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)