Prospective Randomized Trial Comparing Gastrectomy, Metastasectomy Plus Systemic Therapy Versus Systemic Therapy Alone: GYMSSA Trial
Condition: Gastric Cancer
MeSH terms: Stomach Neoplasms
Intervention: Oxaliplatin; Irinotecan; 5-Fluorouracil; Leucovorin; Gastrectomy and/or metastasectomy
Intervention description: Oxaliplatin 460 mg/m^2 diluted in 2.0 L/m^2 of dextrose 5% in water (D5W) given as a heated intraperitoneal perfusion.
Systemic chemotherapy - Oxaliplatin 85 mg/m^2 over 120 minutes,; Irinotecan 165 mg/m^2 IV over 90 minutes; Surgery and heated intraperitoneal chemotherapy with Fluouracil (5-FU) 400 mg/m^2 intravenous (IV) over 5 minutes.
systemic chemotherapy -3200 mg/m^2 continuous intravenous over 48 hours.; surgery and heated intraperitoneal chemotherapy -20 mg/m^2 intravenous over 5 minutes.
systemic chemotherapy - 200 mg/m^2 intravenous over 120 minutes.; Gastrectomy: tumor resection and a bypass; palliative treatment for pain, bleeding, obstruction and/or if deemed in the best interest of the patient.
Metastasectomy: anatomical segmental resection to render the patient no evidence of disease (NED) with at least 1cm negative margins when possible, followed by systemic chemotherapy.
Intervention MeSH terms: Leucovorin; Fluorouracil; Oxaliplatin; Irinotecan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gastric Carcinoma; Chemotherapy; Liver Tumors; Peritoneal Tumors; Metastatic Gastric Cancer; Stomach Cancer; Gastric Cancer

Summary:

      Background:

        -  Gastric (stomach) cancer is a rare cancer. In most cases, by the time it has been
           diagnosed it has spread to other organs in the body and the chance of a cure is very
           small. The standard treatment for gastric cancer is a combination of chemotherapy drugs.

        -  Researchers are interested in finding out if surgically removing all tumors before
           beginning chemotherapy for stomach cancer can slow or halt its spread better than giving
           chemotherapy alone.

      Objectives:

      - To determine whether tumor removal surgery followed by chemotherapy is more effective in
      treating gastric cancer than chemotherapy given alone.

      Eligibility:

      - Patients 18 years of age and older who have been diagnosed with gastric cancer.

      Design:

        -  All patients will undergo an initial physical examination, blood tests, imaging scans,
           and a laparoscopy to determine the extent of the disease.

        -  Half of the participants will be assigned to have surgery first and then chemotherapy;
           the other half will be assigned to have chemotherapy alone.

             -  The surgery-plus-chemotherapy group will have major surgery to remove all tumors in
                the stomach and abdominal area, followed by a recovery time of up to 4 weeks.
                Chemotherapy will begin 6 to 8 weeks after surgery.

             -  The chemotherapy-only group will begin treatment within 2 weeks of laparoscopy.

        -  All patients will receive four chemotherapy drugs: 5-Fluorouracil, leucovorin,
           oxaliplatin, and irinotecan. The drugs are given intravenously over 2 days every 2 weeks
           (one cycle) for 12 cycles (about 6 months), either at the National Institutes of Health
           (NIH) Clinical Center or at home with a referring oncologist. Patients in the surgery
           group who have tumors in the peritoneum will receive an additional set of chemotherapy
           drugs in a separate treatment.

        -  During the chemotherapy cycles, patients will provide blood samples approximately once a
           week and will have physical examinations and scans on a regular basis.

        -  Patients will return to the NIH Clinical Center for follow-up visits about every 4
           months for 2 years, then every 6 months for 3 years and yearly thereafter.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Histologically or cytologically confirmed gastric adenocarcinoma.

          2. Metastatic disease must be measurable by computed tomography (CT) and/or magnetic
             resonance imaging (MRI)

             Or

             There must be a history of positive peritoneal washings or carcinomatosis

          3. All disease should be deemed resectable to negative margins (NED) based on imaging
             studies.

             Note: Patients with both pulmonary and peritoneal metastases will be enrolled at the
             discretion of the Principal Investigator.

               -  Esophageal invasion < 4cm that does not require thoracotomy (Seiwert II and III
                  lesions).

               -  Hepatic metastases (unilateral or bilateral less than or equal to 5 lesions, less
                  than or equal to 15 cm total diameter).

               -  Primary peritoneal metastases (small disease load less than or equal to P2
                  disease) without massive ascites or intestinal obstruction.

               -  Para-aortic lymph node metastases (stations 16 a1 and/or b2).

               -  Lung metastases (less than or equal to 3 unilateral/bilateral, 9 cm total
                  diameter).

               -  Patients who present with both hepatic and peritoneal metastases must have no
                  evidence of extensive para-aortic/retro-pancreatic lymph node metastases.

          4. Greater than or equal to 18 years of age.

          5. Must be able to understand and sign the Informed Consent Document.

          6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) less than or
             equal to 2.

          7. Life expectancy of greater than three months.

          8. Patients of both genders must be willing to practice birth control during and for four
             months after receiving chemotherapy.

          9. Hematology:

               -  Absolute neutrophil count greater than 1300/mm^3 without the support of
                  Filgrastim.

               -  Platelet count greater than 75,000/mm^3.

               -  Hemoglobin greater than 8.0 g/dl.

         10. Chemistry:

               -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than
                  or equal to 5 times the upper limit of normal. Except in the presence of
                  obstructive liver metastases where ALT/AST may be up to 10 times the upper limit
                  of normal.

               -  Serum creatinine less than or equal to 1.5 mg/dl unless the measured creatinine
                  clearance is greater than 60 mL/min/1.73 m^2.

               -  Total bilirubin less than or equal to 2 mg/dl, except in the presence of
                  obstructive metastases.

               -  Prothrombin time (PT) within 2 seconds of the upper limit of normal
                  (International Normalized Ratio (INR) less than or equal to 1.8).

         11. No history of prior/other malignancies within the 2 years prior to enrollment with the
             exception of basal cell carcinoma.

        EXCLUSION CRITERIA:

          1. Prior treatment with 5-FU, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)
             (treatment with any of the components as separate regimens is allowable).

          2. Inability to tolerate any of the chemotherapeutic agents.

          3. Grade 2 or greater neuropathy.

          4. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the chemotherapy on the fetus or infant.

          5. Active systemic infections, coagulation disorders or other major medical illnesses of
             the cardiovascular, respiratory or immune system; myocardial infarction; cardiac
             arrhythmias; obstructive or restrictive pulmonary disease.

          6. Brain metastases or a history of brain metastases.

          7. Childs B or C cirrhosis or with evidence of severe portal hypertension by history,
             endoscopy, or radiologic studies.

          8. Weight less than 40 kg.

          9. Significant ascites, greater than 1000cc in the absence of peritoneal disease.

         10. History of congestive heart failure and/or an left ventricular ejection fraction
             (LVEF) less than 40%.

             Note: Patients at increased risk for coronary artery disease or cardiac dysfunction
             (e.g., greater than 65yo, diabetes, history of hypertension, elevated low-density
             lipoprotein (LDL), first degree relative with coronary artery disease) will undergo
             full cardiac evaluation and will not be eligible if they demonstrate significant
             irreversible ischemia on stress thallium or an ejection fraction < 40%.

         11. Significant chronic obstructive pulmonary disease (COPD) or other chronic pulmonary
             restrictive disease with pulmonary function tests (PFT's) indicating an forced
             expiratory volume 1 (FEV1) less than 50% or a carbon monoxide diffusing capacity
             (DLCO) less than 40% predicted for age.

        Note: Patients who have shortness of breath with minimal exertion or who are at risk for
        pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and will
        not be eligible if their FEV1 is less than 50% of expected.