Clinical and Translational Oncology (2020) 22:236–244 https://doi.org/10.1007/s12094-019-02259-9 CLINICAL GUIDES IN ONCOLOGY SEOM clinical guideline for the diagnosis and treatment of gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJA) (2019) M. Martín‑Richard1 · A. Carmona‑Bayonas2 · Ana. B. Custodio3 · J. Gallego4 · P. Jiménez‑Fonseca5 · J. J. Reina6 · P. Richart7 · F. Rivera8 · M. Alsina9 · J. Sastre10 Received: 30 November 2019 / Accepted: 30 November 2019 / Published online: 27 January 2020 © The Author(s) 2020 Abstract Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, it represents the sixth cause of cancer death. In Western countries, the incidence is decreasing slightly, with an increase in gastroesophageal junction adenocarcinoma (GEJA), a different entity that we separate specifically in the guideline. Molecular biology advances have been done recently, but do not yet lead to the choice in treatment approach except in advanced disease with overexpression of HER2. Endoscopic resection in very early stage, perioperative chemo‑ therapy in locally advanced tumors and preliminary immune therapy resulting in advanced disease are the main treatment innovations in the GC/GEJA treatment. We describe the different evidences and recommendations following the statements of the American College of Physicians. Keywords Gastric cancer · Gastroesophageal junction adenocarcinoma · Diagnosis · Treatment 2 * M. Martín‑Richard Medical Oncology Department, Hospital J.M. Morales mmartinri@santpau.cat Meseguer, Murcia, Spain 3 A. Carmona‑Bayonas Medical Oncology Department, Hospital Universitario La alberto.carmonabayonas@gmail.com Paz, Centro de Investigación Biomédica en Red Cáncer, CB16/12/00398 Madrid, Spain Ana. B. Custodio 4 anabcustodio@gmail.com Medical Oncology Department, Hospital General Universitario de Elche y Vega Baja, Alicante, Spain J. Gallego 5 j.gallegoplazas@gmail.com Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain P. Jiménez‑Fonseca 6 palucaji@hotmail.com Medical Oncology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain J. J. Reina 7 juanjoreinaz@yahoo.es Medical Oncology Department, Hospital Universitari I Politècnic la Fe, Valencia, Spain P. Richart 8 paularichart@gmail.com Medical Oncology Department, Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain F. Rivera 9 fernando.rivera@scsalud.es Medical Oncology Department, Hospital Universitario Vall D’Hebron, Universitat Autònoma de Barcelona (UAB), M. Alsina Barcelona, Spain malsinamaqued@gmail.com 10 Medical Oncology Department, Hospital Clínico J. Sastre Universitario San Carlos, Madrid, Spain jsastrev@salud.madrid.org 1 Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, Sant Antoni Maria Claret, 167, 08025 Barcelona, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2020) 22:236–244 237 Introduction are based on stratifying patients by risk factors and the use of biomarkers. Globally, gastric cancer (GC) is an important worldwide public health concern; it is the third cause of cancer mor‑ tality (after lung and colorectal cancer) and the fifth in Molecular classification and emerging incidence. There is a great variability in this incidence, therapies with the highest values in East Asia, East Europe and in South America. In Spain, the estimated incidence of GC in The biology of GC is heterogeneous. Multiple deregulated 2019 is 7865 cases (ninth most frequent neoplasm), with canonical signaling pathways are known, involving p53, higher incidence in men [1] as in the rest of the Western RAS, Wnt and various transcription factors, among others. countries. The incidence of GC has gradually decreased In addition, > 30 focal amplifications in oncogenes such over the last decade by 33% since 1980. This decrease as HER2, CCNE1, KRAS, MYC, EGFR, CDK6, GATA4, is probably related to the modification of some risk fac‑ GATA6 and ZNF217 have been described. Genetic altera‑ tors of GC: changes in diet, decrease in the incidence of tions tend to be framed in subtypes, making it easier to helicobacter pylori (HP) infection and tobacco/alcohol search for targetable driver genes. The Cancer Genome consumption [2]. Other nonintervention risk factors that Atlas (TCGA) classification [6] divides gastric tumors into have been shown to be associated with GC are age, sex and four subtypes: related to Epstein–Barr virus (EBV) (9%), genetic predisposition. The main familial syndrome asso‑ microsatellite instability (MSI) (22%), genomically sta‑ ciated with GC predisposition is the diffuse hereditary GC ble (20%) and tumors with chromosomal instability (CIN) caused by mutations in the E-cadherin gene. In contrast, (50%). Each subtype has a peculiar biology and specific the incidence of gastroesophageal junction adenocarci‑ genetic aberrations. Thus, in localized GC, the frequency noma (GEJA) has increased over time in Western countries of MSI is 8%, being associated with lower sensitivity to mainly due to risk factors such as obesity and gastroe‑ fluoropyrimidines. HER2 amplifications occur in 9–36% sophageal reflux [3]. GEJA is divided into three subtypes and predict prognosis and sensitivity to anti-HER2 agents. according to the Siewert classification and has often been There are other classifications with common but not equiv‑ grouped together with GC in randomized clinical trials. alent traits, such as Singapore, or Asian Cancer Research In Europe, the GC is usually diagnosed at advanced Group (ACRG) classifications [7, 8]. In addition to iden‑ stages. There are no screening programs for early detec‑ tifying new targets, these findings open the door to the tion, mainly due to the low-to-moderate incidence com‑ development of predictive and prognostic biomarkers. Sev‑ pared to the incidence in East Asia. eral have been proposed, such as Immunoscore, detection From the histological perspective, the vast majority of of circulating tumor DNA (ctDNA) and others. Their supe‑ them (85%) are adenocarcinomas. The two classic histo‑ rior performance with respect to well-established clini‑ logical Lauren subtypes were intestinal and diffuse with cal–pathological factors, such as Lauren’s classification or different epidemiological, genetic and prognostic profiles. the AGAMENON model, is pending confirmation [9, 10]. The WHO classification recognized five subtypes: papil‑ These advances have potential therapeutic implications. lary, tubular, mucinous, poorly cohesive (with or without Immune checkpoint inhibitors could be effective, although signet ring cells) and mixed. the benefit has not yet been fully demonstrated in the first or second line Finally, as a result of molecular characteri‑ Surveillance zation, clinical trials are currently being carried out with PI3K/AKT/mTOR, VEGFR or HER2 signaling pathways The available studies on resected GC follow-up are retro‑ inhibitors, and other novel targets are being explored, such spective, without scientific evidence to improve survival. as ARID1A, Claudin 18.2 (a component of tight junctions), However, most international scientific societies recommend matrix metalloproteinase-9, PARP or cancer stem cells follow-up, although there is no agreement in the tests used or inhibitors. in the frequency [4]. The most sensitive test is the computed tomography (CT) scan with a sensitivity and a specificity of 60–90%. Positron emission tomography (PET) may improve Diagnosis and staging its results, when the results of the CT scan are doubtful. Fol‑ low-up with digestive endoscopy has limited utility, given Gastroscopy is the primary diagnostic tool for GC. Biop‑ the very small number of resectable local recurrences in GC sies of suspicious lesions should always be taken in order to [5]. The most promising research pathways in GC follow-up confirm histology and to classify GC according to the World Health Organization (WHO) criteria and Lauren classifica‑ tion HER2 testing, which should be conducted with the aim 13 238 Clinical and Translational Oncology (2020) 22:236–244 of selecting patients with metastatic disease for treatment Table 1  AJCC prognostic stage 0 Tis N0 M0 with trastuzumab-containing regimen (E: high; R: strong). groups pathological staging (pTNM) GC IA T1 N0 M0 Polymerase chain reaction (PCR) for microsatellite insta‑ bility (MSI) or immunohistochemistry (IHC) for mismatch IB T1 N1 M0 repair deficiency (dMMR) should be tested on advanced T2 N0 M0 GC with a view to predicting the clinical benefit of immune IIA T1 N2 M0 checkpoint inhibitors (CPIs) (E: moderate; R: strong). Pro‑ T2 N1 M0 grammed death ligand 1 (PD-L1) may be considered as T3 N0 M0 potential biomarker for the use of CPIs [11]. IIB T1 N3a M0 Endoscopic ultrasonography (EUS) is helpful in the pre‑ T2 N2 M0 operative staging of GC to evaluate the depth of invasion T3 N1 M0 of tumor and the presence of local lymph node metastases T4a N0 M0 and is recommended if early versus locally advanced dis‑ IIIA T2 N3a M0 ease needs to be determined [12] (E: moderate; R: strong). T3 N2 M0 CT scan of the thorax, abdomen and pelvis is mandatory in T4a N1 M0 preoperative staging of GC. In some patients, PET-CT may T4a N2 M0 improve staging by detecting metastatic disease not visible T4b N0 M0 with other explorations [13]; however, PET-CT may not be IIIB T1 N3b M0 informative in patients with mucinous or diffuse tumors T2 N3b M0 (E: moderate; R: weak). Diagnostic laparoscopy is recom‑ T3 N3a M0 mended in resectable GC with clinical T3 and T4 cancers or T4a N3a M0 in those at higher risk for metastatic disease, such as poorly T4b N1 M0 differentiated cancers and those with a higher nodal burden T4b N2 M0 [14] (E: moderate; R: strong). The cytological examination IIIC T3 N3b M0 of peritoneal lavage, although limited by a low sensitivity, T4a N3b M0 may help identify occult carcinomatosis. Staging is per‑ T4b N3a M0 formed according to the 2017 AJCC TNM classification, T4b N3b M0 8th edition (Tables 1, 2). All patients diagnosed with GC IV Any T Any N M1 or GEJA should be discussed at a multidisciplinary team meeting. Treatment Table 2  AJCC prognostic stage 0 Tis N0 M0 N/A Endoscopic resection groups pathological staging (pTNM) GEJA IA T1A N0 MO G1, X In some selected cases of early GC, endoscopic therapy can IB T1a N0 M0 G2 be used as an alternative to gastrectomy for lesions that have T1b N0 M0 G1-2 a very low risk of lymph node metastasis. This approach can IC T1 N0 M0 G3 be performed in high-volume medical centers with extensive T2 N0 M0 G1-2 experience in these techniques. Endoscopic submucosal dis‑ IIA T2 N0 M0 G3 section (ESD) has been shown to be more effective than IIB T1 N1 M0 Any endoscopic mucosal resection (EMR), but requires greater T3 N0 M0 Any skill and is associated with higher rates of perforation. The IIIA T1 N2 M0 Any classic absolute indications of EMR/ESD include lesions T2 N1 M0 Any limited to the mucosa (T1a), well to moderately differenti‑ IIIB T4 N0-1 M0 Any ated adenocarcinomas, tumors ≤ 2 cm in diameter, absence T3 N1 M0 Any of ulceration and lymphovascular involvement. Additional T2-3 N2 M0 Any treatment is sometimes required based on definitive patho‑ IVA T4a N2 M0 Any logical results (E: moderate; R: strong). T1-4 N3 M0 Any T1-4 N0-3 M1 Any N/A not applicable, X not defined 13 Clinical and Translational Oncology (2020) 22:236–244 239 Surgery (Cisplatin and 5FU : CF); however, no difference in OS was reached. At present, as more contrasted alternatives are Complete resection with adequate margins remains the cor‑ available, this treatment should only be considered within a nerstone of curative treatment of resectable stage I–III GC. clinical trial [16]. Experienced surgical teams generally consider unresectable tumors that invade: pancreatic head, hepatic hilum, trans‑ Chemoradiotherapy (CRT) verse mesocolon, mesenteric artery or aorta. The type of resection in GC, subtotal vs total gastrec‑ The phase III POET study compared two preoperative treat‑ tomy, depends on anatomic location of primary tumor. For ments, CT (CF, 15 weeks) vs CT (CF, 12 weeks) followed by GEJA, a total esophagectomy with a partial gastrectomy or CRT (Cisplatin and Etoposide plus 30 Gy of RT, 3 weeks) an extended gastrectomy is generally performed. in patients with uT3-4NXM0 adenocarcinoma of the lower Extent of lymph node dissection remains controversial, esophagus or gastric cardia [17]. Although the study was while there is consensus that lymphadenectomy should closed early and statistical significance was not achieved, include at least 15 nodes. In Western countries, two large results point to a survival advantage for preoperative CRT RCTs and a meta-analysis of 12 RCTs failed to demonstrate compared with CT in GEJA. an OS benefit for D2 over D1 lymph node dissection. How‑ The phase III CROSS trial compared neoadjuvant CRT ever, mature follow-up data from the Dutch trial showed (Carboplatin and Paclitaxel of RT, 5 weeks) versus surgery a lower locoregional recurrence rate and fewer GC-related alone in patients with T1N1M0 or T2-3N0-1M0 squamous death with D2 lymphadenectomy, and the meta-analysis cell carcinoma (SCC) and adenocarcinoma of the esophagus found a benefit among patients who had resection without or GEJA [18]. Ninety-five percent were able to complete the splenectomy and/or pancreatectomy [15]. entire neoadjuvant CRT with a significant increase of OS in Gastrectomy with D2 lymph node dissection is a recom‑ this group. mended procedure in patients with good PS whenever it is Neoadjuvant CRT followed by resection is preferred carried out in specialized centers, with experienced surgeons than neoadjuvant chemotherapy and could be an alterna‑ and a high-volume interventions (E: high; R: strong). Rou‑ tive to perioperative chemotherapy approach for T1N1 or tine pancreatectomy and splenectomy are no longer recom‑ T2-3N0-1M0 GEJA (E: high; R: strong). mended with D2 lymph node dissection (E: moderate; R: strong). Perioperative treatment Perioperative CT for GC and GEJA was shown to signifi‑ Neoadjuvant treatment cantly increase disease-free survival (DFS) and overall sur‑ vival (OS) as compared to surgery alone in two landmark Chemotherapy (CT) phase 3 trials conducted in Western countries: the MAGIC trial, in which patients received three cycles of Epirrubicin, A RCT by the EORTC (40954) in 144 patients with stage Cisplatin and Fluorouracil (ECF) before and after surgery III–IV (M0) GC or GEJA found a significantly higher rate [19], and the ACCORD-07 using perioperative Cisplatin and of R0 resection among patients receiving neoadjuvant CT Table 3  Phase III trials of perioperative chemotherapy in gastric and gastroesophageal junction adenocarcinoma Study N/N GEJC Design 5-year DFS/PFS 5-year OS MAGIC (1) 503/58 Surgery 23% ECF × 3 → Surgery → ECF × 3 NR 36.3% HR: 0.66 (95% CI 0.53–0.81) HR: 0.75 (95% CI 0.60–0.93) FFCD ACCORD-7 (2) 224/144 Surgery 19% 24% CF × 2 → Surgery → CF × 2 34% 38% HR: 0.65 (95% CI 0.48–0.89) HR: 0.69 (95% CI 0.50–0.95) FLOT4-AIO (4) 716/398 ECF/ECX × 3 → Surgery → ECF/ECX × 3 31% 36% FLOT × 4 → Surgery → FLOTx4 41% 45% HR: 0.75 (95% CI 0.62–0.91) HR: 0.77 (95% CI 0.63–0.94) N number of patients, GEJC gastroesophageal junction cancer, DFS disease-free survival, PFS progression-free survival, OS overall survival, ECF Epirubicin, Cisplatin and 5-Fluorouracil, CF Cisplatin and 5-Fluorouracil, ECX Epirubicin, Cisplatin and Capecitabine, FLOT 5-Fluoro‑ uracil, Leucovorin, Oxaliplatin and Docetaxel, NR not reported, HR hazard ratio, 95% CI 95% confidence interval 13 240 Clinical and Translational Oncology (2020) 22:236–244 Fluorouracil CT [20]. A higher R0 rate was also observed in 5FU, Capecitabine and S1 are acceptable options (E: high; the last study (Table 3). R: strong) [27, 28]. Triplet combinations of Docetaxel, Platinum and Fluo‑ Adjuvant treatment ropyrimidines may be more active than doublet regimens and could be an acceptable option only for fit patients and if When surgery is adopted as first treatment approach for a quick response is needed (E: moderate; R: weak) because localized GC, adjuvant CT or CRT may be considered. they add considerable toxicity [29]. On the other hand, the The benefit of FU-based adjuvant CT versus surgery alone benefit of adding Epirubicin to the Platinum and Fluoropy‑ was initially suggested in an individual patient-level meta- rimidine doublet is nowadays not recommended (E: moder‑ analysis (OS: HR 0.82, p < 0.01; DFS: HR 0.80, p < 0.06) ate; R: weak). based on old randomized studies [23]. Subsequently, S-1 and As an alternative to a Platinum-based treatment in the CAPOX (Capecitabine and Oxaliplatin) both showed statis‑ first-line setting, a doublet of Irinotecan and 5FU might be tically significant benefit in DFS and OS compared to obser‑ considered (E: moderate; R: strong). vation after D2 resection of stage II or III GC [24]. Recently, Anti-HER-2 HER2 is overexpressed (IHC 3+ or IHC the addition of Docetaxel to S1 showed better results than 2+ with FISH+) in 13–25% of patients with GC, being more S1 alone in terms of DFS after D2 resection for stage III GC frequently found in tumors of the intestinal type and those [4]. Hence, even though data come from trials performed in located in the GEJA. The pivotal study performed showed Asian population, adjuvant chemotherapy in resected GC the superiority of the combination of CT (Cisplatin, 5FU or can be considered (E: moderate; R: strong). The particular Capecitabine) and Trastuzumab in front of CT. An increase benefit of this strategy in patients with dMMR GC harboring in radiological (47% vs 35%, p < 0.001), PFS (6.7 vs 5.5 m, has become controversial after limited subgroup analysis in HR 0.71, p < 0.001) and OS (13.8 vs 11.1 months, HR 0.74, this adjuvant and other perioperative clinical trials. p 0.005) was observed. Therefore, this combination is the The first phase III randomized trial to demonstrate benefit standard of care in the first-line treatment in HER2-overex‑ of adjuvant RCT) compared to observation after surgery in pressing tumors (E: high; R: strong) [30]. Other anti-HER-2 stage IB–IV GC was INT-0116 (OS: HR 1.3–2, p = 0.005; therapies such as Lapatinib and Pertuzumab have not yet DFS: HR 1.51, p < 0.001 [25]. Nevertheless, this trial was demonstrated a benefit in OS. criticized due to quality of surgery, CT regimen and radio‑ Other treatments Randomized trials with antiangiogenics therapy (RT) planning. The attempt to improve these results (Bevacizumab, Ramucirumab and Sorafenib) did not show with ECF (Epirubicin, Cisplatin, 5FU) instead of the classic an improvement in OS in the first-line setting. Mayo regimen before and after RT was shown to be futile in The results of the KEYNOTE-062 RCT were recently the CALGB 80101 trial. In order to compare adjuvant CT reported [31], which suggested that Pembrolizumab alone versus CR, the phase III ARTIST trial randomized patients could be equally active and less toxic than CT as first-line after D2-resected GC to adjuvant Cisplatin and Capecitabine treatment in patients with advanced GC or GEJA with with or without Capecitabine-based RT. Only DFS benefit PD-L1 positive tumors (CPS ≥ 1) (E: moderate; R: weak). was suggested for node-positive and intestinal-type disease This study also suggests that the benefit of Pembrolizumab in subgroup analysis [26]. Phase III, three-arm, ARTIST II alone could be greater in the subgroup of patients with trial, including these and other questions in its design, has CPS ≥ 10 (E: low; R: weak). Nevertheless, this trial did not not been able to set firm conclusions so far in this regard. demonstrate a significant benefit with the addition of Pem‑ Considering these results, adjuvant CRT can be established brolizumab to CT vs CT alone. after D0-resected stage IB–IV GC (E: moderate; R: strong). There are currently ongoing other phase III RCTs explor‑ The CT regimen to be used before and after RT and the CT ing the role of other immunotherapies and targeted therapies partner during RT are still topics of discussion. for the first-line treatment of advanced GC, most of them including a biomarker analysis that will probably be very Advanced disease: First‑line treatment important for a proper patient selection. Chemotherapy CT has shown improved OS and quality of Second‑ and third‑line treatment life in patients with advanced gastric cancer (E: high; R: and immunotherapy strong). The most commonly used regimens for the first-line About 50% of the GC and GEJA patients are fit enough to treatment are doublets of a Platinum and a Fluoropyrimi‑ receive a second-line treatment, being only the 20% in the dine, which have demonstrated superiority to other schemes case of the third line. However, the benefit of a second CT without Platinum (E: high; R: strong). Both Oxaliplatin and line (weekly Paclitaxel, Docetaxel or Irinotecan) has been Cisplatin are suitable options (E: high; R: strong) [27]; and 13 Clinical and Translational Oncology (2020) 22:236–244 241 Table 4  List of main phase II/ Clinical trial Ph N Treatment arm Median OS RR III clinical trials evaluating the (a) second- and (b) third- (a) Second-line setting line treatment for gastric and AIO Trial III 40 Irinotecan 4.0 m 0% gastroesophageal junction Thuss-Patience BSC 2.4 m 0% cancer Eur J Can 2011 HR 0.48, p 0.012 Salvage Chemo Triala III 188 Doce/irinotecan 5.3 m Docetaxel 16% Kang BSC 3.8 m Irinotecan 1% J Clin Oncol 2012 HR 0.65, p 0.007 BSC COUGAR 02 III 168 Docetaxel 5.2 m 7% Ford BSC 3.6 m 0% Lancet Oncol 2014 HR 0.67, p 0.01 WJOG4007a III 219 wPaclitaxel 9.5 m 20.9% Hironaka Irinotecan 8.4 m 13.6% J Clin Oncol 2013 HR 1.13, p 0.38 RAINBOW III 665 Pac-ramu 9.6 m 28% Wilke Paclitaxel 7.4 m 16% Lancet Oncol 2014 HR 0.80, p 0.017 REGARD III 355 Ramucirumab 5.2 m 3% Fuchs Placebo 3.8 m 3% Lancet 2014 HR 0.77, p 0.047 TyTAN III 261 Pac + lapatinib 11.0 m 27% Satoh Paclitaxel 8.9 m 9% J Clin Oncol 2014 HR 0.84, p 0.104 GATSBY III 345 T-DM1 7.9 m 20.6% Thuss-Patience Doce/Pac 8.6 m 19.6% Lancet Oncol 2017 HR 1.15, p 0.86 GOLDa III 643 Pac-Olaparib 8.8 m 17% Bang Paclitaxel 6.9 m 11% Lancet Oncol 2017 HR 0.79, p 0.026 KEYNOTE-061 III 592 Pembrolizumab 9.1 m 16% Shitara wPaclitaxel 8.3 m 14% Lancet 2018 HR 0.82, p 0.042 (b) Third line setting and beyond TAGS III 507 FTD/TPI 5.7 m 4% Shitara Placebo 3.6 m 2% Lancet Oncol 2018 HR 0.69, p < 0.001 Apatinib Triala III 267 Apatinib 6.5 m 2.84% Li Placebo 4.7 m 0% J Clin Oncol 2016 HR 0.70, p 0.015 GRANITE-1 III 656 Everolimus 5.4 m 4.5% Othsu Placebo 4.3 m 2.1% J Clin Oncol 2013 HR 0.90, p 0.124 ATT​RAC​TION-2a III 493 Nivolumab 5.26 m 11.2% Kang Lancet 2017 Placebo 4.14 m 0% HR 0.63, p < 0.001 KEYNOTE-059 Cohort 3 II 259 Pembrolizumab 5.5 m 12% Fuchs JAMA Oncol 2018 JAVELIN 300 III 371 Avelumab 4.6 m 2.2% Bang Pac/Irinotecan 5.0 m 4.3% Ann Oncol 2018 HR 1.1, p = 0.81 Ph phase, OS overall survival, RR response rate, BSC best supportive care, HR hazard ratio, Doce Doc‑ etaxel, Pac Paclitaxel, Ramu Ramucirumab, FTD/TPI trifluridine/tipiracil a Trials performed only in Asian population 13 242 Clinical and Translational Oncology (2020) 22:236–244 Table 5  Summary of evidences/ recommendations Diagnosis and staging Case Evidence (E:) Recom‑ mendation (R:) Endoscopy + biopsies Mandatory All E: high; R: strong Mandatory All HER2 determination by IHC/FISH Mandatory Metastatic stage Other molecular factors determination: Useful Metastatic stage E: moderate; R: weak MSIa dMMRb PDL1 expression Consider CPI use = = EUS Mandatory Early stage E: high; R: strong Useful All CT thorax, abdomen, pelvis Mandatory All E: high; R: strong PET-TC Useful All except diffuse AC E: moderate; R: weak Laparoscopy Mandatory T3-4 or higher nodal burden AC E: moderate; R: strong Treatment Stage Detail Treatment Evidence (E:) Recom‑ mendation (R:) Early stage (Tis-I) Tis/T1a Well dif./2 cm/non-ulcerated/ Endoscopic resection E: moderate; R: strong intestinal T1a Others non-ulcerated Endoscopic resection (mucosectomy)/ surgery T1b < 3 cm Submucosal resection/surgery Others T1b Others Surgery Locally advanced (Stage II–III) GEJA Neoadjuvant CT E: moderate; R:weak or CRT (IA) E: high; R: strong or Perioperative CT E: high; R: strong or Adjuvant CRT​ E: high; R: strong GC Neoadjuvant CT E: moderate; R:weak or Perioperative CT E: high; R: strong or Adjuvant CT E:moderate; R: strong or Adjuvant CRT​ E: moderate; R: strong Advanced stage (IV)c First line HER 2+ Cisplatin–fluorop- Trastu E: high; R: strong E: high; R: strong HER2− E: moderate; R:weak E: moderate; R:weak Platinum–fluorop E: moderate; R:strong or ECF or DCF or FOLFIRI or IF Second line Paclitaxel–ramucirumab E: high; R: strong or Irinotecan E: high; R: strong or Docetaxel E: high; R: strong or Paclitaxel E: high; R: strong or Ramucirumab E: high; R: strong Third line Trifluridine/tipiracil E: high; R: strong MSI (microsatellite instability); aby PCR (polymerase chain reaction); dMMR (mismatch repair deficiency); bby IHC (immunochemistry)or CPI (checkpoint inhibitor); EUS (endoscopic sonography); Ct (computed tomography); and AC (adenocarcinoma) c Platinum: Cisplatin or Oxaliplatin; Fluorop: Fluoropyrimidine (5Fu/Capecitabine); Trastu: trastuzumab; ECF: Epirubicin–Cisplatin–Fluoropy‑ rimidine; and DCF: Docetaxel–Cisplatin–Fluoropyrimidine 13 Clinical and Translational Oncology (2020) 22:236–244 243 widely demonstrated in terms of survival and quality of life Open Access This article is licensed under a Creative Commons Attri‑ (E: high; R: strong). The RAINBOW RCT settled the combi‑ bution 4.0 International License, which permits use, sharing, adapta‑ tion, distribution and reproduction in any medium or format, as long nation of Paclitaxel and Ramucirumab as the preferred regi‑ as you give appropriate credit to the original author(s) and the source, men [32] (E: high; R: strong). When considering a third line, provide a link to the Creative Commons licence, and indicate if changes small phase II clinical trials support its efficacy in patients were made. The images or other third party material in this article are with a good performance status (PS) (E: moderate; R: weak). included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in The results from the recent randomized phase III TAGS RCT the article’s Creative Commons licence and your intended use is not confirmed the benefit of a third CT line with trifluridine/ permitted by statutory regulation or exceeds the permitted use, you will tipiracil, in terms of survival and time to ECOG/PS deterio‑ need to obtain permission directly from the copyright holder. To view a ration [4] (E: high, R: strong) (Table 4). copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. Despite the inflammatory carcinogenesis of GC/GEJC and the encouraging efficacy shown in preliminary studies, the effect of immunotherapy is questioned in the second- and third-line treatment due to disappointed results. The References randomized phase III KEYNOTE-061 trial demonstrated a 1. SEOM. Las cifras del cáncer en España 2019. 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Iden‑ Conflict of interest MMR has nothing to disclose. JS reports honoraria tification of molecular subtypes of gastric cancer with different for speaking from Merck, Roche, Servier, Lilly, Ipsen, Shire, Pfizer, responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroen‑ Servier and MSD; advisory role from Roche, Amgen, Merck, Bayer, terology. 2013;145(3):554–65. Celgene, Servier, BMS, Sanofi, Ipsen; and travel expenses from Merck 9. Jiménez-Fonseca P, Carmona-Bayonas A, Hernández R, Custo‑ and Ipsen. JG has nothing to disclose. PR has nothing to disclose. MA dio A, Cano JM, Lacalle A, et al. Lauren subtypes of advanced reports scientific consultancy from Servier, Lilly, BMS and MSD; gastric cancer influence survival and response to chemotherapy: honoraria for speaking from Servier, BMS, MSD, Lilly, Roche and real-world data from the AGAMENON National Cancer Registry. Amgen; and travel expenses from Servier, Roche, Amgen and Lilly. Br J Cancer. 2017;117(6):775–82. JR reports personal fees from Roche and personal fees from Lilly, out‑ 10. Custodio A, Carmona-Bayonas A, Jiménez-Fonseca P, Sánchez side the submitted work. FR reports consultant or advisory role from ML, Viudez A, Hernández R, et al. Nomogram-based predic‑ Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi- tion of survival in patients with advanced oesophagogastric Aventis, Servier, Astra-Zeneca and Bayer; research funding from adenocarcinoma receiving first-line chemotherapy: a multi‑ Roche, Merck-Serono, Amgen, MSD, Lilly, Celgene, Sanofi-Aventis, center prospective study in the era of trastuzumab. Br J Cancer. Bayer and Servier; speaking from Roche, Merck-Serono, Amgen, 2017;116(12):1526–35. MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier and Bayer; and 11. Abbas M, Faggian A, Suntali DN, Khan GJ, Naeem S, Shi M, grant support from Amgen. PJF reports travel grants from Ipsen and et al. Current and future biomarkers in gastric cancer. 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