This is a phase II randomized study of concurrent chemoradiotherapy and local hyperthermia (study group) versus chemoradiotherapy alone (control group) following neoadjuvant chemotherapy in locally advanced pancreatic cancer. Each of the treatment arm would have 39 patients based on the expected overall 1 year survival advantage of +20% over the control group (p0=40%).

This phase II randomized trial is a part of the comprehensive protocol designed for the locally advanced pancreatic cancers (LAPC). All patients of LAPC, fulfilling the following criteria of "Unresectable LAPC" would be considered to be eligible for enrolment in the study.

These include:

1. Major venous infiltration / thrombosis of the portal vein or superior mesenteric vein extending for several centimeters (precluding vein resection and reconstruction)
2. Tumor encasement (≥180°) of the superior mesentric artery or proximal hepatic artery
3. Tumor abutment (<180°) of the celiac trunk
4. Tumor invasion of the aorta
5. Presence of metastasis to lymph nodes beyond the field of resection All patients would be reviewed at the Pancreas Cancer Tumor Board, University Hospital Zurich and those fulfilling the above condition/s would be considered for the study protocol of LAPC. Following a detailed work up, all eligible patients with primary tumours more than 4 cm would be considered for HEATPAC study.

Patients would be randomized by random digit using a double blinded strategy into either (a) Control group : Treated with concurrent chemoradiotherapy or (b) Study group: Treated with local hyperthermia along with concurrent chemoradiotherapy.

Treatment in both groups would be initiated with 4 cycles of neo-adjuvant chemotherapy (FOLFIRINOX). At completion of 4 cycles of neo-adjuvant FOLFIRINIOX, patients would be evaluated by PET-CT, 3-4 week following the last cycle of FOLFIRINIOX. Patients in control group would be taken up for concurrent gemcitabine (400 mg / sq.m weekly) along with loco-regional radiotherapy by SIB-IMRT to a dose of 50.4 Gy in 28 fractions. Patients in the study group would be receiving loco-regional hyperthermia to a temperature of 40-41°C, weekly for 1 hour before gemcitabine and before radiotherapy. The gemcitabine and in loco-regional radiotherapy in study group would be similar to that of the control group.

Following the completion of this treatment, patients of both groups would be considered for 8 cycles of adjuvant FOLFIRINOX and followed up with both clinical, heamatological and imaging studies as detailed in the study protocol.

Primary endpoint:

1. Overall survival at 1 year
2. To assess the acute and the late morbidities associated with hyperthermia and chemoradiotherapy in concurrent chemoradiotherapy compared to concurrent chemoradiotherapy alone.

Secondary endpoints:

1. To compare the disease free survival in patients of locally advanced pancreatic cancers following neoadjuvant chemotherapy with FOLOFIRINOX treated with hyperthermia and chemoradiotherapy versus chemoradiotherapy alone.
2. To assess the patterns of failure (both local and systemic) in patients of both treatment arms.

Inclusion Criteria:

1. Patients of locally advanced pancreatic cancer with

   • Major venous infiltration / thrombosis of the portal vein or superior mesenteric vein extending for several centimeters
   • Tumor encasement (≥180°) of the superior mesentric artery or proximal hepatic artery
   • Tumor abutment (<180°) of the celiac trunk
   • Tumor invasion of the aorta
   • Presence of metastasis to lymph nodes beyond the field of resection

2. Histopathologically proven ductal adenocarcinoma of the pancreas (biopsy /cytology)

3. Eastern Cooperative Oncology Group (ECOG) performance scale 0 and 1

4. Age: 18 to 80 years

5. At least one of the diameters of the primary tumor or regional lymph node or both should be greater than 4 cm, as confirmed on contrast-enhanced computed tomography (CECT).

6. Patients, have primary tumor or regional lymph node or both lesser than 4 cm, as confirmed on CECT but have specific medical contraindications to stereotactic body radiation therapy or irreversible electroporation or as per patient's preference could be considered for HEATPAC.

7. No evidence of any distant metastasis

8. Patients with microscopic peritoneal carcinomatosis, detected on laparoscopy following 4 cycles on neo-adjuvant FOLFIRINOX would be included.

9. Estimated life expectancy of at least 6 months

10. Adequate kidney functionality defined as creatinine clearance >50ml/min

11. Adequate liver functionality defined as total bilirubin ≤ 2x of the upper limit of normal

12. Adequate bone marrow reserves: White blood cell count ≥ 2.5 x 10˄9/L, Platelet count ≥ 100 x 10˄9/L, Hemoglobin ≥ 8.0g/L

13. Women of child-bearing age must secure sufficient contraception control during the clinical trial and six months after the clinical trial is completed

14. For females of child bearing potential, negative pregnancy test within 2 week prior to randomization.

15. Female patients should not be lactating

16. Absence of psychological, familial, sociological or geographical condition that could potentially hamper compliance with the study protocol and follow-up schedule

Exclusion Criteria:

1. Histopathology other than ductal adenocarcinoma pancreas
2. Prior radiotherapy to the site of treatment
3. Patients with unequivocal distant metastasis including liver
4. Patients with gross peritoneal carcinomatosis on laparoscopy
5. No prior or concurrent malignancies other than surgically treated squamous cell or basal cell carcinoma of the skin
6. No serious medical illness which would prevent informed consent or limit survival to less than 2 years
7. Active uncontrolled bacterial, viral or fungal infections until these conditions are corrected or controlled.
8. Psychiatric or addictive disorders or other conditions that would preclude the patient from meeting the study requirements.
9. Patients having metal implants, pacemakers or clustered markers.
10. Metallic endobiliary stenting would be a contraindication, hence plastic stents may be used if biliary drainage is indicated.
11. Patient with a history of myocardial infarction within the past 12 months
12. No connective disease disorders that contraindicate radiotherapy, e.g., Scleroderma
13. Pre-existing grade 2 peripheral neuropathy
14. Any known contraindication or hypersensitivity to the chemotherapeutic agents
15. Pregnancy, lactation period or lack of reliable contraception
16. Any other disease or therapy, which, present a risk to the patient or which are not compatible with the aims of the clinical trial
17. Patients would express their inability to travel on their own to Kantonsspital Aarau, (KSA) for hyperthermia treatment
18. Indications that the person concerned will be noncompliant to the clinical trial plan because of unwillingness to cooperate or difficulties in keeping the check-up appointments