Ablative dose magnetic resonance imaging (MRI) guided hypofractionated radiation therapy delivered using daily adaptive dose planning has shown to improve overall survival, relative to patients receiving lower radiation doses, in patients with locally advanced pancreatic cancer, without increasing the rate of serious gastrointestinal toxicity. The next step is to determine how these results compare to chemotherapy alone.

This is a prospective, randomized controlled trial (2:1) comparing induction chemotherapy followed by ablative Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) versus chemotherapy alone in locally advanced pancreatic cancer patients. Overall survival outcomes at 2-years will be evaluated.

Inclusion Criteria:

1. Locally advanced pancreatic adenocarcinoma or adenosquamous carcinoma as defined by NCCN guidelines.

2. Minimum of 4 months interval from chemotherapy start to administration of the last dose/chemo.

3. Minimum 8 cycles of (m)FOLFIRINOX OR 12 doses of gemcitabine/nab - paclitaxel)

4. No radiographic evidence of local or distant disease progression at any time prior to study enrollment after starting chemotherapy

5. At least 18 years of age

6. ECOG performance status ≤ 1

7. Adequate bone marrow and organ function as defined below:

   1. Absolute neutrophil count ≥ 1,000/mcL
   2. Platelets ≥ 75,000/mcL
   3. Hemoglobin ≥ 8.0 g/dL
   4. Total bilirubin ≤ 1.5 x IULN
   5. AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN

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

9. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

1. CA19-9 > 180 U/mL within 30 days of randomization.
2. Any prior abdominal radiation therapy.
3. History of prior malignancy with the exception of: 1) malignancy treated with curative intent and with no known disease for at least 2 years from treatment to study enrollment, 2) adequately treated carcinoma in situ without evidence of disease (i.e. superficial bladder cancer).
4. Currently receiving any other investigational agents.
5. More than one cytotoxic regimen given for pancreatic cancer.
6. Major abdominal surgery within 4 weeks prior to randomization.
7. Definitive surgery for pancreas cancer completed prior to study enrollment (e.g., Whipple procedure).
8. Subject with planned or scheduled definitive surgery for pancreas at time of study enrollment
9. Grade 3 or greater toxicity during induction chemotherapy that has not resolved to at least grade 2
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
11. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
12. Medical/psychological contraindication to having an MRI scan.