Trial Coordinator:           Sarah Chinchen

                                    topgear@ctc.usyd.edu.au 

AIMS  - The primary objective is to investigate whether the addition of chemoradiotherapy is superior to chemotherapy alone in the neoadjuvant setting by improving pathological complete response (pCR) rates in the first instance, and subsequently overall survival, in patients undergoing adequate surgery (D1+ dissection) for resectable gastric cancer.

BACKGROUND – Gastric cancer remains a significant global public health problem. Although in developed countries its incidence has dramatically decreased, on a worldwide scale it is still a leading cause of cancer related deaths. Surgery is the only potentially curative treatment for gastric cancer.

Although the survival rates for patients with early stage disease (stage 1A and 1B) are good, this subgroup of patients constitutes only 20% of those undergoing resection. The majority of patients will have locally advanced or metastatic disease at presentation, which has an extremely poor prognosis. The current five-year survival rate for gastric cancer in Western countries is approximately 20%, a figure that has improved little over the past 30 years. Despite this rather grim outlook, there have been several important recent advances utilising chemotherapy and radiotherapy in the adjuvant setting that have generated renewed interest and debate in the treatment of resectable gastric cancer.

Since the publication of the INT0116 and MAGIC studies, clinicians have been faced with the dilemma of which adjuvant strategy to employ. Opinions remain divided regarding the relative efficacy of chemoradiation vs chemotherapy and clinical practice varies amongst different institutions. The important question that needs to be addressed is whether chemoradiotherapy is superior to chemotherapy alone in the neoadjuvant treatment of resectable gastric cancer.

STUDY DESIGN – This is an international, intergroup trial led by investigators from the AGITG and the NHMRC Clinical Trials Centre, in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), the European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group (NCIC CTG) in Canada.

TOP GEAR is a multicentre, prospective, randomised, stratified, phase II/III clinical trial. Eligible patients will be randomly allocated to either preoperative chemotherapy or preoperative chemoradiotherapy. The trial will be conducted in two parts. Part 1 is the phase II component of the trial that will recruit 120 patients, while Part II is the phase III component that will recruit a further 632 patients to provide a total sample size of 752 patients. An interim analysis will be performed after 120 patients complete treatment to allow determination of several key safety and feasibility components.

STUDY PROGRESS - TOP GEAR opened to recruitment in September 2009 and 88 patients have been recruited to date. There are currently 21 active sites throughout Australia and New Zealand.

Funding is confirmed from both the EORTC and NCIC CTG to support local coordination and management of the trial. It is expected that 20 sites in Canada and 20-30 sites across 11 European countries will participate. The first European and Canadian sites are expected to open in Q3-Q4 2013.

TRANSLATIONAL RESEARCH – TOP GEAR includes a translational research sub-study led by A/Prof Alex Boussioutas. Where possible, both pre- and post-treatment tissue samples are collected (fresh and/or snap frozen and/or FFPE). In addition, a series of blood samples are collected prior to treatment, during treatment and at regular intervals during follow-up, ideally until recurrence. Specific aims to address as part of this clinical trial are:

1. Are there biomarker and biological determinants of chemotherapeutic and radiotherapeutic response in gastric cancer?
2. Are there biological differences in remnant disease that differs from the primary lesion and could be useful to target specific therapeutics?
3.