Stereotactic Body Radiation Therapy for Inoperable Non-metastasized Pancreatic Adenocarcinoma

This is a multicenter randomized phase II trial that aims to include 160 patients with a non-metastatic (localized), inoperable pancreatic tumor. The study will take place at multiple centers across Europe. The primary objective of the study is to demonstrate superiority in progression free survival (PFS) by adding stereotactic body radiation therapy (SBRT) to chemotherapy for patients with an inoperable non-metastasized pancreatic tumor. SBRT is a radiotherapy technique (i.e. destroying cancer cells by means of ionizing irradiation) in which tumors can be irradiated with a high radiation dose. Surrounding healthy tissue is thus spared to the maximum extent. The primary endpoint of the TORPEDO study is 2-year PFS defined as the percentage of patients who are free of disease progression at 2 years after the date when the patients were drawn into 2 treatment groups (i.e. randomization). Secondary outcomes are, among others, quality of life, acute and late toxicity (i.e. adverse events), metastasis-free survival, local progression-free survival, overall survival, subsequent resectability, R0 resection and surgical morbidity.

During the study, patients without disease progression after 3 months of induction chemotherapy will be randomized 1:1 to either treatment with chemotherapy or treatment with a combination of chemotherapy and SBRT (5 x 8 Gy). After treatment with chemotherapy, alone or followed by SBRT, imaging (CT scan, MRI scan) will be used to determine whether surgery can still be performed to improve patient survival. After treatment (and surgery if applicable), ten-weekly follow-up visits will occur during two years to evaluate the quality of life, general blood parameters and general health condition of the patient. Moreover, toxicity will be evaluated as well as efficiency and safety of the treatment (e.g. by means of imaging).

The occurrence of pancreatic cancer is increasing in Belgium. Although this type of cancer is severe, there are only a limited number of treatment options. The preferred treatment is usually surgery. However, this is only possible in certain circumstances. If surgery is not possible, chemotherapy is administered to improve survival. A combination of chemotherapy and SBRT followed by surgery if possible has already been used in some studies and will be investigated in a larger number of subjects with the TORPEDO study.

A patient needs to sign an informed consent form before participating in the TORPEDO study. Participation in the TORPEDO study consists of the following phases: screening, induction chemotherapy, restaging and randomization, treatment, resectability assessment whether or not followed by surgery and a follow-up phase.

During the screening phase, eligibility of the patient to participate in the study will be assessed. Demographics data, information regarding medical history, prior medications and adverse events will be recorded. Moreover, a clinical assessment, blood tests to assess general blood parameters, a CT chest/abdomen and MRI pancreas will be performed. Eligible patients (according to the inclusion criteria and exclusion criteria) will receive induction chemotherapy (standard of care) during 12 weeks. Either 6 cycles of mFOLFIRINOX or 3 cycles of gemcitabine / nab-paclitaxel will be administered. If, within one week after the end of chemotherapy (restaging), CT chest/abdomen and MRI pancreas do not show extrapancreatic disease and in absence of massive gastric or intestinal invasion, subjects will be randomized 1:1 to either treatment with chemotherapy (arm A) or treatment with a combination of chemotherapy and SBRT (5 x 8 Gy) (arm B).

During the treatment phase, all subjects will receive 4 weeks of chemotherapy (either 2 cycles of mFOLFIRINOX or 1 cycle of gemcitabine/nab-paclitaxel). 7 to 28 days after the end of this chemotherapy treatment, subjects randomized in arm B will undergo SBRT (5 fractions of 8 Gy), preceded by the implantation of fiducial markers and simulation.

28 days after the end of the chemotherapy (arm A) or after the last SBRT fraction (arm B), various data will be collected (e.g. clinical assessment, blood tests such as determination of tumor marker CA19-9 level, CT chest/abdomen and MRI pancreas, questionnaires regarding quality of life and the occurence of adverse events) and resectability will be multidisciplinary determined. At 6 weeks (+/- 2 weeks) after chemotherapy (arm A) or SBRT (arm B), subjects considered suitable will have surgery. All subjects will receive another 8 weeks of chemotherapy (4 cycles of mFOLFIRINOX or 2 cycles of gemcitabine/nab-paclitaxel).

The follow-up phase consists of ten-weekly follow-up visits during 2 years. These follow-up visits consist of a clinical assessment, CT chest/abdomen imaging, blood sampling, elicitation of AE's and assessment of the subject's quality of life through questionnaires. After these 2 years, patients will be followed by standard of care, six monthly during the following 3 years. After five years, patients will be followed on a yearly basis (standard of care). Follow-up data (survival status) will be collected.

Eligibility Criteria:
Inclusion Criteria:

* Participant must be over 18 years of age.
* Participant is able and willing to provide written informed consent which includes compliance with and ability to undergo all study procedures and attend the scheduled follow-up visits per protocol.
* Either locally advanced or borderline resectable pancreatic adenocarcinoma, as confirmed by diagnostic images (CT, MRI or PET-CT scan) and based on vessel involvement according to the NCCN guidelines. Only borderline resectable pancreatic cancer (BRPC) patients who are medically unfit for surgery or refusing surgery can be included.
* Adequate organ function determined by the following laboratory values:

  * Adequate bone marrow function: absolute neutrophil count ≥1500/mm\^3, platelet count ≥100000/mm\^3 and hemoglobin ≥9 g/dl
  * Adequate renal function: Creatinine ≤1.5 x upper normal limit of normal (ULN) or estimated eGFR more than 45 ml/min
  * Adequate liver function: total bilirubin ≤1.5 ULN (after adequate biliairy stenting with metal stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤5x ULN
* An Eastern Cooperative Oncology Group (ECOG) performance status grade of 0-2.
* A life expectancy ≥3 months
* A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

  * Is not a woman of child bearing potential or
  * A woman of child bearing potential must have a negative serum pregnancy test at screening and must use a very effective method of birth control.

Exclusion Criteria:

* Extrapancreatic metastatic disease as defined on diagnostic imaging (CT, MRI or PET-CT scan) or laparoscopy, including distal nodal involvement beyond the peripancreatic tissues and/or distant metastases.
* Massive gastric or intestinal invasion as assessed on imaging and/or endoscopy. Direct invasion of the duodenal mucosa as visible on endoscopic ultrasound (EUS).
* Prior radiation therapy that could hamper adequate dose delivery
* Contraindication to magnetic resonance imaging (MRI)
* Diagnosis of another malignancy within 2 years prior to randomization, except non-melanoma skin cancer, non-invasive bladder cancer, carcinoma in situ of the cervix or non-metastatic prostate cancer. Patients with a history of other malignancies are eligible if they have been continuously disease-free for at least 2 years after definitive primary treatment.
* Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the subject.

Additional exclusion criteria after restaging (i.e. within 1 week after 3 months of induction chemotherapy) and prior to randomization:

* Extrapancreatic metastatic disease as defined on diagnostic imaging, including distal nodal involvement beyond the peripancreatic tissues and/or distant metastases
* Massive gastric or intestinal invasion as assessed on imaging and/or endoscopy. Direct invasion of the duodenal mucosa as visible on EUS.