Pancreatic cancer (PC) is expected to be the third leading cause of cancer death in Canada in 2019 [1]. Localized pancreatic cancer may be classified as resectable, borderline resectable, or locally advanced. To date, radical surgical resection and adjuvant treatment provide the greatest chance of long-term disease control and overall survival [2,3]. Despite this favourable group, the five-year survival rates are approximately 20% [4].

Neoadjuvant therapy (NAT) for resectable pancreatic cancer (RPC) has been widely accepted for the management of borderline resectable PC (BRPC) to increase the likelihood of achieving R0 resection [4-7]. However, to date, NAT for RPC is still an area of debate due to the lack of large prospective randomized controlled trials that compare this technique to surgery plus adjuvant therapy.

Stereotactic ablative radiation therapy (SABR) uses modern radiotherapy planning and targeting technologies to precisely deliver larger, ablative doses of radiotherapy in 1-8 fractions. The role of SABR in RPC has yet to be fully established. The typical goal of radiation therapy in the neoadjuvant setting is to improve local control and increase R0 resection rates. However, there are still concerns about the timing of surgery after SABR and any implementation should be evaluated for safety.

Treatments inherently changes the tumour and can cause immunomodulatory effects. SABR has anti-neoplastic effects both directly on the tumour and by its interactions with the immune system. In addition to the direct DNA damage, it is felt that SABR also increases T-cell priming, antigen production and presentation. Pancreatic cancer's dense, collagen rich stroma has prevented patients from receiving the same benefits of checkpoint inhibition that have been achieved in other cancer sites.

Goals: The primary goals of this study are to evaluate the safety and feasibility of neoadjuvant SABR patients with surgical PC. This proposal is specifically intended to strengthen the correlative sciences evaluating pre- and post-treatment tissue samples and serial plasma samples evaluating the immunomodulatory effects of neoadjuvant SABR.

Population: Patients with upfront resectable pancreatic adenocarcinoma (RPC) with a plan to proceed directly to curative surgery or borderline resectable pancreatic adenocarcinoma (BRPC) with a plan for neoadjuvant FOLFIRINOX chemotherapy with the hopes of then proceeding to a curative surgical resection will be accrued.

Objectives and Endpoints: The primary objective is to determine the safety and feasibility of neoadjuvant SABR in patients with PC. Secondary objectives include (1) determining the tumor perfusion with serial dynamic contrast enhanced CT imaging studies; (2) evaluating serial peripheral blood samples for changes in markers of inflammation or immune activation using O-link's plasma-based proteomics platform; (3) T-cell receptor (TCR) sequencing from RNA isolated from the buffy coat from serial whole blood samples; (4) Digital spatial profiling on FFPE samples from pre-treatment biopsy tissue and post-treatment surgical resection samples to examine CD3, CD8, PD-L1 expression and other markers of immunomodulation; (5) RNA sequencing (RNA-Seq) will be conducted on pre- and post-treatment samples to examine the gene expression profile within specific areas of the tumor environment; (6) examining the influence of SABR on classic biomarkers such as CEA and CA19-9.

Methodology: Upfront RPC (n=10) and BRPC (n=20) with the expectation of approximately 10 participants receiving neoadjuvant SABR on study.

Imaging Studies: Patients in both arms will receive both a hybrid PET/MRI scan and a dynamic contrast enhanced (DCE-CT) scan prior to SABR to define high metabolic regions (using 18F-FDG PET), define the whole tumour border (using MRI), and to define baseline perfusion parameters such as blood flow, blood volume, permeability surface, and mean transit time (using DCE-CT). This information will be used to define regions that will receive high doses of radiation therapy. These patients will also receive a DCE-CT scan six hours after the first of three radiation treatments and 4 weeks following SABR (before surgery) to investigate changes in blood flow.

Inclusion Criteria (Both Arms):

• Age 18 or older
• Able to provide informed consent
• Histologically confirmed primary pancreatic cancer, or willing to undergo endoscopic ultrasound (EUS) with synchronous fiducial marker placement and biopsy
• No evidence of distant metastases (M0)
• Medically fit to undergo surgical resection
• Life expectancy >6 months
• Adequate renal function to tolerate contrast dye for imaging
• ECOG Performance Status 0-2 Inclusion Criteria (Arm 1)
• Upfront resectable pancreatic cancer
• No evidence of nodal disease (N0)
• Appropriate to undergo a pancreaticoduodenectomy within 4-6 weeks of registration

Inclusion Criteria (Arm 2)

• Borderline resectable or upfront resectable pancreatic cancer
• Plan for surgical resection independent of the biochemical or radiographic response to SABR

Exclusion Criteria (Both Arms):

• Serious medical comorbidities or other contraindications to radiotherapy or surgery
• Gross disease involving duodenum or stomach
• Unable to have fiducials placed.
• Recurrent pancreatic cancer
• Prior abdominal radiation at any time
• Inability to attend full course of radiotherapy, surgery, or follow-up visits
• Contrast allergy
• Pregnant or lactating women

Exclusion Criteria (Arm 1):

• Receipt of any neoadjuvant system therapy, standard cytotoxic therapy or experimental

Exclusion Criteria (Arm 2):

• Elevated bilirubin or liver enzymes considered to be a contraindication to irinotecan chemotherapy, unless an intervention is planned to improve hepatic functioning