent right censoring in the primary analysis unless the patient’s vital status can be obtained at end of study. If withdrawal from study is substantial and differential between the treatment groups, supporting analyses will explore the impact of the independent right censoring assumption by use of shared frailty models for time to death and time to withdrawal from study. The analyses of the time-to-event outcomes among the secondary endpoints will follow the same lines as the analyses of the primary endpoint. Quality of life (EORTC QLQ-C30, PAN-26, CIPN20, Q-TWIST) and continuous outcomes assessed repeatedly will be analysed using the so-called Mixed Model Repeated Measures (MMRM) approach. Treatment differences will be reported as least square means with 95% confidence intervals. Safety Standard reporting for adverse events (AEs) and serious adverse events (SAEs). AEs and SAEs will be summarized by frequencies and percentage for each treatment group. AEs will be coded according to MedDRA, analyzed, and presented following ICH E3 Structure and Content of Clinical Study Reports. Events of special interest (e.g. toxicities, post-operative complications) will be analyzed accounting for varying follow-up times and competing events [8]. All details of the statistical analysis including definitions of the analysis sets will be specified in a statistical analysis plan, which will be finalized prior to end of recruitment. Assessment of severity/intensity For the grading of the severity/intensity of an adverse event (AE), the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0 must be used. Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately lifethreatening or result in death or hospitalization but may jeopardize the patient or may require an intervention to prevent one of the outcomes listed in the definition above. These events should also usually be considered serious (SAE). All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions (ADRs). The investigator must report the outcome of AEs and SAEs. All SAEs that have not resolved by the end of treatment visit or discontinuation of IMP treatment, whichever is later, must be followed until the outcome is recovered, recovered with squeal, unchanged/not recovered until death (death due to another cause) or death (due to the SAE). Investigators must report all SAEs immediately within 24 h of knowledge of the event. Regulatory, ethical, legal and trial oversight considerations METAPANC is a phase III clinical trial implemented and reported in accordance with the CTR (EU) 536/2014, ICH-GCP, with applicable Member states regulations, and with the ethical principles laid down in the Declaration of Helsinki. It was submitted, evaluated, and approved via CTIS with Germany as the reporting member state. It is registered under its EU Clinical Trial Number 2023-503558-10-00 in the EU Clinical Trial Register. Informed consent Before enrolment in the clinical trial, the patient will be informed that participation in the clinical trial is voluntary and that he/she may withdraw from the clinical trial at any time without having to give reasons and without penalty or loss of benefits to which the patient is otherwise entitled. The treating physician will provide the patient with information about the treatment methods to be compared and the possible risks involved. At the same time, the nature, significance, implications, expected benefits and potential risks of the clinical trial and alternative treatment will be explained to the patient. During the informed consent discussion, the patient, if applicable, will also be informed about the insurance cover that exists and the insured's obligations. The patient will be given ample time and opportunity to obtain answers to any open questions. All questions relating to the clinical trial should be answered to the satisfaction of the patient and/or his/her legal representative. In addition, the patient will be given a patient information sheet which contains all the important information in writing. Monitoring In German sites, monitoring is performed by the CRAs of the CTU UMG. Risk-based monitoring will be done according to ICH-GCP E6 and standard operating procedures (SOP) to verify that patients’ rights and wellbeing are protected, reported trial data are accurate, complete and verifiable from source documents and that the trial is conducted in compliance with the currently approved protocol/amendment. All investigators will accept monitoring visits before, during and after the clinical trial to ensure that the trial is conducted, recorded and reported according to the trial protocol, SOPs, ICH-GCP and the applicable regulatory requirements. Prior to the trial, a site initiation visit at each site is conducted in order to train and introduce the investigators and their staff to the trial protocol, essential documents, handling of IMP and related trial specific procedures, ICH-GCP and national/local regulatory requirements. During the trial, the CRA will visit the site regularly depending on the recruitment rate and quality of data. During these on-site visits, the CRA verifies that the trial is conducted according to the trial protocol, trial specific procedures, ICH-GCP and national/local regulatory requirements. The presence of signed informed consents, eligibility of patients, primary endpoint, handling of IMP and documentation/reporting of safety data (e.g. AE/SAE) will be verified by the CRA. The CRA performs also source data verification to ensure that the clinical trial data which are recorded in the source data and eCRFs are complete and accurate. Extent of source data verification and monitor visit frequency will be adapted for individual sites in case of lack of data quality or a high number of protocol violations. All trial specific monitoring procedures, monitoring visit frequency and extent of SDV will be predefined in a trial specific monitoring manual. The investigator must maintain source documents for each patient in the trial, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical information, laboratory data, electrocardiograms, and the results of any other tests or assessments. All information recorded on eCRFs must be traceable to source documents in the patient's file. The investigator must also keep the original signed informed consent form (a signed copy is given to the patient). The investigator must give the CRA access to all relevant source documents to confirm their consistency with the eCRF entries Translational research program The translational research program aims to identify biomarkers for better identification of a potential target population which may benefit from intensified multimodal treatment strategies, to identify molecular biomarkers associated with progression or resistance to study treatment and to identify biomarkers adding to the understanding of PDAC tumor biology. The program will focus on collecting high-quality tissue and liquid biopsy samples, fecal samples and imaging data. Exploratory biospecimen analyses - Tissue analyses: samples will be collected and undergo careful pathological quality assessment for subsequent molecular analysis using DNAseq (NGS panel to analyze the mutational status of KRAS, BRCA1/2 and other genes relevant in PDAC pathobiology), RNAseq (to perform signaling pathway analysis, deconvolution of cell lineages and gene expression analysis) and spatial immune profiling (multiplex-Immunofluorescence for tumor and immune markers including tumor markers (cytokeratins, GATA6), fibroblast markers (e.g. alpha-SMA, FAP), immune markers (e.g. CD3, CD4, CD8, Granzyme B) and markers assessing proliferation (KI67) and cell death (e.g. cleaved caspase 3). - Liquid biopsy: collected blood samples will be used to isolate plasma and PBMCs. Quality assessment will be performed, and cell-free DNA and RNA will be isolated for analysis of predictors of response, resistance or toxicity. - Fecal samples: identify biomarkers in the gut microbiome and other biomarkers (e.g. pancreatic enzymes) that are predictive of response to study interventions. Biological samples drawn during the course of the trial will be collected from the investigator sites and stored and further analyzed by a sponsor assigned central laboratory (West German Biobank and Bridge Institute of experimental Tumor Therapy, West German Cancer Center, University Hospital Essen). Detailed instructions on sample collection, processing, handling and shipment are provided in the laboratory manual (Supplementary Information, Additional file 1). Imaging analysis The development of image-based biomarkers for therapy response prediction and disease outcome presents another exploratory endpoint. For this purpose, baseline and follow up imaging data will be collected for a central review process. Existing and newly developed machine learning (ML) algorithms will be applied to identify PDAC subtypes and predictive therapy response patterns as previously described. The imaging biomarker translational program includes: secure imaging data transfer and central storage of imaging data, retrospective central image reading and longitudinal imaging data registration, quantitative imaging biomarker extraction (e.g. tumor / metastases, body composition and comorbidities) and ML-based outcome prediction including various clinical endpoints (e.g. therapy response, molecular marker, outcome). Discussion Patients with oligometastatic PDAC and relatively favorable tumor biology may benefit from simultaneous resection of both the primary tumor and liver metastases. This approach could potentially offer a chance for cure or, at least, lead to a survival benefit compared to conventional palliative chemotherapy in selected patients. However, once distant metastases are detected, tumor resection is still not recommended according to German and NCCN guidelines [9] [10], but resection may be considered in selected patients with oligometastases as part of a multimodal treatment approach within the context of clinical trials. There are no published results from randomized controlled trials on the topic of primary tumor resection in oligometastatic pancreatic cancer. The few systematic reviews consider relatively small case series. The survival prognosis is significantly better in oligometastasis with synchronous resection of the primary tumor and metastases compared to diffuse metastasis [11] [12] [13]. Overall, the predominantly retrospective studies provide evidence that overall survival in selected patients with oligometastatic PDAC could be significantly prolonged by primary synchronous resection of both the primary tumor and metastases, compared to patients who are only offered exploration or palliative bypass with chemotherapy [14] [15]. In the multicentre analysis by Tachezy et al., patients who underwent resection of an M1 pancreatic carcinoma showed a significantly longer survival compared to patients who only underwent exploration: 14 months vs. 8 months, but this applies only to the subgroup of patients with pancreatic head carcinoma [16]. These data, however, do not differ significantly from those achieved in the metastatic stage through systemic chemotherapy. In another study, patients with a body/tail pancreatic carcinoma benefited most from a synchronous resection of the primary tumor and liver metastases. A systematic review reports that patients with simultaneous resection of the primary tumor and liver metastases may even have comparable survival rates to patients who underwent resection without distant metastases. These findings are also observed in more recent, small, non-randomized pilot studies, where the tumor marker CA 125 is considered to play a special role as a resection criterion for liver metastases, and a notable degree of patient selection is apparent [17] [18]. The results after neoadjuvant chemotherapy may be more conclusive [19] [12]. In General, data from controlled and randomized studies are missing. In summary, there is evidence suggesting that synchronous resection of the primary tumor and metastases in oligometastatic pancreatic ductal adenocarcinoma, particularly as part of a multimodal treatment strategy, leads to better overall survival outcomes compared to diffuse metastatic pancreatic cancer. How these results compare to a state-of-the-art systemic therapy without resection must be determined by prospective, randomized studies. Until then, resection of the primary tumor and metastases is not yet a clinical standard, even in oligometastatic cases [20]. In the palliative setting, chemotherapy regimens such as FOLFIRINOX or gemcitabine/nab-paclitaxel have recently been established, demonstrating a significant improvement in overall survival (OS), with medians of 11 and 8.5 months, respectively, compared to 7 or 6.7 months with gemcitabine monotherapy [1] [21]. Multimodal treatment strategies, including local therapies, are recommended to enhance disease control and clinical outcomes in these patients. Distinct clinical courses of oligo- and polymetastasis are observed in tumors of different origins, and a comprehensive approach involving multiple entities is required to identify common underlying mechanisms. In pancreatic cancer, the concept of oligometastasis has not yet been established in clinical practice. Furthermore, it is currently unclear whether true oligometastatic disease exists in pancreatic cancer, as it does in colorectal cancer at known stages. The challenge right now is how to select patients who potentially profite from multimodal surgery treatment. Thus finding a strategy to select patient groups who most likely benefit from additional surgery is urgently needed. In this context the METAPANC trial aims to evaluate the effectiveness of multimodal therapy in patients with the clinical presentation of oligometastasis in pancreatic cancer. The combination of highly effective polychemotherapy (mFOLFIRINOX) followed by complete tumor resection is intended to support the potential for curative treatment in these patients — a group that has previously been considered exclusively palliative. The primary objective of this randomized phase III study is to demonstrate the efficacy of this therapeutic concept in terms of overall survival. METAPANC is currently the only prospective, randomized, controlled, multicentre, phase III trial for curatively intended surgical therapy of oligometastatic pancreatic cancer in Western Europe and the Anglo-American world. In the Asian region, the CSPAC-1 study is currently being conducted as another prospective randomized study in China [4]. As a Phase II study on multimodal therapy for hepatically metastasized pancreatic adenocarcinoma, the HOLIPANC study investigates, in a single-arm study design, the effectiveness and quality of life of a neoadjuvant chemotherapy regimen consisting of liposomal irinotecan combined with oxaliplatin and 5-fluorouracil. The study also evaluates the significance of a curatively intended resection of the primary tumor and oligometastases (up to a maximum of 5 liver metastases). The multimodal surgical therapy of patients with oligometastatic pancreatic cancer could significantly extend the survival of this patient group within the framework of the METAPANC trial. In order to recommend this treatment regimen outside of clinical trials, data from randomized controlled studies are needed first. An exploratory translational research program is implemented to identify patient groups that could benefit from multimodal surgical therapy. In Germany 26 institutions are currently planned as participating centres in Germany (Supplementary Information, Additional file 2). Additionally, international high-volume centres from the Netherlands, Finland, Sweden, and Norway are in preparation. The recruitment of patients has already started. The METAPANC trial is expected to run for at least seven years. Abbreviations 5-FU: 5-fluorouracil ADR: Adverse drug reaction AE: Adverse event ACT: ATC: Anatomical Therapeutic Chemical (Classification System) alpha-SMA: alpha Smooth muscle actin AWMF: Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) BRCA1/2: Breast Cancer Gene 1/2 CA 125: Cancer antigen 125 CA19-9: Carbohydrate Antigen 19-9 CD3: Cluster of Differentiation 3 CD4: Cluster of Differentiation 4 CD8: Cluster of Differentiation 8 CHA: Common hepatic artery CRA: Clinical research associate CR: Complete remission CSPAC: Chinese Study Group for Pancreatic Cancer CTR: Clinical Trials Regulation CT: Computer Tomography CTIS: Clinical Trials Information System CTU UMG: Clinical trials unit University Medicine Göttingen DPCG: Dutch Pancreatic Cancer Group DNAseq: DNA sequencing ECOG: Eastern Cooperative Oncology Group (ECOG Performance Status Scale) eCRF: electronic Case Report Form EORTC: European Organisation For Research And Treatment Of Cancer EORTC QLQ-C30: EORTC Core Quality of Life questionnaire EORTC QLQ-PAN26: EORTC health-related quality of life for people with pancreatic ductal adenocarcinoma FAP: fibroblast activation protein GATA6: GATA binding protein 6 GCP: Good Clinical Practice G-CSF: Granulocyte colony stimulating factor ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use IMP: Investigational Medicinal Product ITT: intention-to-treat KI67: marker of proliferation Kiel 67 KRAS gene: Kirsten rat sarcoma virus proto-oncogene MedDRA: Medical Dictionary for Regulatory Activities mFOLFIRINOX: modified FOLFIRINOX ML: Machine Learning MRI: Magnetic Resonance Imaging NCCN: National Comprehensive Cancer Network NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NGS: Next generation sequencing NYHA: New York Heart Association (NYHA Functional Classification) OS: overall survival PBMC: Peripheral Blood Mononuclear Cell PD: Progressive disease PDAC: Pancreatic ductal adenocarcinoma PFS: progression-free survival PR: Partial response PV: Portal vein Q-TWIST: quality-adjusted time without symptoms or toxicity RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1 RNAseq: RNA sequencing SAE: Severe adverse event SD: Stable disease SDV: Source Data Verification SMA: Superior mesenteric artery SmPC: Summary of product characteristics SMV: Superior mesenteric vein SOP: Standard operating procedure WBC: White Blood Cell Declarations Acknowledgements We want to thank the Clinical Trials Unit, UMG (University Medical Center of Goettingen), in particular Ralph Tostmann, Wibke van Rees, Elisabeth Klingberg, Jasmina Schneider, Marianne Richter and the Clinical Trial Office of the Department of General-, Visceral-, and Pediatric Surgery, UMG, in particular Johanna Kreutzer, Esther Ohanecian, Niklas Hanke, Birgit Juenemann, Jessica Eggert, Chan Rong Lai and Almuth Wiederhold for excellent helpful support. Moreover the authors want to thank all patients, relatives and clinical teams involved in the delivery of the trial. Authors' contributions MG Conceptualization, study design, writing (original draft), project administration, funding acquisition UP Conceptualization, study design, writing (original draft), project administration, funding acquisition MGB Conceptualization, study design JS Conceptualization, study design, writing (original draft), project administration, funding acquisition RT Conceptualization, study design, writing (original draft), project administration, project manager RB Conceptualization, funding acquisition HW Conceptualization, study design MC Conceptualization, manuscript preparation, writing (original draft) AK Conceptualization, study design UK Conceptualization, study design STL Conceptualization, writing, Biobanking KA Conceptualization, statistics BU Project administration, conceptualization HS Conceptualization, study design AN Conceptualization, study design PP Conceptualization, study design OFD Conceptualization, study design KJL Conceptualization, study design MJ Conceptualization, study design SOB Conceptualization, study design TF Conceptualization, statistics, study design, writing (original draft), project administration, funding acquisition PJ Conceptualization, study design, manuscript preparation, writing (original draft), funding acquisition, project administration All authors have read and approved the manuscript. Funding The trial is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) Availability of data and materials The full study protocol and all regulatory documents can be provided by the sponsor upon request. Ethics approval and consent to participate METAPANC is a phase III clinical trial implemented and reported in accordance with the CTR (EU) 536/2014, ICH-GCP, with applicable member states regulations, and with the ethical principles laid down in the Declaration of Helsinki. It was submitted, evaluated, and approved via CTIS with Germany as the reporting member state. A statement of ethical approval and consent was issued by the State Office for Health and Social Affairs (LAGESO) Berlin, Germany. The ethic committee of the federal state of Berlin approved the study. METAPANC is registered under its EU Clinical Trial Number 2023-503558-10-00 in the EU Clinical Trial Register. Consent for publication Not applicable Competing interests TF declares personal fees for statistical consultancies (including data monitoring committees) from Actimed, Apellis, Aslan, AstraZeneca, Bayer, BiosenseWebster, BMS, Cardior, CSL Behring, Daiichi Sankyo, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, PINK! gegen Brustkrebs, PPD, RECARDIO, Recordati, Relaxera, Roche, Servier, Viatris, Vifor, VICO Therapeutics; all outside the submitted work. All other authors declare that they have no competing interests References Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 11;364(19):1817–25. doi: 10.1056/NEJMoa1011923. PMID: 21561347. Kandel P, Wallace MB, Stauffer J, Bolan C, Raimondo M, Woodward TA, Gomez V, Ritter AW, Asbun H, Mody K. Survival of patients with oligometastatic pancreatic ductal adenocarcinoma treated with combined modality treatment including surgical resection: a pilot study. J Pancreat Cancer. 2018 Nov 1;4(1):88–94. doi: 10.1089/pancan.2018.0011. PMID: 30631861. Renz BW, Boeck S, Roeder F, Trumm C, Heinemann V, Werner J. Oligometastatic disease in pancreatic cancer: how to proceed? Visc Med. 2017 Mar;33(1):36–41. doi: 10.1159/000455027. PMID: 28612015. Wei M, Shi S, Hua J, Xu J, Yu X; Chinese Study Group for Pancreatic Cancer (CSPAC). Simultaneous resection of the primary tumour and liver metastases after conversion chemotherapy versus standard therapy in pancreatic cancer with liver oligometastasis: protocol of a multicentre, prospective, randomised phase III control trial (CSPAC-1). BMJ Open. 2019 Dec 8;9(12):e033452. doi: 10.1136/bmjopen-2019-033452. PMID: 31818843. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018 Dec 20;379(25):2395–406. doi: 10.1056/NEJMoa1809775. PMID: 30575490. Tong H, Fan Z, Liu B, et al. The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis. Sci Rep. 2018 Jun 6;8:8666. doi: 10.1038/s41598-018-26811-9. PMID: 29875415. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med. 2011 May 11;364(19):1817–25. doi: 10.1056/NEJMoa1011923. PMID: 21561347 Stegherr, R., Schmoor, C., Beyersmann, J. et al. Survival analysis for AdVerse events with VarYing follow-up times (SAVVY)—estimation of adverse event risks. Trials 22 , 420 (2021). doi: 10.1186/s13063-021-05354-x. PMID: 34187527 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF). S3-Leitlinie Exokrines Pankreaskarzinom, Langversion 3.1, 2024, AWMF-Registernummer: 032-010OL [Internet]. 2024 [cited 2024 Dec 1]. Available from: https://www.leitlinienprogramm-onkologie.de/leitlinien/pankreaskarzinom/. Tempero MA, Malafa MP, Behrman SW, Benson AB 3rd, Casper ES, Chiorean EG, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2014 Aug;12(8):1083–93. doi: 10.6004/jnccn.2014.0106. PMID: 25099441. Hackert T, Niesen W, Hinz U, Tjaden C, Strobel O, Ulrich A, et al. Radical surgery of oligometastatic pancreatic cancer. Eur J Surg Oncol. 2017 Mar;43(3):358–63. doi: 10.1016/j.ejso.2016.10.023. PMID: 27856064. Yang J, Zhang J, Lui W, Huo Y, Fu X, Yang M, et al. Patients with hepatic oligometastatic pancreatic body/tail ductal adenocarcinoma may benefit from synchronous resection. HPB (Oxford). 2020;22(1):91–101. PMID: 31262486. Damanakis AI, Ostertag L, Waldschmidt D, Kutting F, Quaas A, Plum P, et al. Proposal for a definition of 'Oligometastatic disease in pancreatic cancer'. BMC Cancer. 2019 Dec;19(1):1261. doi: 10.1186/s12885-019-6448-9. PMID: 31888547. Kim Y, Kim SC, Song KB, Kim J, Kang DR, Lee JH, et al. Improved survival after palliative resection of unsuspected stage IV pancreatic ductal adenocarcinoma. HPB. 2016 Mar;18(3):325–31. doi: 10.1016/j.hpb.2015.10.014. PMID: 27037201. Lowder CY, Metkus J, Epstein J, Kozak GM, Lavu H, Yeo CJ, et al. Clinical implications of extensive lymph node metastases for resected pancreatic cancer. Ann Surg Oncol. 2018 Dec;25(13):4004–11. doi: 10.1245/s10434-018-6763-4. PMID: 30225835. Tachezy M, Gebauer F, Janot M, Uhl W, Zerbi A, Montorsi M, et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery. 2016 Jul;160(1):136–44. doi: 10.1016/j.surg.2016.02.019. PMID: 27048934. Shi HJ, Jin C, Fu DL. Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: diagnosis and assessment of unresectability. World J Gastroenterol. 2016 Dec;22(45):10024–37. doi: 10.3748/wjg.v22.i45.10024. PMID: 28018110. Kandel P, Wallace MB, Stauffer J, Bolan C, Raimondo M, Woodward TA, et al. Survival of patients with oligometastatic pancreatic ductal adenocarcinoma treated with combined modality treatment including surgical resection: a pilot study. J Pancreat Cancer. 2018 Nov;4(1):88–94. doi: 10.1089/pancan.2018.0011. PMID: 30631861. Crippa S, Bittoni A, Sebastiani E, Partelli S, Zanon S, Lanese A, et al. Is there a role for surgical resection in patients with pancreatic cancer with liver metastases responding to chemotherapy? Eur J Surg Oncol. 2016 Dec;42(12):1533–9. doi: 10.1016/j.ejso.2016.06.398. PMID: 27423449. Gebauer F, Damanakis AI, Bruns C. [Oligometastasis in pancreatic cancer: current state of knowledge and spectrum of local therapy]. Chirurg. 2018 Jun;89(6):510–5. doi: 10.1007/s00104-018-0626-1. PMID: 29557488. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691–703. doi: 10.1056/NEJMoa1304369. PMID: 24131140. Tables Table 1 Objectives and endpoints of the METAPANC trial 1. Objectives 1.1. Primary Objectives • To assess the efficacy of neoadjuvant multimodal chemotherapy followed by complete tumor and metastases resection in patients with hepatic oligometastatic PDAC 1.2. Secondary Objectives • To determine the efficacy and safety of the treatment concept • To determine health-related quality of life (HR-QoL) 1.3. Other Exploratory Objectives • To evaluate biomarkers and imaging data for better identification of a potential target population 2. Endpoints 2.1. Primary Endpoint • Overall survival as the time from randomization to death of any cause 2.2. Secondary Endpoints • Efficacy : Progression-free survival • Safety : grading of the severity/intensity of an adverse event: the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0 • Health-Related Quality of Life : EORTC QLQ-C30, PAN-26, Q-TWIST • Exploratory Endpoints : Translational endpoints Table 2 Treatment regimen mFOLFIRINOX IMP Dose [mg/m²] Route of administration Oxaliplatin 85 2-hour intravenous infusion Leucovorin 400 30 min to 2-hour intravenous infusion Irinotecan 150 90 min intravenous infusion 5-FU 2400 46-hour intravenous infusion Table 3 Resectability criteria for pancreatic adenocarcinoma according to the Dutch Pancreatic Cancer Group, 2012, http://www.dpcg.nl SMA superior mesenteric artery Celiac axis CHA common hepatic artery SMV-PV superior mesenteric vein – portal vein Resectable (all four required) no contact no contact no contact ≤90° contact Borderline resectable (minimally one required) ≤90° contact ≤90° contact ≤90° contact 90°-270° contact and no occlusion Irresectable (minimally one required) contact > 90° contact > 90° contact > 90° contact > 270° or occlusion Additional Declarations Competing interest reported. TF declares personal fees for statistical consultancies (including data monitoring committees) from Actimed, Apellis, Aslan, AstraZeneca, Bayer, BiosenseWebster, BMS, Cardior, CSL Behring, Daiichi Sankyo, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, PINK! gegen Brustkrebs, PPD, RECARDIO, Recordati, Relaxera, Roche, Servier, Viatris, Vifor, VICO Therapeutics; all outside the submitted work. All other authors declare that they have no competing interests Supplementary Files METAPANCLabManualv1.1.2.pdf SupplTableGermanSitesBMC.docx MetapancFillableSPIRITOutcomes2022ChecklistwithSPIRIT2013.pdf Cite Share Download PDF Status: Published Journal Publication published 06 Feb, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 19 Jan, 2025 Editor assigned by journal 13 Jan, 2025 Submission checks completed at journal 13 Jan, 2025 First submitted to journal 12 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5815668","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":401815638,"identity":"0509dfca-eb5e-451a-a182-c4c7f2123f20","order_by":0,"name":"Michael Ghadimi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYFACHiAyYJADsgwYGNhI0GJMqhYGhsQGorXo9q89+OFNwbb0+RHJm18wlNkQ1mJ2412y5ByD27kbb6SVWTCcSyNGyxkDaR6Qltk5ZgaMbYeJ0mL8G6gl3RCi5T8RWs73mIFsSZCXzjF+wNh2gBhbeMwsgX4x3CD/rIwh4VwyMbacMb7x5s9tefmew5s/fCizI6yFQSIBQhscYGCDsQkA/gMQWr6BgfkDUTpGwSgYBaNgxAEAFys+/zSoQesAAAAASUVORK5CYII=","orcid":"","institution":"University Medical Center Goettingen","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"","lastName":"Ghadimi","suffix":""},{"id":401815639,"identity":"bab64f90-6868-4a70-bfb2-2b1325d03349","order_by":1,"name":"Uwe Pelzer","email":"","orcid":"","institution":"Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Uwe","middleName":"","lastName":"Pelzer","suffix":""},{"id":401815640,"identity":"57fd4a04-446e-4cf3-bf57-6252f5024d8a","order_by":2,"name":"Marc G. 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In these cases the liver ablation of selected metastatic lesion(s) can be planned 1-3 weeks after the last mFOLFIRINOX cycle, but within six weeks between the last cycle of chemotherapy and surgery. Alternatively, the ablation can be conducted intraoperatively.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-5815668/v1/b632698f562244971ef4a45b.png"},{"id":73872362,"identity":"f1d7276d-edd8-498b-b455-d5ecfb5c131d","added_by":"auto","created_at":"2025-01-15 12:26:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":283645,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the METAPANC trial\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-5815668/v1/8dbd9f777d4459df076d8f74.png"},{"id":75930132,"identity":"bcb29907-e50a-43d7-b8d0-715115fbc1eb","added_by":"auto","created_at":"2025-02-10 16:10:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1485328,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5815668/v1/c43398cd-b01d-4a75-b680-3e4c7e89f29d.pdf"},{"id":73872363,"identity":"8919a1c8-0c22-421c-bbb9-6efc9e50bb7e","added_by":"auto","created_at":"2025-01-15 12:26:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1293429,"visible":true,"origin":"","legend":"","description":"","filename":"METAPANCLabManualv1.1.2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5815668/v1/c87907d63ad57ae9a6a02ec5.pdf"},{"id":73872367,"identity":"4896a025-0bb3-41c2-abda-95a83054eb1e","added_by":"auto","created_at":"2025-01-15 12:26:47","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":29941,"visible":true,"origin":"","legend":"","description":"","filename":"SupplTableGermanSitesBMC.docx","url":"https://assets-eu.researchsquare.com/files/rs-5815668/v1/47a9e240d9308e9ae4c847bd.docx"},{"id":73872372,"identity":"bb4dccbd-b054-421a-b091-20141fb3fb0c","added_by":"auto","created_at":"2025-01-15 12:26:47","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":264610,"visible":true,"origin":"","legend":"","description":"","filename":"MetapancFillableSPIRITOutcomes2022ChecklistwithSPIRIT2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5815668/v1/6efae05fe70a1521812156c5.pdf"}],"financialInterests":"Competing interest reported. TF declares personal fees for statistical consultancies (including data monitoring committees) from Actimed, Apellis, Aslan, AstraZeneca, Bayer, BiosenseWebster, BMS, Cardior, CSL Behring, Daiichi Sankyo, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, PINK! gegen Brustkrebs, PPD, RECARDIO, Recordati, Relaxera, Roche, Servier, Viatris, Vifor, VICO Therapeutics; all outside the submitted work.\nAll other authors declare that they have no competing interests","formattedTitle":"Intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus chemotherapy alone: a randomized controlled trial (METAPANC)","fulltext":[{"header":"Background","content":"\u003cp\u003ePancreatic ductal adenocarcinoma (PDAC) has a poor overall survival rate of 8% due to early metastasis and therapy resistance. The successful introduction of intensified chemotherapeutic regimens, such as FOLFIRINOX and gemcitabine/nab-paclitaxel, has led to a significant, though still moderate, improvement in response rates, disease control, and overall survival. Current standards recommend systemic chemotherapy but no surgical approach in metastatic (stage IV) PDAC. FOLFIRINOX has the highest rates of response and overall survival and is a current standard-of-care chemotherapy regimen in patients with metastatic PDAC and good performance status [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Given the high rates of recurrence, and without available biomarkers for potential target populations that may benefit from extensive and complex surgical interventions, synchronous or metachronous metastasectomy is not recommended and only rarely performed in individual cases\u003c/p\u003e \u003cp\u003eHowever, pancreatic resections, including pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy, resection of metastases have reached a high-quality level with considerably low morbidity and \u0026lt;\u0026thinsp;5% mortality in high-volume centres. Several case studies have reported favorable outcomes for selected patients with PDAC undergoing resection of metastases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and highly selected patients with oligometastatic PDAC and good response to intensified chemotherapy may potentially benefit from multimodal approaches. Recently, the Chinese Study Group for Pancreatic Cancer (CSPAC) reported on a multicentre, randomized, controlled phase III trial [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], using a similar definition as used in the here proposed METAPANC trial design. In CSPAC-1, various first-line chemotherapeutic regimen are used, and time of treatment and randomization prior to the surgery or control arm is variable. CSPAC-1 aims is to establish a treatment strategy to select patients who might benefit from simultaneous resection of primary pancreatic cancer and liver metastatic sites. The trial is expected to run for at least 7 years. METAPANC uses a similar yet distinct study protocol and is the first international, randomized, controlled, open-label, multicentre, phase III clinical trial for curative intended surgical therapy of oligometastatic pancreatic cancer in Western Europe.\u003c/p\u003e"},{"header":"Objectives and endpoints","content":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary objective of the METAPANC trial is to evaluate the efficacy of neoadjuvant multimodal chemotherapy followed by complete tumor and metastases resection in patients with hepatic oligometastatic PDAC. The principal research question is whether overall survival in patients with oligometastatic pancreatic cancer is superior in patients treated with perioperative modified FOLFIRINOX (mFOLFIRINOX) followed by complete surgical resection compared to standard-of-care mFOLFIRINOX first-line chemotherapy alone. In a prospective randomized trial design, we aim to evaluate survival and quality of life after multimodal therapy with perioperative mFOLFIRINOX chemotherapy (two times 4 cycles prior to resection of the primary tumor and resection / ablation of the metastases), followed by 4 cycles of adjuvant mFOLFIRINOX chemotherapy (total of 12 cycles) vs. mFOLFIRINOX without surgery / ablation (total of 12 cycles) as standard of care first-line treatment (Fig. 1). All patients will be followed-up for at least 2 years. Secondary objectives are to determine the safety of the treatment concept and health-related quality of life. Hereby we explore procedure-related complications and mortality. Furthermore, we seek to evaluate biomarkers and imaging data for better identification of a potential target population which may benefit from intensified multimodal treatment strategies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is overall survival (OS) as the time from randomization to death of any cause. Secondary endpoints include progression-free survival (PFS), quality of life (EORTC QLQ-C30, PAN-26, Q-TWIST) and translational endpoints. PFS is defined as the time from randomization to death or progression whatever occurs first. During the induction phase of the study, response will be assessed according to RECIST v1.1. Progression is based on radiological assessment according to RECIST v1.1.\u003c/p\u003e\n\u003cp\u003eFor translational research purposes, tissue from the initial diagnostic biopsy and the resection specimen will be collected, if possible from both tumor tissue from the primary tumor and from metastases (this should be feasible at least for patients that were surgically explored). Aims are to identify predisposing factors for metastasis, response to mFOLFIRINOX treatment and adaptive molecular changes under chemotherapy. Characterization will address the molecular subtype and clonal evolution to better understand mechanisms of metastasis and to identify chemotherapy response / resistance patterns.\u003c/p\u003e\n\u003cp\u003eBlood samples are taken before each chemotherapeutic cycle, before surgical resection and during maintenance therapy and surveillance. Analysis will focus on circulating tumor DNA, analysis for monitoring of mutational patterns of pancreatic cancer during cancer therapy (prognostic for disease survival, predictive for primary or secondary drug resistance) in comparison to currently used tumor markers (CA19- 9) using e.g. a multiplex amplicon-based sequencing approach.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Objectives and endpoints of the METAPANC trial\u003c/p\u003e"},{"header":"Methods/study design","content":"\u003cp\u003eMETAPANC is an international, randomized, controlled, open-label, multicentre, phase III clinical trial. This trial is composed of two arms, and patients will be randomized to either Arm 1 (perioperative mFOLFIRINOX plus resection of all cancer lesions) or Arm 2 (standard-of-care mFOLFIRINOX chemotherapy). Prior to randomization, all patients will undergo 8 cycles of mFOLFIRINOX induction therapy with response assessment after the fourth and eighth cycles. Patients in Arm 1 will be treated for approximately 12 months (induction chemotherapy with mFOLFIRINOX) followed by surgery and adjuvant of 4 cycles of mFOLFIRINOX-chemotherapy. Patients in Arm 2 will be treated for approximately 6 months with 12 cycles of mFOLFIRINOX-chemotherapy. Follow-up visits will be performed for all patients for a minimum of two years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. 1\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eFlow chart of the entire study including the optional percutaneous interventional ablation of metastases in Arm 1. In these cases the liver ablation of selected metastatic lesion(s) can be planned 1-3 weeks after the last mFOLFIRINOX cycle, but within six weeks between the last cycle of chemotherapy and surgery. Alternatively, the ablation can be conducted intraoperatively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with hepatic oligometastatic pancreatic ductal adenocarcinoma with a maximum of 3 liver metastases who meet the inclusion criteria \u0026nbsp;and do not meet the exclusion criteria will be eligible to participate in this clinical trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients eligible for inclusion in this trial must meet all the following criteria:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. Age \u0026ge; 18 years and \u0026le; 80 years\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. medical and technical operability of the primary tumor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. limited synchronous liver metastatic status (\u0026le;3 resectable/ ablatively treatable liver metastases)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOR\u0026nbsp;\u003c/p\u003e\n\u003cp\u003elimited metachronous liver metastatic status (\u0026le;3 resectable/ ablatively treatable liver metastases), but must have completed adjuvant chemotherapy at least 6 months before start of study treatment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. previous neo-/adjuvant anti-cancer therapy for non-metastatic PDAC with last dose administered \u0026ge;6 months before the start of study treatment are allowed\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. adequate hematological (WBC \u0026ge;3000/\u0026mu;l, platelets \u0026ge;100.000/\u0026mu;l, hemoglobin \u0026ge;8 g/dl), hepatic (bilirubin \u0026le;2.5 x mg/dl) and renal function (creatinine clearance \u0026gt;50 ml/min) parameters\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e7. ECOG performance status \u0026le;1\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e8. written informed consent obtained according to international guidelines and local laws\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e9. measurable disease according to RECIST v1.1. prior to induction therapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients eligible for this trial must not meet any of the following criteria:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. Unresectable pancreatic cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Prior chemotherapy within 6 months or prior radiation therapy within 28 days (e.g. in adjuvant settings).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Exception for previous systemic anti-cancer treatment for metastatic PDAC: Patients with need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFIRINOX or modified FOLFIRINOX prior to study entry (Cycle 0) and may be enrolled.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively and has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. Patients with either peritoneal carcinomatosis or \u0026gt;3 liver metastases or extrahepatic metastasis)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. Known hypersensitivity to the active substances or any of the excipients\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e7. Impaired cardiac function or clinically significant cardio-vascular disease, such as:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026ndash; Congestive heart failure requiring treatment (NYHA grade \u0026gt;2), or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026ndash; Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery \u0026lt; 3 months prior to study entry\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e8. Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registries and diagnostic trials is allowed\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e9. Inability to understand the study and/or comply with the protocol procedures\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e10. Subject pregnant or breast feeding, or planning to become pregnant within 6 months\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e11. Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e12. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. These conditions should be discussed with the patient prior to registration in the trial \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with locally resectable but oligometastatic PDAC will be screened for study enrollment (approximately n= 400) according to the inclusion and exclusion criteria. If enrolled and registered for the study, patients will receive 2 x 4 cycles\u0026nbsp;mFOLFIRINOX with response assessment after 4 and 8 cycles. Patients with progressive disease (PD) will be excluded from the trial. 272 patients with complete response (CR), partial response (PR) or stable disease (SD) according to RECIST v1.1 will be randomized (1:1) into Arm 1 (experimental arm) or Arm 2 (control arm).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the experimental arm patients will receive at least eight cycles of mFOLFIRINOX followed by resection of the primary tumor and metastatic lesions, preferably in one procedure. Local ablation of liver metastases is allowed. After resection, patients receive adjuvant chemotherapy of 4 cycles of mFOLFIRINOX followed by surveillance / follow-up.\u003c/p\u003e\n\u003cp\u003eIn the control arm patients will receive at least 8 cycles of mFOLFIRINOX followed by adjuvant chemotherapy (mFOLFIRINOX for 4 cycles) followed by surveillance / follow-up. All Patients will undergo a follow up of 2 years. Figure 2 shows the study design as flow chart. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. 2\u0026nbsp;\u003c/strong\u003eFlow chart of the METAPANC trial\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;imaging/laparoscopy\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCT or MRI of abdomen with intravenous contrast agents according to specific protocols for imaging of the pancreas and local institutional practice as a standard-of-care procedure. CT/MRI may be used for imaging of the abdomen, Chest imaging by CT for detection of lung metastases.\u0026nbsp;In patients, who have not been surgically explored before application of mFOLFIRNOX chemotherapy, a diagnostic laparoscopy is optional but recommended under certain conditions. The aim of the diagnostic laparoscopy is to exclude patients with peritoneal carcinomatosis or more than three visible liver metastases. In general, a diagnostic laparoscopy should be performed in cases of resectable pancreatic cancer under the following conditions: when imaging shows a large tumor (\u0026gt;3 cm), or if ascites is present, or if there is an elevated tumor marker value of CA 19-9 \u0026gt; 500 U/ml, without cholestasis. In these situations, there is suspicion of occult organ metastasis (liver metastasis and/or peritoneal carcinomatosis). Intraoperative ultrasound, if available, of the liver during the diagnostic laparoscopy procedure is optional. MRI liver assessment at Response Assessment II is mandatory prior to randomization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003cem\u003e\u0026nbsp;\u003c/em\u003eregimen\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eModified FOLFIRINOX (mFOLFIRNOX) is a combination of systemic chemotherapy agents. It consists of:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eOxaliplatin\u0026nbsp;at a dose of 85 mg/m2 given as a 2-hour intravenous infusion\u003c/li\u003e\n \u003cli\u003eLeucovorin at a dose of 400 mg/m2 given as a 30 min to 2-hour intravenous infusion\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIrinotecan at a dose of 150 mg/m2 given as a 90-minute intravenous infusion\u003c/li\u003e\n \u003cli\u003e5-FU at 2400 mg/m2 administrated as an intravenous infusion of over a 46-hour period\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Treatment regimen mFOLFIRINOX\u003c/p\u003e\n\u003cp\u003eDrugs will be used in its commercially available form and will be provided by the local pharmacies, all brands allowed and identified by the ACT code generic versions of oxaliplatin, irinotecan, leucovorin, and 5-FU if commercially available can be used according to local practice and local regulation. Preparation, doses and administration of the mFOLFIRINOX regimen will follow the institutional practice of the study site and instructions given in the local SmPCs. Regimen will be repeated every two weeks. Primary prophylaxis with G-CSF after every cycle of mFOLFIRINOX will follow the institutional practice of the study site.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDose modifications and prerequisites for the start of a new cycle\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA dose modified regimen starting at the first cycle is also allowed at the discretion of the treating physician: irinotecan and oxaliplatin starting dose may be reduced to 80% [1][5][6]. Dose adjustments during treatment should be based on the maximum graded toxicity within the previous cycle, graded using the National Cancer Institute Common Toxicity Criteria (version 5.0).\u003c/p\u003e\n\u003cp\u003eAny toxicity associated with or possibly associated with study drug treatment should be managed with symptomatic treatment and dose modifications. Dose modifications may include dose reduction, dose interruption, and/or dose discontinuation. In case of non recovery after more than 2 weeks delay, stop treatment and refer to sponsor for decision on continuation. If mFOLFIRINOX is interrupted or delayed for \u0026gt; 4 weeks due to toxicity that is suspected to be related to treatment, study treatment should be permanently discontinued. After treatment interruption because of toxicity, the dose of one or more agents of the mFOLFIRINOX regimen may be modified according to maximum graded toxicity within the previous cycle as described below. Dose modifications will be at the discretion of the investigator per medical judgment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrerequisites and surgical procedures after randomization into Arm 1\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt is requested that the surgical procedures should be performed by the most experienced senior surgeons available in the individual centre. Selection of patients according to the inclusion criteria and eligibility of resectability will be performed in certified tumor boards in each participating centre.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSimultaneous resection is performed when the following criteria are met: 1. No peritoneal carcinomatosis or other organ metastases (except liver metastases) 2. No more than 3 liver metastases 3. Both primary tumor and liver metastases must be considered resectable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJudgement of resectability of the primary tumor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultidisciplinary participation is required for resectability judgement. The resectability of the primary tumor will be judged based on the \u0026ldquo;Resectability criteria pancreatic adenocarcinoma\u0026rdquo; of the Dutch Pancreatic Cancer Group (DPCG), 2012, http://www.dpcg.nl. Resectability is determined on preoperative imaging and defined by the DPCG. Resectable disease is defined as no arterial (hepatic artery, superior mesenteric artery, or coeliac trunk) tumor contact and venous (portal vein or superior mesenteric vein) tumor contact of 90 degrees or less. Borderline resectable disease is defined as arterial tumor contact 90 degrees or less and venous contact of 90 to 270 degrees without occlusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e Resectability criteria for pancreatic adenocarcinoma according to the Dutch Pancreatic Cancer Group, 2012, http://www.dpcg.nl\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence of surgical interventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Resection of one liver metastasis during the first explorative laparotomy or diagnostic laparoscopy is allowed for histological confirmation, preferably an atypical small resection of one peripheral liver metastasis. Macroscopic R0 resection should be achievable for the metastatic lesion. In this situation, the primary tumor will be resected after application of 8 cylces of mFOLFIRINOX chemotherapy in combination with the remaining liver metastases (if more than one but less than 3 liver metastases existed).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Explorative laparotomy and resection should be performed within 2-6 weeks after the last mFOLFIRNOX administration according to local institutional practice. Explorative laparoscopy to exclude peritoneal carcinomatosis immediately before laparotomy is optional. All procedures necessary to prepare for surgery, perioperative and postoperative that are standard-of-care, will also follow local institutional practice.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Based on the intraoperative findings during explorative laparotomy, the surgeon will evaluate and decide whether resection of the primary tumor in curative intent can be performed. Intraoperative rapid section analyses are obligatory for the pancreatic transection margin to ensure safe and margin-free resection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. The resection of the primary pancreatic tumor and the liver metastases can be conducted in the open laparotomy or minimally invasive technique. It is up to the surgeon, to conduct the sequence, first the resection of the metastases and secondly the resection of the pancreatic adenocarcinoma, or vice versa. In this decision, also the role of ablation is relevant which may lead to necrotic parts in the liver which could be infected by a subsequent hepaticojejunostomy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgical procedures for the liver metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. We have restricted the extent of liver surgery within the trial up to atypical liver resections of a maximum of three metastases.\u003c/p\u003e\n\u003cp\u003e2. Macroscopic R0 resection or ablation must be achievable for the metastatic lesion(s).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. A bisegmentectomy of segment II/III can be considered in individual cases.\u003c/p\u003e\n\u003cp\u003e4. In patients with metastatic lesions located in the center of the liver, requiring major resections, locally ablative techniques (e.g. radiofrequency or techniques available in the respective local study site) can be combined intraoperatively with surgical removal of resectable metastases. We recommend to conduct the ablation sonoguided intraoperatively according to local institutional practice.\u003c/p\u003e\n\u003cp\u003e5. Alternatively, the ablation can be conducted interventionally (e.g. percutaneous ct-guided) according to local institutional practice. In these cases\u0026nbsp;the liver ablation of selected metastatic lesion(s) can be planned 1-3 weeks after the last mFOLFIRINOX cycle, but within six weeks between the last cycle of chemotherapy and surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size calculation is driven by the primary endpoint overall survival. Recruitment will be over 5 years and all patients will be followed up for at least 2 additional years, unless the patient dies beforehand, resulting in a maximum follow-up of 7 years. Assuming two-year survival probabilities of 15% in the control arm [7] Figure 1A mFOLFIRINOX arm) and 30% in the experimental arm \u0026nbsp;a sample size of 109 patients per group will yield a power of 90% at the usual two-sided significance level of 5%. The assumed two-year survival probability of 30% in the experimental treatment arm corresponds to a hazard ratio of 0.635, which is considered clinically relevant. Adjusting conservatively for about 20% dropout (i.e. study discontinuations following randomization) we aim to randomize a total of 272 patients. The sample size calculation was carried out using nQuery (version 8.2.0.0). Assuming that about two thirds of the screened patients will be eligible for randomization we plan to screen about 400 patients.\u003c/p\u003e\n\u003cp\u003eWe will use an adaptive design in METAPANC. Towards the end of the recruitment period, we will conduct a sample size review verifying planning assumptions such as the overall event and dropout rate, i.e. based on non-comparative data (also referred to as blinded sample size re-estimation); the randomization code will be kept confidential and not be used in the sample size review. Furthermore, a futility analysis will be carried out; futility criteria will be based on the overall event rate and recruitment considerations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary analysis will follow the intention-to-treat (ITT) principle. The primary outcome survival will be analyzed by a Cox proportional hazards regression. The treatment effect will be reported as hazard ratio with 95% confidence intervals and p-value testing the null hypothesis of no effect (i.e. a hazard ratio of 1). Patients withdrawing from study treatment will be followed up for endpoints. Withdrawal from the study will be dealt with as independent right censoring in the primary analysis unless the patient\u0026rsquo;s vital status can be obtained at end of study. If withdrawal from study is substantial and differential between the treatment groups, supporting analyses will explore the impact of the independent right censoring assumption by use of shared frailty models for time to death and time to withdrawal from study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe analyses of the time-to-event outcomes among the secondary endpoints will follow the same lines as the analyses of the primary endpoint. Quality of life (EORTC QLQ-C30, PAN-26, CIPN20, Q-TWIST) and continuous outcomes assessed repeatedly will be analysed using the so-called Mixed Model Repeated Measures (MMRM) approach. Treatment differences will be reported as least square means with 95% confidence intervals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStandard reporting for adverse events (AEs) and serious adverse events (SAEs). AEs and SAEs will be summarized by frequencies and percentage for each treatment group. AEs will be coded according to MedDRA, analyzed, and presented following ICH E3 Structure and Content of Clinical Study Reports. Events of special interest (e.g. toxicities, post-operative complications) will be analyzed accounting for varying follow-up times and competing events [8].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll details of the statistical analysis including definitions of the analysis sets will be specified in a statistical analysis plan, which will be finalized prior to end of recruitment.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e\u003cstrong\u003eAssessment of severity/intensity\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eFor the grading of the severity/intensity of an adverse event (AE), the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0 must be used. Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately lifethreatening or result in death or hospitalization but may jeopardize the patient or may require an intervention to prevent one of the outcomes listed in the definition above. These events should also usually be considered serious (SAE). All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions (ADRs). The investigator must report the outcome of AEs and SAEs. All SAEs that have not resolved by the end of treatment visit or discontinuation of IMP treatment, whichever is later, must be followed until the outcome is recovered, recovered with squeal, unchanged/not recovered until death (death due to another cause) or death (due to the SAE). Investigators must report all SAEs immediately within 24 h of knowledge of the event.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegulatory, ethical, legal and trial oversight considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMETAPANC is a phase III clinical trial implemented and reported in accordance with the CTR (EU) 536/2014, ICH-GCP, with applicable Member states regulations, and with the ethical principles laid down in the Declaration of Helsinki. It was submitted, evaluated, and approved via CTIS with Germany as the reporting member state. It is registered under its EU Clinical Trial Number 2023-503558-10-00 in the EU Clinical Trial Register.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore enrolment in the clinical trial, the patient will be informed that participation in the clinical trial is voluntary and that he/she may withdraw from the clinical trial at any time without having to give reasons and without penalty or loss of benefits to which the patient is otherwise entitled. The treating physician will provide the patient with information about the treatment methods to be compared and the possible risks involved. At the same time, the nature, significance, implications, expected benefits and potential risks of the clinical trial and alternative treatment will be explained to the patient. During the informed consent discussion, the patient, if applicable, will also be informed about the insurance cover that exists and the insured\u0026apos;s obligations. The patient will be given ample time and opportunity to obtain answers to any open questions. All questions relating to the clinical trial should be answered to the satisfaction of the patient and/or his/her legal representative. In addition, the patient will be given a patient information sheet which contains all the important information in writing.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eMonitoring\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eIn German sites, monitoring is performed by the CRAs of the CTU UMG. Risk-based monitoring will be done according to ICH-GCP E6 and standard operating procedures (SOP) to verify that patients\u0026rsquo; rights and wellbeing are protected, reported trial data are accurate, complete and verifiable from source documents and that the trial is conducted in compliance with the currently approved protocol/amendment. All investigators will accept monitoring visits before, during and after the clinical trial to ensure that the trial is conducted, recorded and reported according to the trial protocol, SOPs, ICH-GCP and the applicable regulatory requirements. Prior to the trial, a site initiation visit at each site is conducted in order to train and introduce the investigators and their staff to the trial protocol, essential documents, handling of IMP and related trial specific procedures, ICH-GCP and national/local regulatory requirements. During the trial, the CRA will visit the site regularly depending on the recruitment rate and quality of data. During these on-site visits, the CRA verifies that the trial is conducted according to the trial protocol, trial specific procedures, ICH-GCP and national/local regulatory requirements. The presence of signed informed consents, eligibility of patients, primary endpoint, handling of IMP and documentation/reporting of safety data (e.g. AE/SAE) will be verified by the CRA. The CRA performs also source data verification to ensure that the clinical trial data which are recorded in the source data and eCRFs are complete and accurate. Extent of source data verification and monitor visit frequency will be adapted for individual sites in case of lack of data quality or a high number of protocol violations. All trial specific monitoring procedures, monitoring visit frequency and extent of SDV will be predefined in a trial specific monitoring manual. The investigator must maintain source documents for each patient in the trial, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical information, laboratory data, electrocardiograms, and the results of any other tests or assessments. All information recorded on eCRFs must be traceable to source documents in the patient\u0026apos;s file. The investigator must also keep the original signed informed consent form (a signed copy is given to the patient). The investigator must give the CRA access to all relevant source documents to confirm their consistency with the eCRF entries\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eTranslational research program\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThe translational research program aims to identify biomarkers for better identification of a potential target population which may benefit from intensified multimodal treatment strategies, to identify molecular biomarkers associated with progression or resistance to study treatment and to identify biomarkers adding to the understanding of PDAC tumor biology. The program will focus on collecting high-quality tissue and liquid biopsy samples, fecal samples and imaging data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExploratory biospecimen analyses\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- Tissue analyses: samples will be collected and undergo careful pathological quality assessment for subsequent molecular analysis using DNAseq (NGS panel to analyze the mutational status of KRAS, BRCA1/2 and other genes relevant in PDAC pathobiology), RNAseq (to perform signaling pathway analysis, deconvolution of cell lineages and gene expression analysis) and spatial immune profiling (multiplex-Immunofluorescence for tumor and immune markers including tumor markers (cytokeratins, GATA6), fibroblast markers (e.g. alpha-SMA, FAP), immune markers (e.g. CD3, CD4, CD8, Granzyme B) and markers assessing proliferation (KI67) and cell death (e.g. cleaved caspase 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- Liquid biopsy: collected blood samples will be used to isolate plasma and PBMCs. Quality assessment will be performed, and cell-free DNA and RNA will be isolated for analysis of predictors of response, resistance or toxicity.\u003c/p\u003e\n\u003cp\u003e- Fecal samples: identify biomarkers in the gut microbiome and other biomarkers (e.g. pancreatic enzymes) that are predictive of response to study interventions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBiological samples drawn during the course of the trial will be collected from the investigator sites and stored and further analyzed by a sponsor assigned central laboratory (West German Biobank and Bridge Institute of experimental Tumor Therapy, West German Cancer Center, University Hospital Essen). Detailed instructions on sample collection, processing, handling and shipment are provided in the laboratory manual (Supplementary Information, Additional file 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImaging analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe development of image-based biomarkers for therapy response prediction and disease outcome presents another exploratory endpoint. For this purpose, baseline and follow up imaging data will be collected for a central review process. Existing and newly developed machine learning (ML) algorithms will be applied to identify PDAC subtypes and predictive therapy response patterns as previously described.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe imaging biomarker translational program includes: secure imaging data transfer and central storage of imaging data, retrospective central image reading and longitudinal imaging data registration, quantitative imaging biomarker extraction (e.g. tumor / metastases, body composition and comorbidities) and ML-based outcome prediction including various clinical endpoints (e.g. therapy response, molecular marker, outcome).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with oligometastatic PDAC and relatively favorable tumor biology may benefit from simultaneous resection of both the primary tumor and liver metastases. This approach could potentially offer a chance for cure or, at least, lead to a survival benefit compared to conventional palliative chemotherapy in selected patients. However, once distant metastases are detected, tumor resection is still not recommended according to German and NCCN guidelines [9] [10], but resection may be considered in selected patients with oligometastases as part of a multimodal treatment approach within the context of clinical trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are no published results from randomized controlled trials on the topic of primary tumor resection in oligometastatic pancreatic cancer. The few systematic reviews consider relatively small case series. The survival prognosis is significantly better in oligometastasis with synchronous resection of the primary tumor and metastases compared to diffuse metastasis [11] [12] [13]. Overall, the predominantly retrospective studies provide evidence that overall survival in selected patients with oligometastatic PDAC could be significantly prolonged by primary synchronous resection of both the primary tumor and metastases, compared to patients who are only offered exploration or palliative bypass with chemotherapy [14] [15]. In the multicentre analysis by Tachezy et al., patients who underwent resection of an M1 pancreatic carcinoma showed a significantly longer survival compared to patients who only underwent exploration: 14 months vs. 8 months, but this applies only to the subgroup of patients with pancreatic head carcinoma [16]. These data, however, do not differ significantly from those achieved in the metastatic stage through systemic chemotherapy. In another study, patients with a body/tail pancreatic carcinoma benefited most from a synchronous resection of the primary tumor and liver metastases. A systematic review reports that patients with simultaneous resection of the primary tumor and liver metastases may even have comparable survival rates to patients who underwent resection without distant metastases. These findings are also observed in more recent, small, non-randomized pilot studies, where the tumor marker CA 125 is considered to play a special role as a resection criterion for liver metastases, and a notable degree of patient selection is apparent [17] [18]. The results after neoadjuvant chemotherapy may be more conclusive [19] [12]. In General, data from controlled and randomized studies are missing. In summary, there is evidence suggesting that synchronous resection of the primary tumor and metastases in oligometastatic pancreatic ductal adenocarcinoma, particularly as part of a multimodal treatment strategy, leads to better overall survival outcomes compared to diffuse metastatic pancreatic cancer. How these results compare to a state-of-the-art systemic therapy without resection must be determined by prospective, randomized studies. Until then, resection of the primary tumor and metastases is not yet a clinical standard, even in oligometastatic cases [20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the palliative setting, chemotherapy regimens such as FOLFIRINOX or gemcitabine/nab-paclitaxel have recently been established, demonstrating a significant improvement in overall survival (OS), with medians of 11 and 8.5 months, respectively, compared to 7 or 6.7 months with gemcitabine monotherapy [1] [21].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMultimodal treatment strategies, including local therapies, are recommended to enhance disease control and clinical outcomes in these patients. Distinct clinical courses of oligo- and polymetastasis are observed in tumors of different origins, and a comprehensive approach involving multiple entities is required to identify common underlying mechanisms. In pancreatic cancer, the concept of oligometastasis has not yet been established in clinical practice. Furthermore, it is currently unclear whether true oligometastatic disease exists in pancreatic cancer, as it does in colorectal cancer at known stages. The challenge right now is how to select patients who potentially profite from multimodal surgery treatment. Thus finding a strategy to select patient groups who most likely benefit from additional surgery is urgently needed. In this context the METAPANC trial aims to evaluate the effectiveness of multimodal therapy in patients with the clinical presentation of oligometastasis in pancreatic cancer. The combination of highly effective polychemotherapy (mFOLFIRINOX) followed by complete tumor resection is intended to support the potential for curative treatment in these patients \u0026mdash; a group that has previously been considered exclusively palliative. The primary objective of this randomized phase III study is to demonstrate the efficacy of this therapeutic concept in terms of overall survival.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMETAPANC is currently the only prospective, randomized, controlled, multicentre, phase III trial for curatively intended surgical therapy of oligometastatic pancreatic cancer in Western Europe and the Anglo-American world. In the Asian region, the CSPAC-1 study is currently being conducted as another prospective randomized study in China [4]. As a Phase II study on multimodal therapy for hepatically metastasized pancreatic adenocarcinoma, the HOLIPANC study investigates, in a single-arm study design, the effectiveness and quality of life of a neoadjuvant chemotherapy regimen consisting of liposomal irinotecan combined with oxaliplatin and 5-fluorouracil. The study also evaluates the significance of a curatively intended resection of the primary tumor and oligometastases (up to a maximum of 5 liver metastases).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe multimodal surgical therapy of patients with oligometastatic pancreatic cancer could significantly extend the survival of this patient group within the framework of the METAPANC trial. In order to recommend this treatment regimen outside of clinical trials, data from randomized controlled studies are needed first. An exploratory translational research program is implemented to identify patient groups that could benefit from multimodal surgical therapy. In Germany 26 institutions are currently planned as participating centres in Germany (Supplementary Information, Additional file 2). Additionally, international high-volume centres from the Netherlands, Finland, Sweden, and Norway are in preparation. The recruitment of patients has already started. The METAPANC trial is expected to run for at least seven years.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e5-FU: 5-fluorouracil\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ADR: Adverse drug reaction\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AE: Adverse event\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ACT: ATC: Anatomical Therapeutic Chemical (Classification System)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;alpha-SMA: alpha Smooth muscle actin\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AWMF: Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;BRCA1/2: Breast Cancer Gene 1/2\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CA 125: Cancer antigen 125\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CA19-9: Carbohydrate Antigen 19-9\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CD3: Cluster of Differentiation 3\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CD4: Cluster of Differentiation 4\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CD8: Cluster of Differentiation 8\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CHA: Common hepatic artery\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CRA: Clinical research associate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CR: Complete remission\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CSPAC: Chinese Study Group for Pancreatic Cancer\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CTR: Clinical Trials Regulation\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CT: Computer Tomography\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CTIS: Clinical Trials Information System\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CTU UMG: Clinical trials unit University Medicine G\u0026ouml;ttingen\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DPCG: Dutch Pancreatic Cancer Group\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DNAseq: DNA sequencing\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ECOG: Eastern Cooperative Oncology Group (ECOG Performance Status Scale)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;eCRF: electronic Case Report Form\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;EORTC: European Organisation For Research And Treatment Of Cancer\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;EORTC QLQ-C30: EORTC Core Quality of Life questionnaire\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;EORTC QLQ-PAN26: EORTC health-related quality of life for people with pancreatic ductal adenocarcinoma\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;FAP: fibroblast activation protein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;GATA6: GATA binding protein 6\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;GCP: Good Clinical Practice\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;G-CSF: Granulocyte colony stimulating factor\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IMP: Investigational Medicinal Product\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ITT: intention-to-treat\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;KI67: marker of proliferation Kiel 67\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;KRAS gene: Kirsten rat sarcoma virus proto-oncogene\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MedDRA: Medical Dictionary for Regulatory Activities\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;mFOLFIRINOX: modified FOLFIRINOX\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ML: Machine Learning\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MRI: Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NCCN: National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NGS: Next generation sequencing\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NYHA: New York Heart Association (NYHA Functional Classification)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;OS: overall survival\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PBMC: Peripheral Blood Mononuclear Cell\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PD: Progressive disease\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PDAC: Pancreatic ductal adenocarcinoma\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PFS: progression-free survival\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PR: Partial response\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PV: Portal vein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Q-TWIST: quality-adjusted time without symptoms or toxicity\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;RNAseq: RNA sequencing\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SAE: Severe adverse event\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SD: Stable disease\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SDV: Source Data Verification\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SMA: Superior mesenteric artery\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SmPC: Summary of product characteristics\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SMV: Superior mesenteric vein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SOP: Standard operating procedure\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;WBC: White Blood Cell\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to thank the Clinical Trials Unit, UMG (University Medical Center of Goettingen), in particular Ralph Tostmann, Wibke van Rees, Elisabeth Klingberg, Jasmina Schneider, Marianne Richter and the Clinical Trial Office of the Department of General-, Visceral-, and Pediatric Surgery, UMG, in particular Johanna Kreutzer, Esther Ohanecian, Niklas Hanke, Birgit Juenemann, Jessica Eggert, Chan Rong Lai and Almuth Wiederhold for excellent helpful support. Moreover the authors want to thank all patients, relatives and clinical teams involved in the delivery of the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMG\u003c/strong\u003e Conceptualization, study design, writing (original draft), project administration, funding acquisition\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eUP\u003c/strong\u003e Conceptualization, study design, writing (original draft), project administration, funding acquisition\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eMGB\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eJS\u003c/strong\u003e Conceptualization, study design, writing (original draft), project administration, funding acquisition \u003cstrong\u003eRT\u003c/strong\u003e Conceptualization, study design, writing (original draft), project administration, project manager\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eRB\u003c/strong\u003e Conceptualization, funding acquisition\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eHW\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eMC\u003c/strong\u003e Conceptualization, manuscript preparation, writing (original draft)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAK\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eUK\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSTL\u003c/strong\u003e Conceptualization, writing, Biobanking \u003cstrong\u003eKA\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eConceptualization, statistics \u003cstrong\u003eBU\u0026nbsp;\u003c/strong\u003eProject administration, conceptualization\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eHS\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAN\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePP\u003c/strong\u003e Conceptualization, study design \u003cstrong\u003eOFD\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eConceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eKJL\u003c/strong\u003e Conceptualization, study design \u003cstrong\u003eMJ\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSOB\u003c/strong\u003e Conceptualization, study design\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTF\u003c/strong\u003e Conceptualization, statistics, study design, writing (original draft), project administration, funding acquisition\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePJ\u003c/strong\u003e Conceptualization, study design, manuscript preparation, writing (original draft), funding acquisition,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eproject administration\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe full study protocol and all regulatory documents can be provided by the sponsor upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMETAPANC is a phase III clinical trial implemented and reported in accordance with the CTR (EU) 536/2014, ICH-GCP, with applicable member states regulations, and with the ethical principles laid down in the Declaration of Helsinki. It was submitted, evaluated, and approved via CTIS with Germany as the reporting member state. A statement of ethical approval and consent was issued by the State Office for Health and Social Affairs (LAGESO) Berlin, Germany. The ethic committee of the federal state of Berlin approved the study. METAPANC is registered under its EU Clinical Trial Number 2023-503558-10-00 in the EU Clinical Trial Register.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTF declares personal fees for statistical consultancies (including data monitoring committees) from Actimed, Apellis, Aslan, AstraZeneca, Bayer, BiosenseWebster, BMS, Cardior, CSL Behring, Daiichi Sankyo, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, PINK! gegen Brustkrebs, PPD, RECARDIO, Recordati, Relaxera, Roche, Servier, Viatris, Vifor, VICO Therapeutics; all outside the submitted work.\u003c/p\u003e\n\u003cp\u003eAll other authors declare that they have no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eConroy T, Desseigne F, Ychou M, Bouch\u0026eacute; O, Guimbaud R, B\u0026eacute;couarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 11;364(19):1817\u0026ndash;25. doi: 10.1056/NEJMoa1011923. PMID: 21561347.\u003c/li\u003e\n\u003cli\u003eKandel P, Wallace MB, Stauffer J, Bolan C, Raimondo M, Woodward TA, Gomez V, Ritter AW, Asbun H, Mody K. Survival of patients with oligometastatic pancreatic ductal adenocarcinoma treated with combined modality treatment including surgical resection: a pilot study. J Pancreat Cancer. 2018 Nov 1;4(1):88\u0026ndash;94. doi: 10.1089/pancan.2018.0011. PMID: 30631861.\u003c/li\u003e\n\u003cli\u003eRenz BW, Boeck S, Roeder F, Trumm C, Heinemann V, Werner J. Oligometastatic disease in pancreatic cancer: how to proceed? Visc Med. 2017 Mar;33(1):36\u0026ndash;41. doi: 10.1159/000455027. PMID: 28612015.\u003c/li\u003e\n\u003cli\u003eWei M, Shi S, Hua J, Xu J, Yu X; Chinese Study Group for Pancreatic Cancer (CSPAC). Simultaneous resection of the primary tumour and liver metastases after conversion chemotherapy versus standard therapy in pancreatic cancer with liver oligometastasis: protocol of a multicentre, prospective, randomised phase III control trial (CSPAC-1). BMJ Open. 2019 Dec 8;9(12):e033452. doi: 10.1136/bmjopen-2019-033452. PMID: 31818843.\u003c/li\u003e\n\u003cli\u003eConroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018 Dec 20;379(25):2395\u0026ndash;406. doi: 10.1056/NEJMoa1809775. PMID: 30575490.\u003c/li\u003e\n\u003cli\u003eTong H, Fan Z, Liu B, et al. The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis. Sci Rep. 2018 Jun 6;8:8666. doi: 10.1038/s41598-018-26811-9. PMID: 29875415.\u003c/li\u003e\n\u003cli\u003eConroy T, Desseigne F, Ychou M, Bouch\u0026eacute; O, Guimbaud R, B\u0026eacute;couarn Y, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med. 2011 May 11;364(19):1817\u0026ndash;25. doi: 10.1056/NEJMoa1011923. PMID: 21561347\u003c/li\u003e\n\u003cli\u003eStegherr, R., Schmoor, C., Beyersmann, J. \u003cem\u003eet al.\u003c/em\u003e Survival analysis for AdVerse events with VarYing follow-up times (SAVVY)\u0026mdash;estimation of adverse event risks. \u003cem\u003eTrials\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 420 (2021). doi: 10.1186/s13063-021-05354-x. PMID: 34187527 \u003c/li\u003e\n\u003cli\u003eLeitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF). S3-Leitlinie Exokrines Pankreaskarzinom, Langversion 3.1, 2024, AWMF-Registernummer: 032-010OL [Internet]. 2024 [cited 2024 Dec 1]. Available from: https://www.leitlinienprogramm-onkologie.de/leitlinien/pankreaskarzinom/.\u003c/li\u003e\n\u003cli\u003eTempero MA, Malafa MP, Behrman SW, Benson AB 3rd, Casper ES, Chiorean EG, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2014 Aug;12(8):1083\u0026ndash;93. doi: 10.6004/jnccn.2014.0106. PMID: 25099441.\u003c/li\u003e\n\u003cli\u003eHackert T, Niesen W, Hinz U, Tjaden C, Strobel O, Ulrich A, et al. Radical surgery of oligometastatic pancreatic cancer. Eur J Surg Oncol. 2017 Mar;43(3):358\u0026ndash;63. doi: 10.1016/j.ejso.2016.10.023. PMID: 27856064.\u003c/li\u003e\n\u003cli\u003eYang J, Zhang J, Lui W, Huo Y, Fu X, Yang M, et al. Patients with hepatic oligometastatic pancreatic body/tail ductal adenocarcinoma may benefit from synchronous resection. HPB (Oxford). 2020;22(1):91\u0026ndash;101. PMID: 31262486.\u003c/li\u003e\n\u003cli\u003eDamanakis AI, Ostertag L, Waldschmidt D, Kutting F, Quaas A, Plum P, et al. Proposal for a definition of \u0026apos;Oligometastatic disease in pancreatic cancer\u0026apos;. BMC Cancer. 2019 Dec;19(1):1261. doi: 10.1186/s12885-019-6448-9. PMID: 31888547.\u003c/li\u003e\n\u003cli\u003eKim Y, Kim SC, Song KB, Kim J, Kang DR, Lee JH, et al. Improved survival after palliative resection of unsuspected stage IV pancreatic ductal adenocarcinoma. HPB. 2016 Mar;18(3):325\u0026ndash;31. doi: 10.1016/j.hpb.2015.10.014. PMID: 27037201.\u003c/li\u003e\n\u003cli\u003eLowder CY, Metkus J, Epstein J, Kozak GM, Lavu H, Yeo CJ, et al. Clinical implications of extensive lymph node metastases for resected pancreatic cancer. Ann Surg Oncol. 2018 Dec;25(13):4004\u0026ndash;11. doi: 10.1245/s10434-018-6763-4. PMID: 30225835.\u003c/li\u003e\n\u003cli\u003eTachezy M, Gebauer F, Janot M, Uhl W, Zerbi A, Montorsi M, et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery. 2016 Jul;160(1):136\u0026ndash;44. doi: 10.1016/j.surg.2016.02.019. PMID: 27048934.\u003c/li\u003e\n\u003cli\u003eShi HJ, Jin C, Fu DL. Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: diagnosis and assessment of unresectability. World J Gastroenterol. 2016 Dec;22(45):10024\u0026ndash;37. doi: 10.3748/wjg.v22.i45.10024. PMID: 28018110.\u003c/li\u003e\n\u003cli\u003eKandel P, Wallace MB, Stauffer J, Bolan C, Raimondo M, Woodward TA, et al. Survival of patients with oligometastatic pancreatic ductal adenocarcinoma treated with combined modality treatment including surgical resection: a pilot study. J Pancreat Cancer. 2018 Nov;4(1):88\u0026ndash;94. doi: 10.1089/pancan.2018.0011. PMID: 30631861.\u003c/li\u003e\n\u003cli\u003eCrippa S, Bittoni A, Sebastiani E, Partelli S, Zanon S, Lanese A, et al. Is there a role for surgical resection in patients with pancreatic cancer with liver metastases responding to chemotherapy? Eur J Surg Oncol. 2016 Dec;42(12):1533\u0026ndash;9. doi: 10.1016/j.ejso.2016.06.398. PMID: 27423449.\u003c/li\u003e\n\u003cli\u003eGebauer F, Damanakis AI, Bruns C. [Oligometastasis in pancreatic cancer: current state of knowledge and spectrum of local therapy]. Chirurg. 2018 Jun;89(6):510\u0026ndash;5. doi: 10.1007/s00104-018-0626-1. PMID: 29557488.\u003c/li\u003e\n\u003cli\u003eVon Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691\u0026ndash;703. doi: 10.1056/NEJMoa1304369. PMID: 24131140.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Objectives and endpoints of the METAPANC trial\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1. Objectives\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e1.1. Primary Objectives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026bull; To assess the efficacy of neoadjuvant multimodal chemotherapy followed by complete tumor and metastases resection in patients with hepatic oligometastatic PDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e1.2. Secondary Objectives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026bull; To determine the efficacy and safety of the treatment concept\u003cbr\u003e\u0026nbsp;\u0026bull; To determine health-related quality of life (HR-QoL)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e1.3. Other Exploratory Objectives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026bull; To evaluate biomarkers and imaging data for better identification of a potential target population\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2. Endpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e2.1. Primary Endpoint\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026bull; Overall survival as the time from randomization to death of any cause\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e2.2. Secondary Endpoints\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003e\u0026bull;\u0026nbsp;\u003cem\u003eEfficacy\u003c/em\u003e: Progression-free survival\u003cbr\u003e\u0026bull; \u003cem\u003eSafety\u003c/em\u003e: grading of the severity/intensity of an adverse event: the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0\u003c/p\u003e\n \u003cp\u003e\u0026bull;\u0026nbsp;\u003cem\u003eHealth-Related Quality of Life\u003c/em\u003e: EORTC QLQ-C30, PAN-26, Q-TWIST\u003cbr\u003e\u0026bull; \u003cem\u003eExploratory Endpoints\u003c/em\u003e: Translational endpoints\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Treatment regimen mFOLFIRINOX\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"600\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIMP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose [mg/m\u0026sup2;]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRoute of administration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e2-hour intravenous infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eLeucovorin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e30 min to 2-hour intravenous\u003c/p\u003e\n \u003cp\u003einfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eIrinotecan\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e90 min intravenous infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e5-FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e2400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e46-hour intravenous infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e Resectability criteria for pancreatic adenocarcinoma according to the Dutch Pancreatic Cancer Group, 2012, http://www.dpcg.nl\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003esuperior mesenteric artery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCeliac axis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ecommon hepatic artery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMV-PV\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003esuperior mesenteric vein \u0026ndash; portal vein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResectable\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(all four required)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eno contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eno contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eno contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;90\u0026deg; contact\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBorderline resectable\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(minimally one required)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;90\u0026deg; contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;90\u0026deg; contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;90\u0026deg; contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e90\u0026deg;-270\u0026deg; contact and no occlusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIrresectable\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(minimally one required)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003econtact \u0026gt; 90\u0026deg;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003econtact \u0026gt; 90\u0026deg;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003econtact \u0026gt; 90\u0026deg;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003econtact \u0026gt; 270\u0026deg; or occlusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Oligometastasis, Pancreatic Ductal Carcinoma (PDAC), Oligometastatic Pancreatic Cancer, Liver Metastasis, Multimodal Treatment, Chemotherapy, Pancreatic Surgery, Clinical Trials","lastPublishedDoi":"10.21203/rs.3.rs-5815668/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5815668/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on current guidelines, surgical treatment of hepatic oligometastases in patients with pancreatic ductal adenocarcinoma (PDAC) is not primarily recommended. \u0026nbsp;Systematic chemotherapy is the therapy of choice for these patients. The relevance of subsequent surgical resection after chemotherapy remains unclear. This multicentre, randomized, controlled phase III trial is planned to evaluate whether resection of the primary tumor and liver metastases can improve overall survival in patients with PDAC with hepatic oligometastases in a multimodal treatment setting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter an induction therapy with eight cyles of mFOLFIRINOX and a response assessment after four and eight cycles, patients will be randomized to either Arm 1 (perioperative mFOFIRINOX plus resection of the primary tumor with resection or ablation of all hepatic metastases) or Arm 2 (continuation of 4 cycles of the standard-of-care mFOLFIRINOX chemotherapy). This clinical trial will focus on a well-defined patient group with metastatic disease limited to the liver as the target organ, with a maximum of three metastases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMETAPANC is the first international, randomized, controlled, open-label, multicentre, phase III clinical trial for curative intended surgical therapy of oligometastatic pancreatic cancer in Europe and America. The multimodal surgical treatment of patients with oligometastatic pancreatic cancer could significantly extend the overall survival of this patient group. A possible recommendation of this multimodal treatment regimen outside of clinical trials requires data from randomized controlled trials first. To identify patient subgroups that might benefit from multimodal surgical therapy, additional information on tumor genetics could supplement valid parameters.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e EU Clinical Trials No. 2023-503558-10-00\u003c/p\u003e","manuscriptTitle":"Intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus chemotherapy alone: a randomized controlled trial (METAPANC)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-15 12:26:42","doi":"10.21203/rs.3.rs-5815668/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-20T04:43:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-14T04:48:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-14T04:48:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-01-12T23:45:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68e521bd-3194-4f62-96bd-73fa19e76125","owner":[],"postedDate":"January 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-10T16:01:23+00:00","versionOfRecord":{"articleIdentity":"rs-5815668","link":"https://doi.org/10.1186/s12885-025-13573-7","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-02-06 15:57:21","publishedOnDateReadable":"February 6th, 2025"},"versionCreatedAt":"2025-01-15 12:26:42","video":"","vorDoi":"10.1186/s12885-025-13573-7","vorDoiUrl":"https://doi.org/10.1186/s12885-025-13573-7","workflowStages":[]},"version":"v1","identity":"rs-5815668","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5815668","identity":"rs-5815668","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}