Prospective Randomized Trial Comparing Gastrectomy, Metastasectomy Plus Systemic Therapy Versus Systemic Therapy Alone: GYMSSA Trial

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Udo Rudloff, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00941655
First received: July 16, 2009
Last updated: July 9, 2013
Last verified: July 2013
  Purpose

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.

Condition Intervention Phase
Gastric Cancer
Drug: Oxaliplatin
Drug: Irinotecan
Drug: 5-Fluorouracil
Drug: Leucovorin
Procedure: Gastrectomy and/or metastasectomy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Prospective Randomized Trial Comparing Gastrectomy, Metastasectomy Plus Systemic Therapy Versus Systemic Therapy Alone: GYMSSA Trial

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Overall Survival in Patients With Limited Metastatic Gastric Carcinoma: Arm I [ Time Frame: 12 weeks up to 3 years ] [ Designated as safety issue: No ]
    Time between the first day of treatment and the date of death.

  • Overall Survival in Patients With Limited Metastatic Gastric Carcinoma: Arm II [ Time Frame: 12 weeks up to 3 years ] [ Designated as safety issue: No ]
    Time between the first day of treatment and the date of death


Secondary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: 40.5 months ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.


Enrollment: 16
Study Start Date: July 2009
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Surgery + HIPEC + Systemic Chemotherapy

Surgery -gastric resection, metastasectomy, and heated intraperitoneal chemotherapy with Fluouracil (5-FU) 400 mg/m^2 intravenous (IV) over 5 minutes. Leucovorin 20 mg/m^2 IV and 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 - Irinotecan 165 mg/m^2 IV over 90 minutes, Oxaliplatin 85 mg/m^2 over 120 minutes, Leucovorin 200 mg/m^2 IV 120 minutes, 5FU 3200 mg/m^2 continuous IV infusion over 48 hours.

Drug: Oxaliplatin

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,

Other Name: Eloxatin
Drug: Irinotecan
Irinotecan 165 mg/m^2 IV over 90 minutes
Other Name: Camptosar
Drug: 5-Fluorouracil

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.

Other Names:
  • Efudex
  • Adracil
  • Carac
Drug: Leucovorin

surgery and heated intraperitoneal chemotherapy -20 mg/m^2 intravenous over 5 minutes.

systemic chemotherapy - 200 mg/m^2 intravenous over 120 minutes.

Other Name: Folinic acid
Procedure: Gastrectomy and/or metastasectomy

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.

Experimental: Systemic Chemotherapy Alone
Irinotecan 165 mg/m^2 IV over 90 minutes, Oxaliplatin 85 mg/m^2 over 120 minutes, Leucovorin 200 mg/m^2 IV 120 minutes, 5FU 3200 mg/m^2 continuous IV infusion over 48 hours.
Drug: Oxaliplatin

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,

Other Name: Eloxatin
Drug: Irinotecan
Irinotecan 165 mg/m^2 IV over 90 minutes
Other Name: Camptosar
Drug: 5-Fluorouracil

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.

Other Names:
  • Efudex
  • Adracil
  • Carac
Drug: Leucovorin

surgery and heated intraperitoneal chemotherapy -20 mg/m^2 intravenous over 5 minutes.

systemic chemotherapy - 200 mg/m^2 intravenous over 120 minutes.

Other Name: Folinic acid

Detailed Description:

Background:

  • The standard of care for metastatic gastric cancer (MGC) is systemic therapy resulting in median survival of 6-12 months and rare survivors of up to three years.
  • For patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and/or metastasectomy plus systemic therapy (e.g. median survival after liver resection for metastatic gastric cancer of 15-37 months, with a five year survival rate of 25%).
  • This prospective randomized trial for patients with MGC and limited metastases is designed to compare two therapeutic approaches-gastrectomy with metastasectomy plus systemic therapy (GYMS) vs. systemic therapy alone (SA)-- and to evaluate outcome in light of selection criteria to define those patients who may benefit from the more aggressive approach.

Objectives:

Primary Objective:

- To compare two therapeutic approaches--GYMS vs. SA--in terms of overall survival in patients with limited MGC.

Secondary Objectives:

  • To analyze selection criteria for patients who might benefit from the GYMS approach.
  • To determine progression-free survival in both arms.

Eligibility:

  • MGC with limited metastatic disease thought to be resectable to no evidence of disease.
  • 18 years old or greater with an Eastern Cooperative Oncology Group (ECOG) 0-2
  • Laboratory and physical examination parameters within acceptable limits by standard of practice guidelines prior to surgery

Design:

  • Patients will be randomized to receive gastrectomy and metastasectomy followed by systemic chemotherapy (GYMS) or systemic chemotherapy (SA) alone and will be stratified based on sites of metastatic disease, previous therapy and disease free interval.
  • Patients in both arms will receive the FOLFOXIRI regimen (5-FU, leucovorin, oxaliplatin and irinotecan)
  • No cross over will be allowed.
  • Survival analysis will be done in intention to treat fashion from time of randomization.
  • Based on estimated 12 and 20 months overall survival for the SA and the GYMS arms respectively, 68 patients per arm (power=0.80, 0.05 two-tailed log-rank test) will be enrolled. Patients will be recruited over 6 years and followed for an additional 2 years from the date of entry of the last patient.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00941655

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Udo Rudloff, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Udo Rudloff, M.D., Principal investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00941655     History of Changes
Other Study ID Numbers: 090189, 09-C-0189
Study First Received: July 16, 2009
Results First Received: April 25, 2013
Last Updated: July 9, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Gastric Carcinoma
Chemotherapy
Liver Tumors
Peritoneal Tumors
Metastatic Gastric Cancer
Stomach Cancer
Gastric Cancer

Additional relevant MeSH terms:
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Fluorouracil
Oxaliplatin
Irinotecan
Leucovorin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Antidotes
Protective Agents
Antineoplastic Agents, Phytogenic
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on July 28, 2014