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Study Protocol of a Randomized Phase III Trial of Comparing Preoperative Liu et al. BMC Cancer (2019) 19:606 https://doi.org/10.1186/s12885-019-5728-8 STUDY PROTOCOL Open Access Study protocol of a randomized phase III trial of comparing preoperative chemoradiation with preoperative chemotherapy in patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma: PREACT Xiaowen Liu1,2, Jiejie Jin1,2, Hong Cai1,2, Hua Huang1,2, Guangfa Zhao1,2, Ye Zhou1,2, Jianghong Wu1,2, Chunyan Du1,2, Ziwen Long1,2, Yantian Fang1,2, Mingze Ma1,2, Guichao Li2,3, Menglong Zhou2,3, Jiliang Yin2,4, Xiaodong Zhu2,4, Ji zhu2,3, Weiqi Sheng2,5, Dan Huang2,5, Hui Zhu2,6, Zhaozhen Zhang2,7,QiLu2,8, Li Xie9, Zhen Zhang2,3* and Yanong Wang1,2* Abstract Background: The prognosis of patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma is still dismal. There are no standard treatment strategies for these patients. Multidisciplinary team (MDT) approach is a good choice for making a high-quality decision. Generally, MDT will recommend these patients to receive preoperative chemotherapy or preoperative chemoradiation based on all kinds of treatment guidelines. However, the preferred preoperative treatment is still not established. In order to solve this problem, we carry out this randomized phase III trial of comparing preoperative chemoradiation with preoperative chemotherapy in patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma. Methods: Eligible patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma are randomized to receive preoperative chemoradiation or preoperative chemotherapy, followed by surgery and postoperative chemotherapy. In the preoperative chemoradiation arm (Pre-CRT), patients receive two cycles of S-1 and oxaliplatin (SOX), chemoradiation, then followed by surgery and three more cycles of SOX chemotherapy. In the preoperative chemotherapy arm (Pre-CT), patients receive three cycles of SOX, following surgery three more cycles of SOX are given. The primary endpoint of this trial is to verify that preoperative chemoradiation could significantly improve the 3-year disease free survival (DFS) of patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma compared to preoperative chemotherapy. Discussion: The results from this trial will provide important information about whether preoperative chemoradiation could improve survival compared to preoperative chemotherapy among patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma. (Continued on next page) * Correspondence: [email protected]; [email protected] 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 1Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. Liu et al. BMC Cancer (2019) 19:606 Page 2 of 6 (Continued from previous page) Trial registration: ClinicalTrials.gov Identifier: NCT03013010. First posted January 6, 2017. Keywords: Gastric cancer, Esophagogastric junction adenocarcinoma, Preoperative chemotherapy, Preoperative Chemoradiation, Gastrectomy, Adjuvant chemotherapy Background Methods/design Gastric cancer is still the sixth most common cancer Study setting around the world, and approximately 40% of new pa- PREACT is a randomized phase III trial, which is carried tients with gastric cancer are diagnosed in China [1]. out at multicenter in China. Eligible patients with locally Surgery is still the most effective treatment modality. advanced gastric cancer or esophagogastric junction adeno- However, most Chinese patients with gastric cancer lose carcinoma are randomized to receive preoperative chemo- the chance to undergo surgery due to being diagnosed radiation or preoperative chemotherapy, followed by as advanced stage. Among these patients, those with lo- surgery and postoperative chemotherapy (Fig. 1). Patients cally advanced stage still have potential opportunity to were randomized by the way of stratified permutated block receive surgery after preoperative chemotherapy or che- randomization on Web-based system. Lauren classification moradiation, which is also recommended by the NCCN is stratification factor. In Pre-CRT arm, patients receive two guideline [2]. Based on MAGIC and FNCLCC/FFCD cycles of SOX plus chemoradiation, followed by surgery trial, perioperative chemotherapy has been established as and three more cycles of SOX chemotherapy. In the Pre- an alternative option for patients with resectable gastric CT arm, patients receive three cycles of SOX, following cancer [3, 4]. Additionally, there are some preoperative chemoradiation reports in gastric cancer. A prospective, randomized trial showed that preoperative chemoradia- tion followed by surgery was superior to surgery in pa- tients with resectable adenocarcinoma of the esophagus and gastric cardia [5]. Some phase II studies also showed that preoperative chemoradiation resulted in substantial pathologic response and R0 resection rate [6–8]. In our previous published research, 67% patients with locally advanced gastric cancer received curative gastrectomy after receiving chemoradiation [8]. Based on the publica- tion of above-mentioned studies, clinicians have been faced with the dilemma of which preoperative therapy, chemotherapy or chemoradiation, should be applied to patients with locally advanced gastric cancer. A phase III study of comparing preoperative chemotherapy with chemoradiation was carried to solve this problem [9]. Unfortunately, this study was closed prematurely due to low accrual. Therefore, a randomized phase III trial comparing preoperative chemotherapy with chemoradia- tion is needed is deeply needed. The aim of this study is to compare perioperative S-1 and oxaliplatin (SOX) chemotherapy with preoperative chemoradiation plus perioperative SOX chemotherapy in patients with locally advanced gastric cancer. Among the various chemotherapy regimes, S-1 and oxaliplatin (SOX) appears to be effective. Some studies have shown that SOX had a favorable tumor response rate with a relatively mild toxicity profile [10, 11].The study proto- col of this trial, which has the acronym PREACT, is de- scribed in this article. This trial is an prospective, Fig. 1 Flow chart multicenter study be conducted in China. Liu et al. BMC Cancer (2019) 19:606 Page 3 of 6 surgery three more cycles of SOX are given. The protocol Exclusion criteria has been approved by the Ethics Committee of Fudan Uni- versity Shanghai Cancer Center, as well as other institu- 1) Pregnant or lactating females or planning to tional ethics committees. All patients provided written become pregnant or lactating. informed consent before enrollment. Monitoring will be 2) There is evidence of metastatic disease. carried out in this trial. 3) Prior chemotherapy or radiotherapy. 4) Patients have a history of cancer in the five years Primary endpoint before randomization except for the squamous or 3-year disease free survival (DFS). basal cell carcinoma of the skin that has been effectively treated, and carcinoma in situ of the cervix that has been treated by operation. Secondary endpoint 5) Patients with central nervous system (CNS) 3-year overall survival (OS), curative gastrectomy rate, disorder or peripheral nervous system disorder or pathological response rate, treatment toxicity, and postop- psychiatric disease. erative complications. 6) Patients with known history of uncontrolled or symptomatic angina, uncontrolled arrhythmias and Recruitment hypertension, or congestive heart failure, or cardiac Patients with locally advanced, histologically confirmed infarction within 6 months prior to study gastric cancer or esophagogastric junction adenocarcinoma enrollment, or cardiac insufficiency. are recruited. All the patients should take following exami- 7) Patients with severe infection. nations: chest radiography, CT scan, and endoscopic ultra- 8) Patients with severe gastrointestinal bleeding, sonography. Six hundred and eighty-two patients will be gastrointestinal perforation, or unable to swallow. enrolled in China. If the patients meets all the inclusion 9) Patients with known hypersensitivity reaction or criteria, staging laparoscopy or laparotomy will be metabolic disorder to S-1or oxaliplatin in this study. performed to exclude peritoneal dissemination. 10) Patients with linitis plastica. Treatments Inclusion criteria Chemotherapy SOX consists of S-1 and oxaliplatin. A course of chemo- therapy will last 21 days. S-1 is administered orally with 1) Age ≥ 18 years. 40–60 mg, twice a day for 14 consecutive days, followed 2) Eastern Cooperative Oncology Group performance by a 7-day rest period (Fig. 2). The dose of S-1 was status 0–1. accorded to body-surface area (BSA): patients with a 3) Life expectancy ≥6 months. BSA of less than 1.25 m2 receive 80 mg daily;
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