Inclusion Criteria:

• Histologic proof of primary head of pancreas invasive adenocarcinoma managed with a potentially curative resection (i.e., removal of all gross tumor) involving a classic pancreaticoduodenectomy (Whipple) or a pylorus preserving pancreaticoduodenectomy; patients with invasive adenocarcinoma that also contains a component of intraductal papillary mucinous neoplasm (IPMN) are eligible
  • The operating surgeon must document in the operative note that a complete gross excision of the primary tumor was achieved; the pathology report must include documentation of the margin status and the size of the tumor; the pathology report must also include the status of the three major margins—bile duct, pancreatic parenchyma, and retroperitoneal (uncinate)
• Interval between definitive tumor-related surgery and 1st step registration between 21-70 days
• Patients will be staged according to the 6th edition American Joint Committee on Cancer (AJCC) staging system with pathologic stage T1-3, N0-1, M-0 being eligible
• Zubrod performance status 0 or 1
• Complete history and physical examination including weight and Zubrod status within 31 days of study entry
• Before starting therapy the patient should be able to maintain adequate oral nutrition of ≥ 1500 calories estimated caloric intake per day and be free of significant nausea and vomiting
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• Platelets ≥ 100,000/mm^3
• Hemoglobin (Hgb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable)
• Post resection serum cancer antigen (CA)19-9 ≤ 180 units/mL within 21 days of registration on study
• Serum total bilirubin ≤ twice the institutional upper limit of normal (ULN) within 21 days of registration on study
• Creatinine levels ≤ twice the institutional upper limit of normal within 21 days of registration on study
• Serum glutamic oxaloacetic transaminase (SGOT) must be ≤ 2.5 x institutional ULN within 21 days of registration on study
• Negative serum pregnancy test for women of childbearing potential within 14 days of study registration
• Abdominal/pelvic computed tomography (CT) scan with contrast is preferred; abdominal CT alone is acceptable only if insurance restrictions are experienced; chest CT/x-ray (CT of chest preferred) within 31 days of registration on study; patients allergic to intravenous (IV) contrast can have magnetic resonance imaging (MRI) of the abdomen/pelvis instead
• Signed study-specific informed consent
• Consultation, agreement, and documentation in the patient's chart by a radiation oncologist that patient is suitable to receive radiotherapy per this protocol
• Women of childbearing potential and male participants must practice adequate contraception
• Patients with active human immunodeficiency virus (HIV) infection are eligible if their cluster of differentiation (CD)4 count is > 499/cu mm and their viral load is < 50 copies/ml; use of highly active antiretroviral treatment (HAART) is allowed

Exclusion Criteria:

• Patients with non-adenocarcinomas, adenosquamous carcinomas, islet cell (neuroendocrine) tumors, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile duct, and ampullary carcinomas; patients with tumors that are largely IPMN with a minimal or minor component of invasive carcinoma are not eligible; patients with acinar carcinomas are not eligible; patients with IPMN's that contain some secondary (minor) foci of adenocarcinoma are also not eligible
• Patients managed with a total pancreatectomy, a distal pancreatectomy, or central pancreatectomy
• Prior systemic chemotherapy for pancreas cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Previous history of invasive malignancy (except non-melanoma skin cancer) unless the patient has been disease free for at least 2 years prior to study entry (patients with a previous history of carcinoma in situ are eligible)
• Severe, active co-morbidity, defined as follows:
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the 3 months of study registration
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
• Pregnant or lactating women
• Women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• If surgical margin status cannot be determined after consultation with the operating surgeon and the institutional pathologist, the patient will be ineligible