Standard of Care Chemotherapy with or Without Stereotactic Body Radiation Therapy for Oligometastatic Pancreatic Cancer

This phase II trial studies the effect of standard of care chemotherapy with or with out stereotactic body radiation therapy in treating patients with pancreatic cancer that has spread to a limited amount of places in the body (oligometastatic). Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with stereotactic body radiation therapy may help improve tumor control, decrease risk of tumor spreading more, decrease side effects, and prolong survival.

PRIMARY OBJECTIVE:

I. Compare progression free survival (PFS) between stereotactic body radiation therapy (SBRT) + standard chemotherapy versus (vs.) standard chemotherapy alone in patients with oligometastatic pancreatic cancer.

SECONDARY OBJECTIVES:

I. Confirmed response rate. II. Overall survival. III. Adverse events. IV. Longitudinal assessment of circulating tumor cells (CTC) and circulating tumor deoxyribonucleic acid (ctDNA).

CORRELATIVE RESEARCH OBJECTIVE:

I. To evaluate fatigue, and other patient-reported outcomes.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients undergo SBRT once daily (QD) or every other day for 5 fractions and receive chemotherapy per standard of care on study. Additionally, patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and blood collection throughout the study.

GROUP II: Patients receive chemotherapy per standard of care on study. Additionally, patients undergo CT, MRI, and blood collection throughout the study. Patients who have local disease progression at known sites and no new sites of progression may crossover to the radiotherapy arm.

After completion of study treatment, patients are followed up at 7 and 14 days, and then every 8-12 weeks for 2 years.

Eligibility Criteria:
Inclusion Criteria:

* Age \>= 18 years
* Histologically confirmed adenocarcinoma of pancreatic origin with pathologic material reviewed by the Department of Pathology at Mayo Clinic, if available and applicable
* Image proven oligometastatic pancreatic cancer patients (i.e., synchronous \& metachronous)

  * Oligometastatic defined as: =\< 5 extracranial metastatic tumors (brain metastasis patients are excluded; indeterminate lung nodules stable on 2 consecutive imaging studies spaced more than 4 weeks apart will not count as sites of oligometastatic disease)
  * All sites must be amenable to SBRT (positive peritoneal washings cytology or Kras cell free (cf)DNA, and positive peritoneal biopsy would be considered ineligible)
* Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
* Non-measurable disease

  * NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Negative pregnancy test done =\< 7days prior to registration, for women of childbearing potential only

  * NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Ability to complete questionnaire(s) by themselves or with assistance
* Provide written informed consent
* Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
* Willing to provide tissue and/or blood samples for correlative research purposes
* Hemoglobin \>= 9.0 g/dL (obtained =\< 28 days prior to registration)
* Absolute neutrophil count (ANC) \>= 1500/mm\^3 (obtained =\< 28 days prior to registration)
* Platelet count \>= 100,000/mm\^3 (obtained =\< 28 days prior to registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) (If known Gilbert's syndrome, then =\< 3.0 x ULN) (obtained =\< 28 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 3 x ULN (=\< 5 x ULN for patients with liver involvement) (obtained =\< 28 days prior to registration)
* Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =\< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =\< 28 days prior to registration)
* Calculated creatinine clearance \>= 45 ml/min using the Cockcroft-Gault formula (obtained =\< 28 days prior to registration)

Exclusion Criteria:

* Pregnant women
* Nursing women
* Men or women of childbearing potential who are unwilling to employ adequate contraception
* Any of the following prior therapies:

  * Surgery =\< 3 weeks prior to registration
  * Prior radiation to an overlapping area
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* 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
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* Other active malignancy =\< 1 year prior to registration

  * EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
  * NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
* History of myocardial infarction =\< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias