Due to COVID and other recruitment issues the trial could not be initiated.

To determine if carbon ion radiotherapy improves overall survival versus photon therapy in patients with locally advanced, unresectable pancreatic cancer

To compare the efficacy of carbon ion-based chemo radiotherapy with x-ray-based chemo radiotherapy for the treatment of locally advanced pancreatic adenocarcinoma by comparison of overall survival at 2 years following treatment.

Patient has 2 in 3 chance of receiving Arm A and 1 in 3 chance of receiving Arm B.

Arm A (chemoradiation takes place in Japan):

CIRT in 12 fractions/treatments plus concurrent gemcitabine, followed by 4 cycles of gemcitabine + nab-Paclitaxel, or until progression or intolerance of therapy

Arm B:

IMRT in 28 fractions plus concurrent gemcitabine or capecitabine, followed by 4 cycles of gemcitabine + nab-Paclitaxel, or until progression or intolerance of therapy

Per investigator discretion, patients may receive either:

1. Definitive treatment :
2. Neoadjuvant treatment:

Adjuvant chemotherapy 4 cycles of gemcitabine/nab-paclitaxel or FOLFIRNOX, Gemcitabine alone if these regimens are unavailable

Inclusion Criteria:

1. All patients must be willing and capable to provide informed consent within the 30 days prior to registration to participate in the protocol.

2. Histological and/or cytological diagnosis of pancreas adenocarcinoma must be done at any point prior to registration

3. Unresectable by radiographic or exploration within 30 days of registration

4. Age ≥ 18 years.

5. Distance from the pancreas tumor edge to the bowel and stomach > 3 mm (in both the prone and supine positions)

6. Tumor does not exceed 15 cm in greatest dimension

7. No evidence for metastatic disease as assessed by CT imaging of the chest, abdomen and pelvis OR by PET-CT within the 30 days prior to registration. Pancreas-protocol CT or magnetic resonance imaging (MRI) with gadolinium (for patients who cannot receive CT contrast) is required as part of this evaluation.

8. Zubrod performance status of 0-1, within 30 days prior to registration.

9. Adequate hematologic, renal, and liver function as defined by:Adequate hematologic, renal, and liver function as defined by:

   Absolute neutrophil count > 1500 cells/mm3 Creatinine <1.5 mg/dL Hemoglobin ≥ 8.0 g/dL AST and ALT < 2.5 X ULN Bilirubin ≤ 1.5 times the ULN (after stent placement, if necessary)

10. Patients must complete all required pretreatment evaluations

11. Able to travel to a foreign country within approximately 4 weeks of randomization (for patients enrolled outside of Japan and Italy)

12. If a patient receives 1 or 2 cycles of chemotherapy at an outside facility, pre-treatment laboratory values must meet the above criteria. If the protocol-compliant imaging had not been obtained prior to chemotherapy, they may be performed prior to registration and any additional chemotherapy being infused.

13. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

1. Subjects receiving other investigational agents.
2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or nab-paclitaxel or other agents used in study.
3. Subjects who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
4. Prior radiation to the upper abdomen
5. Placement of a metal stent for relief of biliary obstruction (metal stents may be placed following completion of radiation therapy).
6. Body weight >100 kg
7. Active inflammatory bowel disease or active gastric/duodenal ulcer
8. Metal implants in the upper abdomen
9. Expected medical intolerance of radiotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
10. History of HIV or hepatitis B or C