Please select the eligibility criteria that correspond to the clinical trial below.
Title: Prospective Randomized Trial Comparing Gastrectomy, Metastasectomy Plus Systemic Therapy Versus Systemic Therapy Alone: GYMSSA Trial
Brief 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.


Options:
A: 1. Metastatic disease of the esophagus or gastroesophageal junction

   1. Histologic, cytologic or radiologic documentation of metastatic squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction. Radiologic, endoscopic, histologic or cytologic evidence of locally recurrent or locally residual (post-resection) disease is also permitted.
   2. For the purposes of this study, undifferentiated adenocarcinomas and adenosquamous tumors will be considered as adenocarcinomas. In addition, tumors involving the gastroesophageal junction will be defined by the Siewert classification.
   3. Patients with gastroesophageal junction tumors who are eligible:

      * AEG Type I: Adenocarcinoma of the distal esophagus which usually arises from an area with specialized intestinal metaplasia of the esophagus (eg, Barrett's esophagus, and may infiltrate the esophagogastric junction from above).
      * AEG Type II: True carcinoma of the cardia arising from the cardiac epithelium or short segments with intestinal metaplasia at the esophagogastric junction.
   4. Patients with gastroesophageal junction tumors who are NOT eligible:

      * AEG Type III: Subcardial gastric carcinoma which infiltrates the esophagogastric junction and distal esophagus from below.
2. Patients must have at least one paraffin block available (or at least 15 unstained slides for analysis of tumor EGFR status.

   1. Patients with a history of esophageal and GE junction carcinoma treated by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease OR the primary cancer was stage I.
   2. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic esophageal or GE junction carcinoma if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.
3. Patients with Measurable Disease - Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan.
4. Prior Treatment:

   1. No prior chemotherapy or radiotherapy. No prior therapy which specifically and directly targets the EGF(R) pathway.
   2. No prior allergic reaction to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies (HAMA).
   3. Patients must have completed any major surgery ≥ 4 weeks or any minor surgery ≥ 2 weeks before registration. Patients must have fully recovered from the procedure. Insertion of a vascular access device is not considered major or minor surgery.
   4. No concurrent use of investigational agents is allowed while participating in this study.
5. Patient Characteristics:

   1. ECOG Performance Status of 0-2
   2. ≥ 18 years of age
   3. Patients must be documented to have a stable weight (or less than one pound weight loss) for at least one week prior to registration.
   4. Non-pregnant and not breast-feeding. The effects of cetuximab, cisplatin, epirubicin, fluorouracil, leucovorin, irinotecan, and oxaliplatin on a developing human fetus are not well-known. Because the risk of toxicity in nursing infants secondary to cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, and oxaliplatin treatment of the mother is unknown but may be harmful, breastfeeding must be discontinued.
6. No myocardial infarction \< 6 months prior to registration or New York Heart Association classification III or IV.
7. No ≥ grade 2 diarrhea within 7 days prior to registration.
8. Patients may not concurrently have any of the following conditions:

   1. Known central nervous system metastases or carcinomatous meningitis
   2. Interstitial pneumonia or symptomatic interstitial fibrosis of the lung
   3. Seizure disorder or active neurological disease requiring anti-epileptic medication
   4. ≥ grade 2 peripheral neuropathy
9. No evidence of Gilbert's Syndrome - Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38, the active metabolite of irinotecan. Evidence of Gilbert's Syndrome would include documentation of elevation of indirect bilirubin at any time in the patient's medical history.
10. Required Initial Laboratory Data:

    1. Granulocytes ≥ 1500/µl
    2. Platelet count ≥ 100,000/µl
    3. Creatinine ≤ 1.5 mg/dL
    4. AST (SGOT) ≤ 5.0 x Upper limits of normal
    5. Total bilirubin ≤ 1.5 mg/dL
    6. Albumin ≥ 2.5 grams/dL
B: -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.
C: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the stomach with inoperable locally advanced or recurrent and/or metastatic disease.
* Male or female.
* Age 18 -75.
* Previous chemotherapy for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrolment into the study).
* Measurable disease, according to the Response Evaluation Criteria in Solid Tumours(RECIST)
* ECOG Performance status 0, 1 or 2
* Haematological, Biochemical and Organ Function: Neutrophil count \>2.0 × 10 9/L, platelet count \> 100 ×10 9/L. Serum bilirubin\< 1.5 × upper limit of normal (ULN); or, AST or ALT \< 2.5 × ULN (or \< 5 × ULN in patients with liver metastases); or, alkaline phosphatase\< 2.5 × ULN (or \> 5 × ULN in patients with liver metastases,Creatinine clearance \> 60 mL/min.
* Signed informed consent.

Exclusion Criteria:

* prior adjuvant/neoadjuvant therapy more than two regiments.
* Received any investigational drug treatment within 30 days of start of study treatment.
* Patients with active gastrointestinal bleeding.
* Neurological toxicity ≥ grade 2 NCI-CTCAE.
* Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma.
* History or clinical evidence of brain metastases.
* Serious uncontrolled systemic intercurrent illness, e.g. infections or poorly controlled diabetes.
* Pregnancy women.
* Subjects with reproductive potential not willing to use an effective method of contraception.
* Patients with known active infection with HIV.
* Known hypersensitivity to any of the study drugs.
D: Inclusion Criteria - All Patients

* Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction, or stomach.
* Completion of 18 weeks of first-line chemotherapy with either CX/ CAPOX or FOLFOX (HER2 negative) or CX/ CF + trastuzumab (HER2 positive) for locally advanced / metastatic disease with \> stable disease on the end of treatment CT scan (HER2 positive patients must have received at least one cycle of trastuzumab alongside first line chemotherapy; patients receiving chemotherapy delivered on a 3-weekly basis eg CX/ CAPOX should have received 6 cycles and on a two weekly basis e.g. FOLFOX should have received 9 cycles).
* Disease which, following first-line chemotherapy, remains inoperable and unsuitable for definitive chemoradiotherapy.
* Able to proceed with maintenance treatment within 28 days of the last day of the last cycle of chemotherapy.
* Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for biomarker analysis.
* Any prior chemotherapy or radiotherapy in the adjuvant setting must have been completed at least 6 months prior to the first occurrence of metastatic disease.
* No prior radiotherapy in the advanced disease setting. Patients receiving palliative radiotherapy to sites of disease that are not measurable may be eligible and should be discussed with the Chief Investigator.
* Male/female patients aged ≥18 years.
* WHO Performance status 0, 1 or 2.
* Patients should have a projected life expectancy of at least 3 months.
* Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell count ≥ 3x109/l; platelets ≥ 100x109/l; haemoglobin (Hb) ≥ 9g/dl (can be post-transfusion).
* Adequate renal function: calculated creatinine clearance ≥50ml/minute.
* Adequate liver function: serum bilirubin ≤1.5x ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN (5 × ULN is acceptable for ALT, AST and ALP if liver metastases are present).
* Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 7 months following the last dose of assigned study drug(s).
* Written informed consent must be obtained from the patient before any study-specific procedures are performed.

Exclusion Criteria - All Patients

* Concurrent enrolment in another clinical trial unless it is an observational (non-interventional) clinical study.
* Tumours of squamous histology.
* Documented brain metastases, central nervous system metastases or leptomeningeal disease.
* Patients who have not recovered from clinically significant effects of any prior surgery, radiotherapy or any other anti-neoplastic therapies. All toxicities must have resolved to grade 1 or less, with the exception of peripheral neuropathy which must be less than or equal to grade 2 according to NCI CTCAE version 4.0.
* Any major surgery within 4 weeks prior to the start of study treatment.
* Uncontrolled hypertension (systolic blood pressure \>180 mm Hg or diastolic blood pressure \>100 mm Hg).
* Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any prior history of clinically significant cardiac failure are excluded from study entry.
* History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
* Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
* Patients who are pregnant or lactating.
* Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection.
* Other clinically significant disease or co-morbidity which may adversely affect the safe delivery of treatment within this trial.
* Any other malignancies within the last 3 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
* Treatment with another investigational agent within 30 days of commencing study treatment.

Additional Inclusion / Exclusion Criteria - HER-2 Negative Patients (Arm A)

* Patients must have histologically or cytologically confirmed HER-2 negative disease (HER-2 0-2 by IHC; note if ISH testing is performed this must not demonstrate evidence of gene amplification).
* Patients with known capecitabine intolerance are excluded. This includes patients with previous coronary artery spasm or chest pain deemed to be capecitabine-related.
* Patients with homozygous DPYD gene mutations are excluded. Patients with heterozygous DPYD gene mutations who have tolerated dose-reduced fluoropyrimidines during first-line chemotherapy as per local guidelines are eligible.
* Prior treatment with a PARP inhibitor is excluded (only applicable for A4 \& A5 patients).
* Any Grade 3 or 4 GI bleeding within 3 months prior to enrollment are excluded
* Any Grade 3 or 4 venous thromboembolic event (VTE) that is considered by the investigator to be life threatening or that is symptomatic and not adequately treated by anticoagulation therapy, within 3 months prior to randomization are excluded.
* History of GI perforation within 6 months of randomisation are excluded
* History of hepatic encephalopathy or cirrhosis (level Child-Pugh B or worse) are excluded
* Patients must have adequate coagulation function as defined by International Normalised Ratio (INR) ≤1.5 and a partial thromboplastin time/activated partial thromboplastin time (PTT or aPTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy. Patients receiving warfarin must be switched to low molecular weight heparin prior to randomisation.
* Patients with a serious or non-healing wound, ulcer or bone fracture within 28 days prior to randomisation are excluded.
* The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (if urine dipstick is

  * 2+, a 24 hour urine collection for protein must demonstrate \< 1000mg of protein in 24 hours.
* Patients experiencing thromboembolic events, including but not limited to myocardial infarction, transient ischaemic attack, cerebrovascular accident, unstable angina, within 6 months prior to first dose of protocol therapy are excluded.
* Patients who have undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/ subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy are excluded.
* Patients receiving chronic anti-platelet therapy or NSAIDS including ibuprofen, naproxen, dipyridamole or clopidogrel, or similar agents are excluded. Once daily aspirin use (up to 325mg/day) is permitted.

Additional Inclusion / Exclusion Criteria - HER-2 Positive Patients (Arm B)

* Patients must have histologically or cytologically confirmed HER-2 positive disease (HER-2 3+ by IHC or HER-2 2+ by IHC and HER-2 gene amplified by ISH).
* Patients must have left ventricular ejection fraction (LVEF) \>50% as measured by echocardiogram or \>45% measured by MUGA (must also be greater than lower limit of normal at institution).
* Patients with active or prior history of New York Heart Association (NYHA) congestive heart failure are excluded.
* Patients with a known history of hypersensitivity to trastuzumab or any of its components are excluded.

Answer: B