This phase I trial tests the safety and effectiveness of stereotactic body radiation therapy (SBRT) followed by 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in treating patients with large well-differentiated grade 1-2 digestive system neuroendocrine tumors that cannot be removed by surgery (unresectable). SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body. The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. 177Lu-DOTATATE is a radioactive drug. It binds to a protein called somatostatin receptor, which is found on some neuroendocrine tumor cells. 177Lu-DOTATATE builds up in these cells and gives off radiation that may kill them. It is a type of radioconjugate and a type of somatostatin analog. Giving PRRT after SBRT may reduce the chances of the disease returning or getting worse, compared to the standard treatment of PRRT alone.

PRIMARY OBJECTIVE:

I. To determine the rate of acute grade 3+ non-hematologic toxicity of PRRT after external radiation compared to historical control of PRRT alone.

SECONDARY OBJECTIVES:

I. To determine the rate of acute grade 2+ toxicity compared to historical control of PRRT alone.

II. To determine response rate of both large and small lesions at 3 months following treatment.

III. To determine progression free survival. IV. To describe patient-reported outcomes (PROs) of toxicity.

OUTLINE:

Patients undergo SBRT over 5 fractions in the absence of disease progression or unacceptable toxicity. Starting 4-10 weeks after completion of SBRT, patients receive standard of care (SOC) lutetium-177 DOTATATE (177Lu-DOTATATE) intravenously (IV) once every 8 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the trial and undergo gallium Ga 68-DOTATATE positron emission tomography (PET)/CT before treatment.

After completion of study treatment, patients are followed up at 90 days and then every 3 months for 12 months.

Inclusion Criteria:

• Male or female
• Age ≥ 18 years
• Patient must be able to provide study specific informed consent
• Pathologically confirmed neuroendocrine tumor fulfilling all of the following criteria
• Well-differentiated, grade 1-2
• Unresectable (prior resection is allowable), verified by tumor board or surgical oncology (surg onc)
• Progression after one or two prior lines of systemic therapy
• Somatostatin-receptor positive disease as determined by positive radiotracer-labeled DOTATATE PET/CT scan (modified Krenning score 3+)
• One or more large lesions measuring 3 or more cm on contrast-enhanced CT or MRI
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Estimated glomerular filtration rate (GFR) > 30 mL/min (within 90 days prior to study registration)
• Total bilirubin ≤ 3 x upper limit of normal (within 90 days prior to study registration)
• Albumin > 30 g/L (within 90 days prior to study registration)
• White blood cell (WBC) ≥ 2,000 cells/mm^3 (within 90 days prior to study registration)
• Platelets ≥ 70000 cells/mm^3 (within 90 days prior to study registration)
• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable.) (within 90 days prior to study registration)

Exclusion Criteria:

• Any prior radiation therapy including prior PRRT, external radiation, or Yttrium-90 radioembolization to the same site/region
• Contraindications to radiation therapy including inflammatory bowel disease, systemic sclerosis, etc.
• Brain metastases or any metastases extending into the spinal canal
• Unable to obtain confirmation of payment coverage for any planned radiation treatment