Testing Higher Dose Radiation Therapy for Locally Advanced Pancreatic Cancer

This phase III trial compares the effect of dose-escalated radiation therapy to usual care in patients with locally advanced unresectable pancreatic ductal adenocarcinoma who have received an initial 4-6 months of chemotherapy. Usual care options include additional chemotherapy, observation, or standard lower-dose radiation therapy. These treatments may delay tumor growth but have not been shown to improve survival. Radiation therapy uses high energy X-rays to kill cancer cells and shrink tumors. Dose-escalated radiation therapy involves the precise delivery of higher doses to the tumor, often over a shorter period of time. This trial assesses whether using dose-escalated radiation therapy can prolong survival.

PRIMARY OBJECTIVE:

1. To evaluate whether dose-escalated radiation therapy (RT) improves 3-year overall survival (OS) compared to standard treatments without dose-escalated RT, in locally advanced pancreatic cancer patients without radiographic progression and with biochemical response after an initial interval of chemotherapy.

SECONDARY OBJECTIVES:

1. To evaluate and compare local progression between the two treatment arms. II. To evaluate and compare progression-free survival (PFS) between the two treatment arms.

III. To evaluate and compare chemotherapy-free interval between the two treatment arms.

IV. To evaluate and compare toxicity within and between the two treatment arms.

HEALTH-RELATED QUALITY-OF-LIFE (HRQOL) OBJECTIVES:

1. Primary: To compare Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Total Score at 6 months between the two treatment arms.

II. Secondary: To compare nadir of HRQoL scores over course of study participation between the two treatment arms.

III. Secondary: To evaluate HRQoL scores over time between the two treatment arms.

EXPLORATORY OBJECTIVE:

1. Biospecimen collection for future correlative analyses.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (STANDARD OF CARE): Patients are assigned to 1 of 3 treatment options per physician's decision.

OPTION 1: Patients continue to receive fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin (FOLFIRINOX or modified FOLFIRINOX [mFOLFIRINOX]) or fluorouracil, liposomal irinotecan, leucovorin calcium, and oxaliplatin (NALIRIFOX) or gemcitabine/nab-paclitaxel per standard of care for a total of 6 months of treatment. Patients may continue treatment beyond 6 months at physician's discretion.

OPTION 2: Patients undergo standard dose radiation therapy once daily for 28 or 30 fractions and receive concurrent fluorouracil or capecitabine per standard of care during radiation therapy. After completing concurrent chemoradiation, patients who received less than 6 months of chemotherapy at study entry are encouraged to receive the remaining chemotherapy to total 6 months of chemotherapy. Patients may continue chemotherapy treatment beyond 6 months at physician's discretion.

OPTION 3: Patients undergo observation per standard of care. (It is recommended [but not required] that this option only be for patients that have already completed total 6 months chemotherapy pre-randomization.)

Additionally, patients undergo blood sample collection, computed tomography (CT), magnetic resonance imaging (MRI) and tumor tissue biopsy throughout the study.

ARM II (DOSE-ESCALATED RADIATION THERAPY): Patients undergo dose-escalated RT daily, every other day, or twice weekly for 5 fractions or daily for 25 fractions (with or without concurrent fluorouracil or capecitabine for 25 fractions only). The 5-fraction regimen is preferred when feasible. After completing dose-escalated RT, patients who received less than 6 months of chemotherapy at study entry are encouraged to receive the remaining chemotherapy to total 6 months of chemotherapy. Patients may continue chemotherapy treatment beyond 6 months at physician's discretion. Additionally, patients undergo blood sample collection, CT, MRI and tumor tissue biopsy throughout the study.

Patients are followed every 3 months from study entry for 2 years then annually for 3 years.