Preoperative mFOLFIRINOX (or Gem-Nab-P) +/- Isotoxic High-dose SBRT for Borderline Resectable Pancreatic Adenocarcinoma

Inclusion criteria:

* Cytologic or histologic proof of adenocarcinoma of the pancreatic head or uncinated process or body or tail. Diagnosis should be verified by local pathologist
* cTNM stage: T1-4N0-2M0
* Confirmation of clinical and radiographic stage as borderline resectable (CT scan and/or MRI scan with contrast according to the NCCN criteria) by a multidisciplinary board, composed by a dedicated oncological surgeon, radiologist and GI oncologist)
* Age \> 18 years old
* No prior chemotherapy or radiation for pancreatic cancer
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* No grade ≥ 2 neuropathy
* Laboratory parameters as follows:
* Absolute neutrophil count (ANC) ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 9 g/dL
* Creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated GFR \>45 mL/min
* Bilirubin ≤ 1.5 x ULN, including after adequate biliary stenting with metal stent (ideally 4 cm length)
* Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5x ULN
* CA 19.9 \< 2500 kU/l (baseline, prior to any therapy and absence of cholestasis)

Exclusion Criteria:

* Evidence of extrapancreatic disease on diagnostic imaging (CT, MRI or PET scan), histologically proven or at laparoscopy, including distal nodal involvement beyond the peripancreatic tissues (including non-regional lymph node involvement, ie: proven involvement of precaval lumbar lymphadenopathy(ies) and/or distant metastases
* Locally advanced disease as defined by the NCCN criteria (version 2.2021) ie \> 180° arterial encasement (SMA and CA) unreconstructible venous encasement (SMV/PV) due to tumor involvement or occlusion of a long segment.
* CA 19.9 \> 2500 kU/l (baseline and absence of cholestasis)
* Contraindication of surgery (general)
* Contraindications to receive FFX or gemcitabine-nab-Paclitaxel
* History of radiotherapy of the upper abdomen
* Prior treatment with oxaliplatin, irinotecan, fluoruouracil or capecitabin
* Patient \< 18 years old
* Major surgery within 4 weeks of study entry
* Uncontrolled pre-existing disease including, but not limited to: active infection, symptomatic congestive heart failure, unstable angina, social / psychiatric disorder that would limit compliance to treatment and good understanding of the informed consent form
* Other concurrent anticancer therapies
* Existence of another active neoplasia other than basal cell carcinoma of the skin, cervical carcinoma in situ or non-metastatic prostate cancer. Patients who have a history of neoplasia must have been in remission for more than 5 years to be included in the protocol
* Pregnant or breastfeeding women; for women of childbearing potential only, a negative pregnancy test done \< 7 days prior to registration is required. Using of reliable contraception for at least 1 month before treatment is mandatory
* Chronic concomitant treatment with strong inhibitors of cytochrome p450, family 3, subfamily a, polypeptide 4 gene (CYP3A4) is not allowed on this study; patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study

Additional exclusion criteria before randomisation:

* Progressive disease (RECIST or PETCT, including non locoregional nodal involvement and increase of CA 19.9 by 20%) after receiving 4 cycles of FFX (or G/NP), including shift chemotherapy in case of early progression.
* CA 19.9 \> 1000 kU/l after neoadjuvant therapy.
* Presence of unmanageable toxicity during the first part of neoadjuvant chemotherapy (first 4 cycles or 6 doses of FFX or G/NP, respectively.
* Pancreatic tumour \> 7.0 cm in greatest axial dimension at the time of randomization
* Massive invasion of the stomach or intestines and/or direct intestinal invasion of the mucosae visible at ultrasoundendoscopy
* Active gastric or duodenal ulcer disease at the time of randomization. Tolerated in case of antecedent without active ulcer (confirmation by endoscopy before iHD-SBRT)