Toihata et al. J Cancer Metastasis Treat 2018;4:24 Journal of Cancer DOI: 10.20517/2394-4722.2017.82 Metastasis and Treatment Review Open Access Management of metastatic esophagogastric junction adenocarcinoma Tasuku Toihata1,2, Yu Imamura2, Masayuki Watanabe2, Hideo Baba1 1Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-0811, Japan. 2Gastroenterological Surgery, Cancer Institute Hospital, Tokyo 135-8550, Japan. Correspondence to: Dr. Masayuki Watanabe, Gastroenterological Surgery, Cancer Institute Hospital, Tokyo 135-8550, Japan. E-mail: [email protected] How to cite this article: Toihata T, Imamura Y, Watanabe M, Baba H. Management of metastatic esophagogastric junction adenocarcinoma. J Cancer Metastasis Treat 2018;4:24. http://dx.doi.org/10.20517/2394-4722.2017.82 Received: 14 Dec 2017 First Decision: 18 Jan 2018 Revised: 4 Apr 2018 Accepted: 23 Apr 2018 Published: 17 May 2018 Science Editors: Lucio Miele Copy Editor: Jun-Yao Li Production Editor: Huan-Liang Wu Abstract The prognosis of metastatic disease of esophagogastric junction adenocarcinoma remains poor, despite using a variety of regimens using cytotoxic agents. Recent understanding of molecular characteristic and tumor microenvironment of this cancer is currently instigating new therapeutic options. In this review, we summarized previous evidences of cytotoxic agents widely used worldwide, and updated recent developments of molecular targeted drugs, and immune checkpoint inhibitors. Keywords: Esophagogastric junction, adenocarcinoma, advanced, molecular targeted drug, immune checkpoint inhibitor, immunotherapy INTRODUCTION The esophagogastric junction (EGJ) adenocarcinoma is defined as tumors which have their center within 5 cm proximal or distal to the anatomical esophagogastric junction[1-3]. In Western countries, the incidence of EGJ adenocarcinoma has been increasing rapidly over the last few decades, in the background of decreasing rate of Helicobacter pylori infection, and increasing trends of obesity and gastroesophageal reflux disease (GERD). EGJ adenocarcinoma is usually diagnosed with unresectable disease because of difficulty in early detection. Even after curative resection, many cases experience recurrent disease, resulting in lower survival rates of this tumor[4,5]. In spite of multidisciplinary treatments, median overall survival (OS) is around 12 months in advanced EGJ or gastric adenocarcinoma[6,7]. Therefore, the treatment goal for metastatic © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as 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. www.jcmtjournal.com Page 2 of 10 Toihata et al. J Cancer Metastasis Treat 2018;4:24 I http://dx.doi.org/10.20517/2394-4722.2017.82 disease of this tumor should include survival benefit with symptom relief, and systemic chemotherapy is a major treatment option for those cases[8]. Treatments for advanced EGJ adenocarcinoma has been developed as a type of advanced gastric cancer, and many clinical trials were conducted targeting both EGJ and gastric adenocarcinoma. Recent comprehensive molecular analysis for upper GI cancers reveals molecular differences between EGJ and gastric adenocarcinoma[9,10]. Here, we update recent evidences of treatments for advanced EGJ adenocarcinoma, and discuss future perspective. CYTOTOXIC AGENTS (FOR HER2-NEGATIVE TUMORS) Fluoropyrimidine (ftorafur, S-1, or capecitabine), platinum (cisplatin, or oxaliplatin), irinotecan, and taxanes (paclitaxel, or docetaxel) are globally used for metastatic disease of EGJ adenocarcinoma. In addition, trastuzumab is a humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor, and approved for tumors with HER2+ [protein overexpression by immunohistochemistry (IHC) or gene amplification by in situ hybridization (FISH)] EGJ adenocarcinoma. Considering chemotherapeutic managements, tumor HER2 status is a valuable information for adding trastuzumab to cytotoxic agents. As a first-line therapy, there is no widely accepted first-line standard regimen for advanced EGJ adenocarcinoma. In the USA and Europe, fluorouracil and platinum-based agents (CF) or docetaxel, fluorouracil, and cisplatin (DCF) is widely used regimen based on the clinical trial. In 2006, the V-325 study group showed no superiority between DCF and DC (docetaxel and cisplatin) in OS. Median OS was 9.6 months for DCF, and 10.5 months for DC. The incidence of hematologic toxicities was high, but it was comparable between DCF and DC. Grade 3 or 4 neutropenia was the most common in hematologic toxicity; it occurred in 86% in the patients with DCF, and 87% in DC cases, although non-hematologic toxicities of DCF had a higher incidence than that of DC[11]. In Europe, epirubicin, cisplatin, and fluorouracil (ECF), epirubicin, cisplatin, and capecitabine (ECX), epirubicin, oxaliplatin, and fluorouracil (EOF), or epirubicin, oxaliplatin, and capecitabine (EOX) is a major regimen for advanced EGJ or stomach adenocarcinoma. The REAL-2 trial assessed above-mentioned four regimens with different three-drug combination, and showed median OS of 9.9 months with ECF, 9.9 months with ECX, 9.3 months with EOF, and 11.2 months with EOX, respectively. One-year-survival rates were 37.7%, 40.8%, 40.4%, and 46.8%. The trial showed capecitabine and oxaliplatin were as effective as fluorouracil and cisplatin[12]. In Asia, the recommended first-line treatment is S-1 plus cisplatin (SP) or capecitabine plus cisplatin (XP). In the SPIRITS trial [phase III, including advanced gastric adenocarcinoma (n = 298)], OS was better in patients treated with SP than with S-1 alone. Median OS was 13.0 months [interquartile range (IQR) 7.6-21.9] in those assigned to SP compared with 11.0 months (IQR 5.6-19.8) in those assigned to S-1 alone [hazard ratio (HR) 0.77; 95% CI 0.61-0.98; P = 0.04]. Progression-free survival (PFS) was significantly longer in those assigned to SP than S-1 alone [median PFS 6.0 months (3.3-12.9) for SP vs. 4.0 months (2.1-6.8) for S-1 alone; P < 0.0001]. The trial showed more grade 3 or 4 adverse events including leucopenia, neutropenia, anemia, nausea, and anorexia, in patients assigned to SP than in patients assigned to S-1 alone[13]. However, the incidence of EGJ cancer remains low in Japan, and this clinical trial included only gastric cancer patients. Therefore, the standard treatment for EGJ cancer has not yet been established in Japan and patients with EGJ cancer are usually treated based on the evidence for gastric cancer. MOLECULARLY TARGETED DRUG In the first decade of this century, molecularly targeted drugs have been developed for advanced EGJ adenocarcinoma [Table 1]. To date, trastuzumab and ramucirumab are the only molecularly targeted drugs Toihata et al. J Cancer Metastasis Treat 2018;4:24 I http://dx.doi.org/10.20517/2394-4722.2017.82 Page 3 of 10 Table 1. Clinical trials testing targeted therapies for esophagogastric junction and gastric adenocarcinoma Outcome Patients Outcome Outcome Primary Trial Target Treatment (EGJ + gastric Refs (EGJ) (EGJ) (gastric) endpoint cases) 1st line ToGA HER2 594 XP vs. Positive Negative Positive OS [6] (106) XP + trastuzumab LOGiC HER2 545 CapeOx vs. Negative Negative Negative OS [18] (49) CapeOx + lapatinib EXPAND EGFR 904 XP vs. Negative Negative Negative OS [24] (144) XP + cetuximab REAL3 EGFR 553 EOC vs. Negative Negative Positive OS [26] (169) EOC + panitumumab RILOMET-1 MET 609 ECX vs. Negative Negative Positive OS [27] (124) ECX + rilotumumab METGastric MET/HGF 562 mFOLFOX6 vs. Negative Negative Negative OS [29] (130) mFOLFOX6+onartuzumab AVAGAST VEGFR-A 774 XP i. Negative Negative Negative OS [17,49] (130) XP + bevacizumab 2nd line RAINBOW VEGFR2 665 Paclitaxel vs. Positive Positive Positive OS [7] (137) paclitaxel + ramucirumab REGARD VEGFR2 355 Placebo vs. Positive Negative Negative OS [14] (90) paclitaxel + ramucirumab TyTAN HER2 261 Paclitaxel or docetaxel vs. Negative Negative Negative OS [19] (2) trastuzumab-emtansine GATSBY HER2 345 Paclitaxel vs. Negative Negative Negative OS [31] (110) paclitaxel + lapatinib GRANITE-1 mTOR 656 Placebo vs. Negative Negative Negative OS [50,51] (187) everolimus CapeOx: capecitabine and oxaliplatin; EGFR: epidermal growth factor receptor; ECX: epirubicin, cisplatin and capecitabine; EOC: epirubicin, oxaliplatin and capecitabine; HER2: human epidermal growth factor 2; HGF: hepatocyte growth factor; mFOLFOX6: leucovorin, fluorouracil and oxaliplatin; mTOR: mechanistic target of rapamycin; OS: overall survival; PFS: progression-free survival; VEGF-A: vascular endothelial growth factor A; VEGFR2: vascular endothelial growth factor receptor 2; XP: capecitabine and cisplatin with confirmed survival benefit in phase III trials. In this section, we focus on the results of phase III clinical trials. Trastuzumab (anti-HER2 antibody) Trastuzumab is a monoclonal antibody targeting HER2. In 2010, ToGA trial [phase III, including EGJ (n = 106) and advanced gastric adenocarcinoma (n = 478)] was to assess the efficacy and safety of trastuzumab plus first-line chemotherapy (XP or FP) of