This trial is a single-arm, prospective, multi-center clinical trial designed to demonstrate that stereotactic adaptive radiotherapy using an ablatively dosed (50Gy,5fx) for treatment of borderline-resectable, locally-advanced , or medically inoperable pancreatic adenocarcinoma will translate into a decreased toxicity. The study will evaluate GI toxicity, overall survival, local control, quality of life, and workflow metrics.

Inclusion Criteria:

1. Histologically or cytologically confirmed borderline-resectable (based on NCCN criteria), locally-advanced (based on NCCN criteria), or medically inoperable pancreatic adenocarcinoma.

2. ECOG performance status 0-1

3. Receipt of at least two months of lead-in chemotherapy (regimen at the discretion of the treating physician) prior to planned initiation of CT-STAR.

4. Limited regional lymphadenopathy permitted. Node positive patients are restricted to those with up to 3 clinically involved (greater than 1cm on cross-sectional imaging or pathologically proven) nodes provided that the lymph nodes are adjacent to the primary tumor.

5. At least 18 years of age.

6. Must be able to take an interruption in systemic therapy at least one week prior to planned start of CT-STAR (two weeks preferred) lasting for the duration of CT-STAR and continuing for at least one week following end of CT-STAR (two weeks preferred).

7. Capable of a single end-exhale breath-hold of at least 20 seconds in duration and of repeated end-exhale or deep inspiratory breath-hold of at least 10 seconds in duration upon verbal instruction.

8. Anatomy of target and adjacent OARs adequately visualized on ETHOS simulation imaging, as determined by treating and study physicians.

   Note: central review of simulation imaging and initial plan target/OAR contours by the Principal Investigator and Physics lead is required for the first two patients at each participating institution prior to study treatment delivery. Patients with inadequate anatomic visualization at simulation will be considered screen-failures and treated off-protocol as per institutional standard-of-care.

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

Exclusion Criteria:

1. Past history of radiotherapy within the projected treatment field
2. Prior, intercurrent, or planned receipt (within 90 days prior to or following SBRT) of any investigational agents related to pancreatic cancer diagnosis.
3. Competing, active cancer diagnosis within the preceding one year.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
5. Gross tumor invasion of the stomach or duodenum (defined either radiographically or endoscopically).
6. Pregnant and/or breastfeeding. Patients of childbearing potential must have a negative pregnancy test within 14 days of study entry.