This research study is studying a combination of interventions as a possible treatment for gastroesophageal (GE) junction cancer.

The interventions involved in this study are:

-FOLFIRINOX which is made up of 4 different drugs:

• 5-Fluorouracil (5-FU)
• Oxaliplatin
• Irinotecan
• Leucovorin
• Paclitaxel
• Carboplatin
• Proton Beam Radiation Therapy

This research study is a Pilot Study, which is the first time investigators are examining this study intervention.

In this research study, the investigators are studying the combination of FOLFIRINOX followed by radiation with paclitaxel and carboplatin before surgery. The investigators believe that this intervention may help decrease the growth and spread of the cancer cells.

FOLFIRINOX has shown to be very effective in patients whom disease has spread. The investigators are evaluating this regimen to see if there is an increase in curability when the cancer has not spread.

The FDA (the U.S. Food and Drug Administration) has approved FOLFIRINOX as a treatment option for this disease.

The FDA has not approved Paclitaxel or Carboplatin for this specific disease but they have both been approved for other uses.

FOLFIRINOX is a combination of 4 chemotherapy agents that may help shrink the tumor before surgery.

Carboplatin may stop the cancer cells from growing and paclitaxel may stop the cancer cells from growing and spreading

Inclusion Criteria:

• Histologically or cytologically confirmed T 3/4 or N+ (> 1 cm in size or FDG avid) gastric or gastroesophageal (GE) junction cancer. Diagnosis must be confirmed by the Mass General Hospital pathology department.

• Age 18 years or older. There will be no upper age restriction.

• ECOG performance status ≤ 1

• Life expectancy of greater than 3 months

• Participants must have adequate organ and marrow function as defined below:

  • absolute neutrophil count ≥ 1,500 cells/mm3
  • platelets ≥ 75,000 cells/mm3
  • total bilirubin ≤ 1.5 x upper limit of normal, or, for patients who have
  • undergone biliary stenting, total bilirubin of ≤ 2 or two down trending values.
  • AST(SGOT) ≤ 2.5 × upper limit of normal
  • ALT (SGPT) ≤ 2.5 x upper limit of normal
  • creatinine ≤ 1.5 mg/dL, or
  • creatinine clearance ≥ 30 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

• The effects of both radiation therapy and the chemotherapy agents used in this trial are known to be teratogenic. Therefore, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation plus 30 days from the last date of study drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Evidence of metastatic disease as determined by chest CT scan, abdomen/pelvis CT scan (or MRI with gadolinium and/or manganese) within six weeks of study entry. Distant nodal disease is allowed if it is in the radiation port.
• Any prior chemotherapy, targeted/biologic therapy, or radiation for treatment of the participant's gastric or GE junction cancer.
• Receipt of chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Treatment of other invasive carcinomas within the last five years with greater than 5% risk of recurrence at time of eligibility screening. Carcinoma in-situ and basal cell carcinoma/ squamous cell carcinoma of the skin are allowed.
• Receipt of any other investigational agents within 4 weeks preceding the start of study treatment.
• Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator), such as significant cardiac or pulmonary morbidity (e.g. congestive heart failure, symptomatic coronary artery disease and/or cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months, or ongoing infection as manifested by fever.
• History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance or drug intake.
• Pregnant women are excluded from this study because radiation therapy and the chemotherapy agents to be used have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the mother is receiving protocol therapy.
• Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery.
• No concurrent administration of cimetidine (as it can decrease the clearance of 5-FU). Another H2-blocker or proton pump inhibitor may be substituted before study entry.
• Known, existing uncontrolled coagulopathy.
• Prior systemic fluoropyrimidine therapy (unless given in an adjuvant setting and at least six months earlier). Prior topical fluoropyrimidine use is allowed.
• Known hypersensitivity to 5-fluorouracil or known DPD deficiency.
• History of allergic reaction(s) attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, irinotecan, or oxaliplatin