Neo-adjuvant Chemotherapy in Locally Advanced Gastric Cancer
Condition: Stage T3-4NxM0 Gastric Cancer
MeSH terms: Stomach Neoplasms
Intervention: Docetaxel; Capecitabine
Intervention description: Docetaxel 60 mg/m2 IV on day 1; Capecitabine 900 mg/m2 PO two times per day from day 1 to day 14 every 3 weeks for 2 cycles.
Intervention MeSH terms: Docetaxel; Capecitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: gastric cancer, neo-adjuvant chemotherapy

Summary:

      Thymidylate Synthase (TS) is a key enzyme in the synthesis of DNA and the target enzyme
      inhibited by 5-fluorouracil (5-FU). TS level in the tumour cells has been reported as
      predictive to response to 5-FU and a prognostic factor in colorectal and gastric cancer
      patients. We plan to study TS by immunohistochemistry (IHC) in the paraffin blocks of tumour
      tissue.

      A combined comparative genomic hybridization (CGH) and expression microarray analysis of
      gastric cancer specimens before and after neoadjuvant chemotherapy. CGH will be performed
      using standard technique routinely done in Dr Patrick Tan's laboratory at the National Cancer
      Centre, which determines the gain or loss of DNA copies of each chromosome. Total RNA will be
      extracted from at least one biopsy sample which contains at least 50% cancer cells by
      homogenization of the tumour tissue and tri-sol method. 5 ug of RNA were amplified and
      hybridized with the C-DNA microarrays of 18K targets.

      Primary Objective 1. Feasibility and safety of pre-operative chemotherapy in locally advanced
      gastric cancer.

      Secondary Objective

        1. Complete clinical and pathological response rates to pre-operative chemotherapy in
           locally advanced gastric cancer

        2. Complete resection rate.

        3. Time to recurrence, disease free and overall survival

        4. Correlation of clinical outcome with (Runt-related transcription factor) RUNX-3
           methylation status and Thymidylate synthetase in the tumor tissue.

        5. Correlation of CGH and gene expression profile and their changes after chemotherapy with
           clinical outcome.

           Patients may be included in the study only if they meet all of the following criteria:

           Age at least 18 years. Histologic or cytologic diagnosis of adenocarcinoma of stomach or
           gastric cardia (Siewert Classification Type III) Preoperative Stage T3-4NxM0 by
           endoscopic ultrasound, CT of the abdomen/pelvis and laparoscopy. (CT of the chest if it
           is a cardia lesion).

           Absence of malignant cells in peritoneal lavage fluid during laparoscopic examination.

           Patients must not have received any prior chemotherapy or hormonal therapy for the
           treatment of gastric cancer.

           Karnofsky performance status of 70 or higher. Estimated life expectancy of at least 12
           weeks.

           Adequate organ function including the following:

           - Bone marrow: White blood cells (WBC) at least 3.5 x 109/L Absolute neutrophil
           (segmented and bands) count (ANC) at least 1.5 x 109/L Platelets at least 100 x 109/L
           Haemoglobin at least 9g/dL

           - Hepatic: Bilirubin within upper limit of normal (ULN), Aspartate transaminase (ALT) or
           Alanine transaminase (AST) not more than 2.5x ULN Alkaline phosphatase not more than
           2.5x ULN.

           - Renal: creatinine not more than 1.5x ULN Signed informed consent by patient or legal
           representative. Patients with reproductive potential must use an approved contraceptive
           method if appropriate (eg, intrauterine device, birth control pills, or barrier device)
           during and for three months after the study. Females with childbearing potential must
           have a negative serum pregnancy test within 7 days prior to study enrollment.

           The study plans to recruit 30 patients in 12-18 months.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age greater than or equal 18 years.

          -  Histologic or cytologic diagnosis of adenocarcinoma of stomach or gastric cardia
             (Siewert Classification Type III)

          -  Preoperative Stage T3-4NxM0 by endoscopic ultrasound, CT of the abdomen/pelvis and
             laparoscopy. (CT of the chest if it is a cardia lesion).

          -  Absence of malignant cells in peritoneal lavage fluid during laparoscopic examination.

          -  Patients must not have received any prior chemotherapy or hormonal therapy for the
             treatment of gastric cancer.

          -  Karnofsky performance status of 70 or higher.

          -  Estimated life expectancy of at least 12 weeks.

          -  Adequate organ function including the following:

          -  Bone marrow:

               -  White blood cells (WBC) greater than or equal 3.5 x 109/L

               -  Absolute neutrophil (segmented and bands) count (ANC) greater than or equal 1.5 x
                  109/L

               -  Platelets greater than or equal 100 x 109/L

               -  Haemoglobin greater than or equal 9g/dL

          -  Hepatic:

               -  Bilirubin within upper limit of normal (ULN),

               -  ALT or AST less than or equal 2.5x ULN

               -  Alkaline phosphatase less than or equal 2.5x ULN.

          -  Renal:

               -  creatinine less than or equal 1.5x ULN

          -  Signed informed consent by patient or legal representative.

          -  Patients with reproductive potential must use an approved contraceptive method if
             appropriate (eg, intrauterine device, birth control pills, or barrier device) during
             and for three months after the study. Females with childbearing potential must have a
             negative serum pregnancy test within 7 days prior to study enrollment.

        Exclusion Criteria:

          -  Prior treatment for locally advanced or metastatic gastric cancer. Any metastatic
             disease will render patient ineligible according to American Joint Committee on Cancer
             (AJCC) staging manual. (See appendix 11.4).

          -  Treatment within the last 30 days with any investigational drug.

          -  Concurrent administration of any other cancer therapy, including cytotoxic
             chemotherapy, hormonal therapy, and immunotherapy.

          -  Active infection that in the opinion of the investigator would compromise the
             patient's ability to tolerate therapy.

          -  Pregnancy.

          -  Breast-feeding.

          -  Serious concomitant disorders that would compromise the safety of the patient or
             compromise the patient's ability to complete the study, at the discretion of the
             investigator.

          -  Poorly controlled diabetes mellitus with fasting blood sugar > 18 mmol/L(mM).

          -  Second primary malignancy that is clinically detectable at the time of consideration
             for study enrollment.

          -  History of significant neurological or mental disorder, including seizures or
             dementia.

          -  History of hypersensitivity to drugs formulated in Tween 80, the vehicle used for
             commercial docetaxel formulations.

          -  History of hypersensitivity to 5-fluorouracil