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Zusammenfassung: HINTERGRUND: Zum Zeitpunkt der Diagnosestellung des Magenkarzinoms haben ca. zwei Drittel der Patienten bereits Metastasen. Wichtig ist es, die Oligometastasierung von der diffus metastasierten Situation abzugrenzen. Die S3-Leitlinie hat die Definition der Oligometastasierung erstmals in die Leitlinie aufgenommen.Fragestellung: Kann das Überleben von Patienten mit Oligometastasierung mittels Resektion des Tumors und der Metastase kombiniert mit perioperativer Chemotherapie verbessert werden?Material und methoden: In dieser Übersichtsarbeit wird die Datenlage der aktuellen Literatur dargestellt.Ergebnisse: Die holländische Magenkarzinomstudie stellte ein verbessertes medianes Überleben für Patienten mit singulären Metastasen fest, wenn diese reseziert wurden. Aufgrund der Resultate der deutschen AIO-FLOT3-Studie, in der sich das mediane Überleben von Patienten mit Oligometastasen mit multimodaler Therapie verdoppelte, wurde die AIO-FLOT5(RENAISSANCE)-Studie initiiert. Diese randomisiert limitiert metastatische Patienten nach neoadjuvanter Chemotherapie entweder zu Resektion gefolgt von Chemotherapie oder zu definitiver Chemotherapie. Weitere randomisierende Studien untersuchen den Nutzen von Antikörpern und Immun-Checkpoint-Inhibitoren beim lokoregionalen und metastasierten Magenkarzinom mit vielversprechenden Resultaten.Diskussion: Die Resultate der aktuellen Studien werden zeigen, ob Patienten mit Oligometastasierung von einer multimodalen Therapie mit Resektion profitieren. Die eindeutige Definition der Oligometastasierung, eine Beurteilung des Ansprechens nach neoadjuvanter Chemotherapie und eine realistische Einschätzung der R0-Resektion werden bei der entsprechenden Patientenselektion hilfreich sein. Background: At the time of diagnosis of gastric cancer approximately one third of patients already have metastases. It is important to differentiate between oligometastasis and the diffuse metastatic situation. For the first time the definition of oligometastasis has been integrated into the German S3 guidelines.Objective: Can multimodal treatment with tumor resection and metastasectomy combined with perioperative chemotherapy, increase the chances of survival in oligometastatic patients?Material and methods: In this review article the data situation of the current literature is discussed.Results: The Dutch D1/D2 trial reported an increased median survival for a subgroup of patients with single metastasis who underwent resection. Multimodal treatment with resection doubled the median survival of oligometastatic patients in the German AIO-FLOT 3 study and as a consequence, the AIO-FLOT 5 (RENAISSANCE) trial was designed. Patients with oligometastatic gastric and esophagogastric junction cancer are randomized after chemotherapy to either undergo resection followed by adjuvant chemotherapy or to undergo definitive chemotherapy. Further randomized trials investigate the benefit of antibodies and immune checkpoint inhibitors in locoregional and advanced metastatic gastric cancer with promising results.Conclusion: The results of the ongoing randomized trials will show if oligometastatic patients benefit from a multimodal treatment with resection. The clear definition of the oligometastatic state, assessment of the response to neoadjuvant chemotherapy and realistic estimation of the R0 resectability will be useful for patient selection.

IMPORTANCE: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. OBJECTIVE: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection. DESIGN, SETTING, AND PARTICIPANTS: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013. INTERVENTIONS: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. RESULTS: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P

In the scenario of personalized medicine, targeted therapies are currently the focus of cancer drug development. These drugs can block the growth and spread of tumor cells by interfering with key molecules involved in malignancy, such as receptor tyrosine kinases (RTKs). MET and Recepteur d’Origine Nantais (RON), which are RTKs frequently overactivated in gastric cancer, are glycoprotein receptors whose activation have been shown to be modulated by the cellular glycosylation. In this work, we address the role of sialylation in gastric cancer therapy using an innovative 3D high-throughput cell culture methodology that mimics better the in vivo tumor features. We evaluate the response to targeted treatment of glycoengineered gastric cancer cell models overexpressing the sialyltransferases ST3GAL4 or ST3GAL6 by subjecting 3D spheroids to the tyrosine kinase inhibitor crizotinib. We show here that 3D spheroids of ST3GAL4 or ST3GAL6 overexpressing MKN45 gastric cancer cells are less affected by the inhibitor. In addition, we disclose a potential compensatory pathway via activation of the Insulin Receptor upon crizotinib treatment. Our results suggest that cell sialylation, in addition of being involved in tumor progression, could play a critical role in the response to tyrosine kinase inhibitors in gastric cancer. This research was funded by the project NORTE-01-0145-FEDER-000029, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was also funded by FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE (POCI-01-0145-FEDER-016585 and POCI-01-0145-FEDER-007274); and National Funds through the Foundation for Science and Technology (FCT), under the projects: PTDC/BBB-EBI/0567/2014 and PTDC/BBB-ECT/2518/2014. We acknowledge the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 748880 awarded to MB. We thank FCT for the PhD fellowship awarded to FD (SFRH/BD/137896/2018), for the IF research position IF/00296/2015 to CCB and the CEECIND/02760/2017 to S.M. Acknowledgments: The authors would like to thank Rossana Correia (HEMS, i3S Scientific platform) for support on cells processing. The authors acknowledge the support of the ALM i3S Scientific Platform, member of the PPBI (PPBI-POCI-01-0145-FEDER-022122).

Background: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection.Methods: In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2on day 1, intravenous cisplatin 60 mg/m2on day 1, and either fluorouracil 200 mg/m2as continuous intravenous infusion or capecitabine 1250 mg/m2orally (two doses of 625 mg/m2per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. Findings: Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). Interpretation: Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma.

Presently, there is no scientific evidence supporting a definite role for follow-up after gastrectomy for cancer, and clinical practices are quite different around the globe. The aim of this consensus conference was to present an ideal prototype of follow-up after gastrectomy for cancer, based on shared experiences and taking into account the need to rationalize the diagnostic course without losing the possibility of detecting local recurrence at a potentially curable stage. On June 19–22, 2013 in Verona (Italy), during the 10th International Gastric Cancer Congress (IGCC) of the International Gastric Cancer Association, a consensus meeting was held, concluding a 6-month, Web-based, consensus conference entitled “Rationale of oncological follow-up after gastrectomy for cancer.” Forty-eight experts, with a geographical distribution reflecting different health cultures worldwide, participated in the consensus conference, and 39 attended the consensus meeting. Six statements were finally approved, displayed in a plenary session and signed by the vast majority of the 10th IGCC participants. These statements are attached as an annex to the Charter Scaligero on Gastric Cancer. After gastrectomy for cancer, oncological follow-up should be offered to patients; it should be tailored to the stage of the disease, mainly based on cross-sectional imaging, and should be discontinued after 5 years.