TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/TROG/EORTC/NCIC CTG)

Leong et al. BMC Cancer (2015) 15:532 DOI 10.1186/s12885-015-1529-x STUDY PROTOCOL Open Access TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/ TROG/EORTC/NCIC CTG) Trevor Leong1*, B Mark Smithers2, Michael Michael1, Val Gebski3, Alex Boussioutas1, Danielle Miller3, John Simes3, John Zalcberg4, Karin Haustermans5, Florian Lordick6, Christoph Schuhmacher7, Carol Swallow8, Gail Darling9 and Rebecca Wong10 Abstract Background: The optimal management of patients with resectable gastric cancer continues to evolve in Western countries. Following publication of the US Intergroup 0116 and UK Medical Research Council MAGIC trials, there are now two standards of care for adjuvant therapy in resectable gastric cancer, at least in the Western world: postoperative chemoradiotherapy and perioperative epirubicin/cisplatin/fluorouracil (ECF) chemotherapy. We hypothesize that adding chemoradiation to standard perioperative ECF chemotherapy will achieve further survival gains. We also believe there are advantages to administering chemoradiation in the preoperative rather than postoperative setting. In this article, we describe the TOPGEAR trial, which is a randomised phase III trial comparing control arm therapy of perioperative ECF chemotherapy with experimental arm therapy of preoperative chemoradiation plus perioperative ECF chemotherapy. Methods/Design: Eligible patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either perioperative chemotherapy alone (3 preoperative and 3 postoperative cycles of ECF) or perioperative chemotherapy plus preoperative chemoradiation. In the chemoradiation arm, patients receive 2 cycles of ECF plus chemoradiation prior to surgery, and then following surgery 3 further cycles of ECF are given. The trial is being conducted in two Parts; Part 1 (phase II component) has recruited 120 patients with the aim of assessing feasibility, safety and preliminary efficacy of preoperative chemoradiation. Part 2 (phase III component) will recruit a further 632 patients to provide a total sample size of 752 patients. The primary endpoint of the phase III trial is overall survival. The trial includes quality of life and biological substudies, as well as a health economic evaluation. In addition, the trial incorporates a rigorous quality assurance program that includes real time central review of radiotherapy plans and central review of surgical technique. (Continued on next page) * Correspondence: 1 Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Victoria 8006, Australia Full list of author information is available at the end of the article © 2015 Leong et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Leong et al. BMC Cancer (2015) 15:532 Page 2 of 6 (Continued from previous page) Discussion: TOPGEAR is an international, intergroup collaboration led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group. It addresses a globally significant question that will help inform future international standards for clinical practice in resectable gastric cancer. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12609000035224. Registered 30 May 2009 Keywords: Gastric cancer, Preoperative chemoradiotherapy, Perioperative chemotherapy, Adjuvant therapy Background The optimal management of patients with resectable gastric cancer continues to evolve in Western countries. Following publication of the US Intergroup trial 0116 in 2001, postoperative chemoradiation became a standard of care for patients who had undergone potentially curative surgery [1]. This trial randomly assigned 556 patients following surgery to either observation or adjuvant therapy with 4 monthly cycles of bolus 5-fluorouracil (5-FU) and leucovorin combined with 45 Gy of radiotherapy. With a median follow-up of 5 years, the 3-year survival rate was 50 % in the chemoradiation group versus 41 % in the surgery alone group (p = 0.005). Although adjuvant chemoradiotherapy has been adopted as standard of care in North America and some parts of the world, it is still uncommonly used in other countries. This relates mainly to criticism of INT0116 with regard to surgical quality as 54 % of patients underwent less than a D1 lymph node dissection despite the recommendation for a D2 dissection. There are also concerns amongst medical and radiation oncologists regarding the outdated chemoradiation regimen that was employed. The UK Medical Research Council MAGIC trial that was published in 2006 provides an alternative standard of care for adjuvant therapy in resectable gastric cancer [2]. This trial randomly assigned 503 patients with resectable gastric cancer to either perioperative chemotherapy and surgery or surgery alone. Chemotherapy consisted of 3 preoperative and 3 postoperative cycles of epirubicin, cisplatin and 5-FU (ECF). With a median follow-up of 4 years, the 5-year survival rate was 36 % in the perioperative chemotherapy group versus 23 % in the surgery alone group (hazard ratio 0.75; p = 0.009). A significantly greater proportion of patients in the perioperative chemotherapy group underwent curative R0 resection (79 % vs 70 %), and resected tumors were significantly smaller and less advanced in this group. Of those patients who started chemotherapy, 90.7 % completed preoperative chemotherapy. However, of those who completed preoperative chemotherapy and surgery, only 49.5 % also completed postoperative chemotherapy. Since the publication of the INT0116 and MAGIC studies, clinicians and patients have been faced with the dilemma of which adjuvant or neoadjuvant strategy to employ. By analysing failure patterns, each approach appears to improve survival through different mechanisms. The perioperative chemotherapy approach using ECF reduces systemic failure, while postoperative chemoradiation improves locoregional control. Since both strategies provide moderate gains in survival, we hypothesize that adding chemoradiation to standard perioperative ECF chemotherapy will achieve even greater survival gains in a similar patient population. Furthermore, we believe there are advantages to testing the addition of chemoradiation by administering it in the preo (...truncated)