This is an interventional, single-arm, open-label study with high dose short course radiotherapy for patients with locally advanced pancreatic cancer.

This is an interventional, open label, trial of definitive hypofractionated radiotherapy for patients with locally advanced pancreatic cancer.

Within this study radiotherapy shall be delivered with active scanning particle-therapy using proton- or carbon ions radiotherapy.

Particle therapy will be performed with a simultaneous integrated boost (SIB) treating a larger target volume, including elective lymph node stations and neural plexus, at a lower dose and boosting macroscopic disease.

The investigator will explore the efficacy of these treatment in a real world scenario in which patients are allowed to receive standard systemic treatment and standard surgical treatment (if conversion to resectability is achieved).

However, and in order to record and to gain better understanding of the influence of systemic therapies on the outcomes parameters of this study, patients will be sub-stratified in 3 groups: i) patients receiving FOLFIRINOX, ii) patients receiving Gemcitabine + Nanoparticle Albumin Bound Paclitaxel (NAB-Paclitaxel), iii) patients receiving other systemic therapies or not receiving antineoplastic systemic therapy.

Inclusion Criteria:

1. The patient has histologically or cytological confirmed diagnosis of pancreatic cancer (cases with radiological findings suspicious of pancreatic cancer AND elevated CA 19-9 may be enrolled even without positive cytology)

2. The patient is not candidate for radical surgical resection because of one or more of the following reasons:

   1. the patient is staged as locally advanced and with unresectable disease according to the international consensus definition. Specific criteria are: there is involvement of portal vein/superior mesenteric vein with bilateral narrowing/occlusion, exceeding the inferior border of the duodenum; or tumor contact/invasion of 180 or more degree of the superior mesenteric artery or of the truncus coeliacus; or tumor contact/invasion of the proper hepatic artery/ celiac artery; or tumor contact or invasion of the aorta.
   2. the patient is not a candidate for radical surgery because of radiographic or biochemical (CA 19-9) progression during neoadjuvant chemotherapy despite being initially classified as resectable or borderline resectable according to the international consensus definition.
   3. the patient is not candidate for radical surgery because of cN+ stage

3. The patient is not candidate to (further) neoadjuvant chemotherapy because of one or more of the following reasons:

   1. the patient is not fit for chemotherapy
   2. the patient has progressed under chemotherapy
   3. the patient has received neoadjuvant chemotherapy but is judged still not a candidate for explorative surgery.

4. Negative staging for distant metastasis

5. Age > 18 years

6. Karnofsky index ≥ 70

7. No tumor infiltration of stomach or duodenum

8. The patient is informed of the diagnosis and is able to give informed consent (Ability of patient to understand character and individual consequences of the study protocol)

9. Women of fertile age must have adequate conception prevention measures and must not breast feed

10. Signed Informed Consent (must be available before study inclusion)

Exclusion Criteria:

1. Non-exocrine tumors
2. Major medical or psychiatric comorbidities that contraindicate radiotherapy
3. Presence of distant metastasis
4. Pregnancy or unwilling to do adequate conception prevention
5. Lactating and unwilling to discontinue lactation
6. Men of procreative potential not willing to use effective means of contraception
7. Metallic prosthesis or other conditions - IF it prevents an adequate imaging for target volume definition or treatment planning at the discretion of the treating institution contraindicate radiotherapy e.g. active infections in the area
8. Previous abdominal radiotherapy
9. Severe hepatic or renal impairment at discretion of treating institution
10. Patient refusal