lack of clinical cases

The study addresses two primary questions, according to its factorial design:

• to compare the efficacy in terms of overall survival (OS) of a peri-operative vs. a post-operative chemotherapy (CHT) treatment, irrespectively of the presence of a post-surgical chemo-radiotherapy (CHT-RTX) (Timing Study);
• to compare the efficacy in terms of relapse free survival (l-RFS) of a post-surgical CHT-RTX treatment vs. no other treatment, irrespectively of the timing of CHT (RTX Study).

The study has a 2x2 factorial design, thus consisting of two independent, following specific eligibility criteria and with different randomization scheme studies, the Timing Study and the RTX Study.

Both studies are Italian, multicentre, open-label, randomized, superiority, phase III trials conducted in patients with histologically confirmed, localized gastric adenocarcinoma, which is considered operable.

In the Timing Study patients fulfilling the eligibility criteria will be randomized with a 1:1 ratio to receive:

• peri-operative CHT (Arm A) or
• post-operative CHT (Arm B) Once randomized in the Timing Study, patients may also be randomized in the RTX

Study to receive in addition to CHT a post-operative CHT-RTX treatment or no other treatment. This is possible since the randomization will be done in two steps: the first for the Timing Study for all the participating centres (peri-operative CHT vs. post-operative CHT) and the second one for the RTX Study, only for those centres with the radiotherapist willing and able to participate (post- surgical CHT-RTX vs. no other treatment). Thus the following four arms will be generated:

• peri-operative CHT (Arm A)
• post-operative CHT (Arm B)
• peri-operative CHT + post-operative CHT-RTX (Arm C)
• post-operative CHT + post-operative CHT-RTX (Arm D) The study will be conducted in more than one hundred experimental centres. Follow-up F(-up) procedures and timing of the visits will be consistent with current clinical practice.

Based on case-mix of sample 1000-1180 patients are needed in the Timing study and 420-520 in the RTX study.

Inclusion Criteria:

• age >18 years
• Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) 0-1
• T3 or T4 carcinoma without lymphnode involvement (N0) and any T-stage with (N+) lymphnode involvement
• no distant metastases (M0)
• fitness to receive CHT and CHT-RTX
• no peripheral neuropathy greater than grade 1
• absence of peritoneal carcinomatosis
• written informed consents (one for each trial) given before the randomization, according to International Conference on Harmonisation/Good Clinical Practice (ICH/GCP)

Exclusion Criteria:

• adenocarcinoma of the gastro-esophageal junction
• previous CHT or RTX
• abnormal haematological, hepatic or renal functions, assessed within 7 days prior to randomization
• lymphnode metastases (biopsy proof, if possible) outside the loco-regional field, such as supraclavicular, mediastinal or para-aortic nodes
• positive peritoneal cytology
• clinical significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤ 6 months), myocardial infarction (≤ 6 months), instable angina, New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
• lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication
• history or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or patients at high risk from treatment complications
• pregnancy or breast feeding. Women of childbearing potential and their parents must be willing to practice acceptable methods of birth control to prevent pregnancy
• presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and f-up schedule