Irinotecan, Oxaliplatin, and Capecitabine as First-Line Therapy in Treating Patients With Metastatic or Unresectable Locally Advanced Small Bowel Cancer

Inclusion Criteria

* Confirmation UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A1) TA indel genotype of 6/6, 6/7, or 7/7 after pre-registration but prior to registration
* Patient willingness to provide a serum sample for analysis for celiac disease (tissue transglutaminase antibodies)
* Small bowel adenocarcinoma, either metastatic or locally advanced and not surgically resectable; NOTE: periampullary carcinoma and appendiceal cancer are not eligible
* Histologic or cytologic confirmation of adenocarcinoma consistent with small bowel origin; biopsy can be of primary tumor or can be from a metastatic site if there is a primary small bowel tumor currently or previously present
* Measurable disease; for patients with lesions \>= 1 cm but \< 2 cm, spiral computed tomography (CT) scan imaging must be used for tumor assessments
* Life expectancy \>= 12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
* \>= 4 weeks since prior major surgery to time of registration
* \>= 2 weeks from completion of any radiation treatment
* Absolute neutrophil count (ANC) \>= 1,500/mm\^3
* Platelets \>= 100,000/mm\^3
* Serum glutamic oxaloacetic transaminase (SGOT) =\< 5 x upper normal limit (UNL); =\< 2.5 x UNL if no liver metastases
* Total bilirubin:

  * For 6/6 patients: =\< upper limit of normal (ULN)
  * For 6/7 or 7/7 patients: =\< 2.0 x ULN
* Hemoglobin \>= 9.0 g/dL
* Creatinine =\< 1.5 x UNL (if \> 1.5 x UNL, calculated creatinine clearance should be checked.; if it is \> 60 mL/min, then the patient is eligible for the study)
* Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only

Exclusion Criteria

* Prior chemotherapy regimen for advanced small bowel cancer (prior adjuvant chemotherapy with fluorouracil (5FU)/leucovorin is permitted if last dose was administered \>= 3 months prior to registration); prior oxaliplatin or irinotecan use as adjuvant therapy is not permitted
* Prior radiotherapy to \> 25% of bone marrow
* Active or uncontrolled infection
* Evidence of serious intercurrent illness (e.g., unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia)
* Pregnant women; women of child-bearing potential and men must agree to use adequate contraception (diaphragm, birth control pills, injections, foams, intrauterine device \[IUD\], or abstinence, etc.) for the duration of study participation; if a woman becomes pregnant or suspects that she is pregnant while participating in this study, she should inform her treating physician immediately and all study treatment discontinued
* Nursing women; breast-feeding should be discontinued when the mother is treated with these agents
* Men or women of childbearing potential who are unwilling to employ adequate contraception
* Current evidence of other malignancy besides small bowel adenocarcinoma, with exception of non-melanoma skin cancer
* Known central nervous system metastases or carcinomatous meningitis
* Preexisting sensory neuropathy \>= grade 2 from any cause interfering with function
* Concurrent therapy with sorivudine, brivudine, lamivudine, or stavudine