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)

For patients who have not started their chemotherapy prior to registration, the interval between definitive tumor-related surgery and 1st step registration must be between 21-70 days; for patients entering on the study who have already received up to 3 months of adjuvant chemotherapy as per the treating institution, the interval between definitive tumor-related surgery and day one of adjuvant chemotherapy must be between 21-77 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. Pathologic reporting using the College of American Pathologists (CAPS) format is strongly encouraged

Age \>= 18

Zubrod performance status 0 or 1

Complete history and physical examination including weight and Zubrod status within 31 days of study entry (or within 31 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)

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

Complete blood count (CBC)/differential obtained within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)

Absolute neutrophil count (ANC) \>= 1,500/mm\^3

Platelets \>= 100,000/mm\^3

Hemoglobin \>= 8.0 g/dL (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 8.0 g/dl is acceptable)

Post resection serum cancer antigen (CA)19-9 =\< 180 units/mL AND prior to any systemic treatment

Serum total bilirubin =\< twice the institutional upper limit of normal (ULN) within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)

Creatinine levels =\< twice the institutional upper limit of normal within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)

Serum glutamic oxaloacetic transaminase (SGOT) must be =\< 2.5 x the institutional upper limit of normal within 21 days of registration on study (or within 21 days prior to day 1 of chemotherapy post-surgery for those patients having started chemotherapy prior to first step registration)

Negative serum pregnancy test for women of childbearing potential within 14 days of study registration

Abdominal/pelvic 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 (or within 31 days prior to day 1 of chemo post-surgery for those patients having started chemotherapy prior to first step registration); patients allergic to IV contrast can have 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

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 intraductal papillary mucinous neoplasms (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

Patients entering on the study after pancreaticoduodenectomy, who have not already started chemotherapy must not have had prior systemic chemotherapy for pancreas cancer; note that prior chemotherapy for a different cancer is allowable; for patients entering on the study who have already received up to 3 months of adjuvant chemotherapy as per the treating institution, patients must not have received adjuvant chemotherapy with agents other than gemcitabine, nab-paclitaxel, oxaliplatin, fluoropyrimidine, or irinotecan for the current pancreatic cancer; 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 (or first day of chemotherapy for patients having started chemotherapy prior to first step registration); patients with a previous history of carcinoma in situ are eligible

Severe, active co-morbidity, defined as follows per time points indicated below (or per time points indicated below prior to the first day of chemotherapy for patients having started chemotherapy prior to first step registration):

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; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic

If surgical margin status cannot be determined after consultation with the operating surgeon and the institutional pathologist, the patient will be ineligible

• Adenocarcinoma

• Anti-Infective Agents

• Antimetabolites

• Antimetabolites, Antineoplastic

• Antineoplastic Agents

• Antiviral Agents

• Capecitabine

• Carcinoma

• Carcinoma, Acinar Cell

• Digestive System Diseases

• Digestive System Neoplasms

• Endocrine Gland Neoplasms

• Endocrine System Diseases

• Enzyme Inhibitors

• Erlotinib

• Fluorouracil

• Gemcitabine

• Immunologic Factors

• Immunosuppressive Agents

• Molecular Mechanisms of Pharmacological Action

• Neoplasms

• Neoplasms by Histologic Type

• Neoplasms by Site

• Neoplasms, Glandular and Epithelial

• Pancreatic Diseases

• Pancreatic Neoplasms

• Pharmacologic Actions

• Physiological Effects of Drugs

• Radiation-Sensitizing Agents

• RTOG 0848

• Therapeutic Uses

• Oncology (Adult)

• National Cancer Institute (NCI)