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 Address: Dr. Masayuki Watanabe, Gastroenterological Surgery, Cancer Institute Hospital, Tokyo 135-8550, Japan. E-mail:
© 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.
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.
Esophagogastric junction, adenocarcinoma, advanced, molecular targeted drug, immune checkpoint inhibitor, immunotherapy
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 disease of this tumor should include survival benefit with symptom relief, and systemic chemotherapy is a major treatment option for those cases. 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.
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.
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.
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. 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.
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 with confirmed survival benefit in phase III trials. In this section, we focus on the results of phase III clinical trials.
Clinical trials testing targeted therapies for esophagogastric junction and gastric adenocarcinoma
|Trial||Target||Patients (EGJ)||Treatment||Outcome (EGJ + gastric cases)||Outcome (EGJ)||Outcome (gastric)||Primary endpoint||Refs|
|ToGA||HER2||594 (106)||XP vs. XP + trastuzumab||Positive||Negative||Positive||OS|||
|LOGiC||HER2||545 (49)||CapeOx vs. CapeOx + lapatinib||Negative||Negative||Negative||OS|||
|EXPAND||EGFR||904 (144)||XP vs. XP + cetuximab||Negative||Negative||Negative||OS|||
|REAL3||EGFR||553 (169)||EOC vs. EOC + panitumumab||Negative||Negative||Positive||OS|||
|RILOMET-1||MET||609 (124)||ECX vs. ECX + rilotumumab||Negative||Negative||Positive||OS|||
|METGastric||MET/HGF||562 (130)||mFOLFOX6 vs. mFOLFOX6+onartuzumab||Negative||Negative||Negative||OS|||
|AVAGAST||VEGFR-A||774 (130)||XP i. XP + bevacizumab||Negative||Negative||Negative||OS||[17,49]|
|RAINBOW||VEGFR2||665 (137)||Paclitaxel vs. paclitaxel + ramucirumab||Positive||Positive||Positive||OS|||
|REGARD||VEGFR2||355 (90)||Placebo vs. paclitaxel + ramucirumab||Positive||Negative||Negative||OS|||
|TyTAN||HER2||261 (2)||Paclitaxel or docetaxel vs. trastuzumab-emtansine||Negative||Negative||Negative||OS|||
|GATSBY||HER2||345 (110)||Paclitaxel vs. paclitaxel + lapatinib||Negative||Negative||Negative||OS|||
|GRANITE-1||mTOR||656 (187)||Placebo vs. everolimus||Negative||Negative||Negative||OS||[50,51]|
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 advanced HER2 positive 106 EGJ and 478 gastric adenocarcinoma. HER2 status was tested by IHC and FISH. HER2 positivity was defined as samples with 3+ by IHC, or those with both 2+ IHC and FISH positive. HER2 positivity was frequently observed in tumors located at EGJ, compared to those in stomach (33.2% for EGJ vs. 20.9% for stomach; P < 0.001). Median OS was significantly longer in trastuzumab plus chemotherapy groups than in chemotherapy alone [median 13.8 months (95% CI 12-16) vs. median 11.1 months (95% CI 10-13), HR 0.74; 95% CI 0.60-0.91; P = 0.0046]. However, in a subgroup analysis of EGJ adenocarcinoma, there were no survival benefit of trastuzumab (trastuzumab plus chemotherapy groups vs. chemotherapy alone, HR 0.67; 95% CI 0.42-1.08). The most common adverse events in both groups were nausea, vomiting and neutropenia. Rate of overall grade 3-4 adverse events (68% in trastuzumab plus chemotherapy groups vs. 68% in chemotherapy alone) and cardiac adverse events (6% in trastuzumab plus chemotherapy groups vs. 6% in chemotherapy alone) did not differ between the groups. NCCN guideline recommends the addition of trastuzumab to any chemotherapy combination for patients with HER2-positive tumors.
Ramucirumab is a human IgG1 monoclonal antibody VEGFR-2 antagonist. The REGARD trial and the RAINBOW trial showed a significant benefit of ramucirumab for advanced EGJ and gastric adenocarcinoma, as the second-line chemotherapy.
The REGARD trial [phase III, including advanced EGJ (n = 90) and gastric adenocarcinoma (n = 265)] exhibited a significant benefit of ramucirumab (OS 5.2 months for ramucirumab vs. OS 3.8 months for placebo; HR 0.776, 95% CI 0.603-0.998; P = 0.047). However, in a subgroup analysis of EGJ adenocarcinoma, the trial did not exhibit any significant benefit of ramucirumab (ramucirumab groups vs. placebo groups, HR 0.76; 95% CI 0.47-1.21). The incidence of hypertension was higher in the ramucirumab group than in the placebo group (16% vs. 8%). In the RAINBOW trial [phase III, including advanced EGJ (n = 137) and gastric adenocarcinoma (n = 528)], the ramucirumab plus paclitaxel conferred a significantly prolonged OS, compared to the placebo plus paclitaxel group (9.6 vs. 7.4 months, HR 0.807; 95% CI 0.678-0.962; P = 0.017). In a subgroup analysis of EGJ adenocarcinoma, the trial revealed survival benefit of adding ramucirumab, either (ramucirumab plus paclitaxel groups vs. placebo plus paclitaxel groups, HR 0.39; 95% CI 0.26-0.59). Grade 3 or 4 adverse events that occurred in more than 5% of patients in the ramucirumab and paclitaxel group vs. placebo and paclitaxel group were as follow; neutropenia (41% vs. 19%), leucopenia (17% vs. 7%), hypertension (14% vs. 2%), fatigue (12% vs. 5%), anemia (9% vs. 10%), and abdominal pain (6% vs. 3%).
Bevacizumab, which is a monoclonal antibody that targets vascular endothelial growth factor A (VEGF-A), inhibiting tumor growth in preclinical studies[15,16]. In AVAGAST trial [phase III, including advanced EGJ (n = 103) and gastric adenocarcinoma (n = 671)], bevacizumab did not confer any survival benefit (median OS 12.1 months in bevacizumab plus XP; vs. median OS 10.1 months in XP alone). In a subgroup analysis of EGJ adenocarcinoma, there was no survival benefit (data not available).
Lapatinib is the dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases. In the TRIO-013/LOGiC trial [phase III, including advanced EGJ (n = 46), esophageal (n = 20) and gastric adenocarcinoma (n = 424)], lapatinib plus capecitabine and oxaliplatin (CapeOX) showed no additional efficacy as the first-line treatment for HER2 positive patients [median OS 12.2 months in CapeOX + lapatinib groups (95% CI 10.6-14.2) vs. median OS 10.5 months in CapeOX groups (95% CI 9.0-11.3), HR 0.91; 95% CI 0.73-1.12; P = 0.35]. In a subgroup analysis of EGJ adenocarcinoma, there was no survival benefit (CapeOX + lapatinib groups vs. CapeOX groups, HR 0.90; 95% CI 0.44-1.85; P = 0.77).
TyTan study [phase III, including advanced EGJ (n = 2) and gastric adenocarcinoma (n = 259)] demonstrated that lapatinib plus paclitaxel did not improve OS in HER2-positive patients compared to paclitaxel alone [median OS 11.0 months in lapatinib plus paclitaxel group (95% CI 9.5-14.5) vs. median OS 8.9 months in paclitaxel alone group (95% CI 7.4-11.1), HR 0.84; 95% CI 0.64-1.11; P = 0.1044].
Cetuximab is an EGFR antibody, widely used for patients with KRAS wild-type metastatic colorectal cancer[20,21], recurrence or metastatic squamous-cell carcinoma of the head and neck, and advanced non-small-cell lung cancer. In the EXPAND trial [phase III, including advanced EGJ (n = 144) and gastric adenocarcinoma (n = 747)], the efficacy of adding cetuximab to capecitabine plus cisplatin was examined. However, there was no benefit to adding of cetuximab to chemotherapy compared to chemotherapy alone in the first-line treatment [median PFS 4.4 months in cetuximab plus capecitabine and cisplatin groups (95% CI 4.2-5.5); vs. median PFS 5.6 months in capecitabine and cisplatin alone groups (95% CI 5.1-5.7); HR 1.09; 95% CI 0.92-1.29; P = 0.32]. In a subgroup analysis of EGJ adenocarcinoma, there was no benefit to add cetuximab, either [median PFS 5.6 months in cetuximab plus capecitabine and cisplatin groups vs. median PFS 5.6 months in capecitabine and cisplatin alone groups; HR 1.12; 95% CI 0.73-1.71].
Panitumumab is a fully human immunoglobulin G2 monoclonal antibody targeting EGFR. In advanced colorectal adenocarcinoma, panitumumab significantly improved PFS. The REAL3 trial [phase III, including advanced EGJ (n = 169), esophageal (n = 220) and gastric adenocarcinoma (n = 167)] revealed no survival benefit of adding panitumumab to epirubicin, oxaliplatin and capecitabine (EOC) chemotherapy [median OS 11.3 months in EOC alone groups (95% CI 9.6-13.0) vs. median OS 8.8 months in panitumumab plus EOC groups (95% CI 7.7-9.8), HR 1.37; 95% CI 1.07-1.76; P = 0.013]. In a subgroup analysis of EGJ adenocarcinoma, the trial revealed no survival benefit of adding panitumumab, either (EOC alone groups vs. panitumumab plus EOC groups, HR 1.27; 95% CI 0.78-2.07).
Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). In the RILOMET-1 trial [phase III, including advanced EGJ (n = 124), distal esophageal (n = 67) and gastric adenocarcinoma (n = 63)], median OS was 8.8 months (95% CI 7.7-10.2) in the rilotumumab group, compared with 10.7 months (95% CI 9.6-12.4) in the placebo group (HR 1.34, 95% CI 1.10-1.63; P = 0.003), demonstrating that rilotumumab conferred no survival benefit. In a subgroup analysis of EGJ adenocarcinoma, rilotumumab conferred no survival benefit (the rilotumumab group vs. the placebo group, HR 1.28; 95% CI 0.83-1.98).
Onartuzumab is a recombinant, fully humanized, monovalent monoclonal antibody that binds the extracellular domain of MET, blocking interaction with HGF. In METGastric trial [phase III, HER2-negative and MET-positive tumors, including advanced EGJ (n = 130) and gastric adenocarcinoma (n = 432)], no survival benefit was observed in onartuzumab plus mFOLFOX group, compared to placebo plus mFOLFOX (median OS 11.3 months in placebo plus mFOLFOX group vs. median OS 11.0 months in onartuzumab plus mFOLFOX group, HR 0.82; 95% CI 0.59-1.15; P = 0.24). In a subgroup analysis of EGJ adenocarcinoma, no survival benefit was observed in onartuzumab plus mFOLFOX group (median OS not estimable in placebo plus mFOLFOX group vs. median OS 11.0 months in onartuzumab plus mFOLFOX group, HR 1.12; 95% CI 0.58-2.19).
Everolimus is an oral mTOR inhibitor. In GRANITE-1 [phase III, including advanced EGJ (n = 187) and gastric adenocarcinoma (n = 656)], everolimus did not significantly improve OS, compared to placebo alone (median OS, 5.4 months in everolimus vs. median OS, 4.3 months in placebo, HR 0.90; 95% CI 0.75-1.08; P = 0.124). In a subgroup analysis of EGJ adenocarcinoma, everolimus did not significantly improve OS, either (everolimus vs. placebo, HR 0.84; 95% CI 0.61-1.16).
Trastuzumab emtansine (T-DM1) is anti-HER2 monoclonal antibody consisting of trastuzumab linked to emtansine (DM1), which is a microtubule inhibitor. In GATSBY [phase II/III, including HER2-positive advanced EGJ (n = 110) and gastric adenocarcinoma (n = 235)], there was no superiority of T-DM1 to taxane [median OS 7.9 months with T-DM1 (95% CI 6.7-9.5) vs. median OS 8.6 months with taxane (95% CI 7.1-11.2), HR 1.15; 95% CI 0.87-1.51; P = 0.86]. In a subgroup analysis of EGJ adenocarcinoma, similarly to the above, there was no superiority of T-DM1 to taxane (median OS 7.1 months with T-DM1 vs. median OS 8.5 months with taxane, HR 1.18; 95% CI 0.70-2.01).
Although precision medicine still remains developing for the upper gastrointestinal malignancies, there are some new approaches such as VIKTORY, and PANGEA trials. PANGEA is a phase II trial that gastroesophageal tumors are classified into the following six categories (HER2+, MET+, FGFR2+, VEGFR2+, MSI-H, and EGFR+), and then paired specific targeted therapies (trastuzumab, TBD, anti-EGFR antibody ABT-806, TBD2, ramucirumab, and nivolmab) are assigned according to the biomarkers, along with standard chemotherapy. VIKTORY is a screening trial without drug intervention for metastatic GC patients who failed or progressed on first-line chemotherapy, using cancer panel/nanostring CNV and immunohistochemistry. These efforts may create new algorithms in upper gastrointestinal cancers.
The most advanced of the emerging development in EGJ and gastric adenocarcinoma is immunotherapy. Programmed death protein 1 (PD1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte protein 4 (CTLA4) are the key drugs to regulate cellular immune functions. Pembrolizumab and nivolumab, which are being developed as anti-PD1 antibodies, have been examined in clinical trials.
Pembrolizumab is a selective, humanized, high-affinity IgG4-κ monoclonal antibody. By binding to PD1, pembrolizumab block the interaction between PD-1 and its ligands. In the USA, pembrolizumab was approved by the FDA for the treatment of melanoma, non-small-cell lung cancer and head and neck cancer. In a phase Ib trial (KEYNOTE-012), the safety and activity of pembrolizumab was assessed in patients with PD-L1 positive advanced EGJ and gastric adenocarcinoma. The median PFS and the median OS were 1.9 months (95% CI 1.8-3.5) and 11.4 months (95% CI 5.7) respectively. The KEYNOTE-061 is a phase III trial as a second-line therapy for PD-L1-positive patients, comparing pembrolizumab with paclitaxel. The KEYNOTE-062 is phase III trial of pembrolizumab alone or combination with FP or capecitabine vs. FP or capecitabine alone as a first-line therapy for PD-L1-positive patients. Both of these trials are still in progress.
Nivolumab is a fully human IgG4 monoclonal antibody inhibitor of PD-1. In the ATTRACTION-2 study, which was a randomized phase III trial, investigating the efficacy and safety of nivolumab as a third-line for unresectable advanced and recurrent EGJ and gastric adenocarcinoma regardless of PD-L1 expression. Median OS was 5.26 months (95% CI 4.60-6.37) in the nivolumab group and 4.14 months (95% CI 3.42-4.86) in the placebo group (HR 0.63, 95% CI 0.51-0.78; P < 0.0001), resulting in a new treatment option for these cancers. The other anti PD-L1 antibody, such as avelumab, durvalumab and atezolizumab have been expected to advanced EGJ and gastric adenocarcinoma. Two randomized phase III trials of avelumab in EGJ and gastric adenocarcinoma are undergoing [Table 2].
The phase III clinical trials of immunotherapy for esophagogastric junction and gastric adenocarcinoma
|Trial||Drug||Target||Patients (EGJ)||Treatment||Primary endpoint|
|CheckMate 649 (NCT02872116)||Nivolumab||PD1||594 (106)||Nivolumab and ipilimumab vs. 5-FU and oxaliplatin||OS|
|KEYNOTE-062 (NCT02494583)||Pembrolizumab||PD1||545 (49)||Pembrolizumab vs. pembrolizumab, 5-FU and cisplatin or capecitabine vs. 5-FU and cisplatin||PFS and OS|
|KEYNOTE-061 (NCT02370498)||Pembrolizumab||PD1||665 (137)||Pembrolizumab vs. paclitaxel||PFS and OS|
|ONO-4538-12 (NCT02267343)||Nivolumab||PD1||261 (0)||Nivolumab vs. placebo||OS|
CheckMate-032 is an ongoing trial, evaluating nivolumab alone, and nivolumab in combination with ipilimumab, for various solid tumors including previously treated advanced EGJ and gastric adenocarcinoma, regardless of PD-L1 expression status. Patients were randomly assigned in to the following three groups, NIVO3 group (nivolumab: 3 mg/kg, once every 2 weeks), NIVO1 plus IPI3 group (nivolumab: 1 mg/kg plus ipilimumab: 3 mg/kg, once every 3 weeks) and NIVO3 plus IPI1 group (nivolumab: 3 mg/kg plus ipilimumab: 1 mg/kg, once every 3 weeks). The median OS were 6.2 months (95% CI 3.4-12.4) in NIVO3 group, 6.9 months (95% CI 3.7-11.5) in NIVO1 plus IPI3 group and 4.8 months (95% CI 3.0-8.4) in NIVO3 plus IPI1 group[36,37]. In addition, CheckMate 649 examining nivolumab plus ipilimumab or nivolumab plus chemotherapy compared with patients receiving chemotherapy alone are also in progress. Utilizing nivolumab in combination with the other agents may be a major option for EGJ and gastric adenocarcinoma.
Many study reported that PD-L1 expression has been related with poor prognosis and associated with response to immunotherapy[39-42]. On the other hands, only a few studies reported that PD-L1 blockade was effective without PD-L1 expression. These results indicated that PD-L1 is not yet established as a biomarker for PD-L1 inhibitors. Recent reports suggested that host microbiome and tumor and stromal genomic profiles may be related with response to immune checkpoint blockade[9,10]. The diversity and abundance of specific bacterial species in the oral and fecal microbiome enhanced systemic and antitumor immunity[43,44]. For example, in the patients with advanced tumor who received immunotherapy, the use of antibiotics caused poor prognosis. In addition, oral administration of bacteria improved anti-tumor effect. Some immune checkpoints, such as lymphocyte activation gene 3 protein (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), T-cell immune-receptor with Ig and ITIM domains (TIGIT) are being currently investigated in clinical trials, in order to develop new drugs in the near future.
Global standard treatment for metastatic EGJ and gastric adenocarcinoma is the combination of platinum-agents and fluoropyrimidine. The availability of targeted agents such as trastuzumab or ramucirumab, have become a new hope to the patients with this aggressive tumor. Immune checkpoint inhibitors have emerged as a novel therapeutic option. Discovering the best combination of these drugs may lead a dramatic improvement of the prognosis of these aggressive tumors.
Concept, design, literature search and manuscript preparation: Toihata T
Concept, design, and manuscript editing: Imamura Y
Manuscript review: Watanabe M, Baba HFinancial support and sponsorship
None.Conflicts of interest
There are no conflicts of interest.Patient consent
Not applicable.Ethics approval
© The Author(s) 2018.
1. Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998;85:1457-9.DOIPubMed
2. Stein HJ, Feith M, Siewert JR. Cancer of the esophagogastric junction. Surg Oncol 2000;9:35-41.DOI
3. Gronnier C, Piessen G, Mariette C. Diagnosis and treatment of non-metastatic esophagogastric junction adenocarcinoma: what are the current options? J Visc Surg 2012;149:e23-33.DOIPubMed
4. Tajima Y, Yamazaki K, Makino R, Nishino N, Masuda Y, Aoki S, Kato M, Morohara K, Kusano M. Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach. Br J Cancer 2007;96:631-8.DOIPubMedPMC
5. Li-Chang HH, Kasaian K, Ng Y, Lum A, Kong E, Lim H, Jones SJ, Huntsman DG, Schaeffer DF, Yip S. Retrospective review using targeted deep sequencing reveals mutational differences between gastroesophageal junction and gastric carcinomas. BMC Cancer 2015;15:32.DOIPubMedPMC
6. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97.DOI
7. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-35.DOI
8. Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2017;8:CD004064.DOI
9. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-9.DOIPubMedPMC
10. Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 2017;541:169-75.DOIPubMedPMC
11. Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol 2005;23:5660-7.DOIPubMed
12. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36-46.DOIPubMed
13. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008;9:215-21.DOI
14. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31-9.DOI
15. Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol 2017;18:357-70.DOI
16. Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005;65:671-80.PubMed
17. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011;29:3968-76.DOIPubMed
18. Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, Salman P, Li J, Protsenko SA, Wainberg ZA, Buyse M, Afenjar K, Houe V, Garcia A, Kaneko T, Huang Y, Khan-Wasti S, Santillana S, Press MF, Slamon D. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC--a randomized phase III trial. J Clin Oncol 2016;34:443-51.DOIPubMed
19. Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol 2014;32:2039-49.DOIPubMed
20. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011;22:1535-46.DOIPubMed
21. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29:2011-9.DOIPubMed
22. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.DOIPubMed
23. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525-31.DOI
24. Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Gotte H, Melezinkova H, Moehler M. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 2013;14:490-9.DOI
25. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697-705.DOIPubMed
26. Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, Ferry D, Mansoor W, Crosby T, Coxon F, Smith D, Waters J, Iveson T, Falk S, Slater S, Peckitt C, Barbachano Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013;14:481-9.DOI
27. Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1467-82.DOI
28. Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol 2017;35:412-20.DOIPubMed
29. Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, Bruey JM, Smith D, McCaffery I, Shames DS, Phan S, Cunningham D. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol 2017;3:620-7.DOIPubMedPMC
30. Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013;31:3935-43.DOIPubMed
31. Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol 2017;18:640-53.DOI
32. Catenacci DV. Next-generation clinical trials: novel strategies to address the challenge of tumor molecular heterogeneity. Mol Oncol 2015;9:967-96.DOIPubMedPMC
33. Ajani JA, Lee J, Sano T, Janjigian YY, Fan D, Song S. Gastric adenocarcinoma. Nat Rev Dis Primers 2017;3:17036.DOIPubMed
34. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B, McRee AJ, Lin CC, Pathiraja K, Lunceford J, Emancipator K, Juco J, Koshiji M, Bang YJ. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016;17:717-26.DOI
35. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:2461-71.DOI
36. Le DT, Bendell JC, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Bono P, Jaeger D, Evans TRJ, Braud FGD, Chau I, Christensen O, Harbison C, Lin CS, Janjigian YY. Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): results from the CheckMate-032 study. J Clin Oncol 2016;34 suppl 4:abstr6.
37. Janjigian YY, Bendell JC, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Bono P, Jaeger D, Evans TRJ, Braud FGD, Chau I, Tschaika M, Harbison CT, Lin C-S C, Le DT. CheckMate-032: Phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol 2016;34 suppl 15:abstr4010.
38. Janjigian YY, Adenis A, Aucoin J-S J, Barone C, Boku N, Chau I, Cleary JM, Feeney K, Franke FA, Moehler M, Roca EL, Schenker M, Li M, Ajani JA. Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer. J Clin Oncol 2017;35 suppl 4:abstrTPS213.
39. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563-7.DOIPubMedPMC
40. Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, Xu H, Yao S, Pons A, Chen L, Pardoll DM, Brahmer JR, Topalian SL. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 2013;19:462-8.DOIPubMedPMC
41. Lote H, Cafferkey C, Chau I. PD-1 and PD-L1 blockade in gastrointestinal malignancies. Cancer Treat Rev 2015;41:893-903.DOIPubMed
42. Zhang M, Dong Y, Liu H, Wang Y, Zhao S, Xuan Q, Wang Y, Zhang Q. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients. Sci Rep 2016;6:37933.DOIPubMedPMC
43. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97-103.DOIPubMedPMC
44. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350:1079-84.DOIPubMedPMC
45. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91-7.DOIPubMed
46. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol 2015;15:45-56.DOIPubMed
47. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016;44:989-1004.DOIPubMedPMC
48. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 2015;15:243-54.DOIPubMed
49. Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, Peng Yong W, Langer B, Delmar P, Scherer SJ, Shah MA. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 2012;30:2119-27.DOIPubMed
50. Bruzzi JF, Swisher SG, Truong MT, Munden RF, Hofstetter WL, Macapinlac HA, Correa AM, Mawlawi O, Ajani JA, Komaki RR, Fukami N, Erasmus JJ. Detection of interval distant metastases: clinical utility of integrated CT-PET imaging in patients with esophageal carcinoma after neoadjuvant therapy. Cancer 2007;109:125-34.DOIPubMed
51. Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, Kim YH, Park JO, Chun HG, Zang DY, Fielding A, Rowbottom J, Hodgson D, O'Connor MJ, Yin X, Kim WH. Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 2015;33:3858-65.DOIPubMed