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Summarizing discussion and future perspectives1156chapter 4 compared to the pemetrexed study of Vogelzang et al. (used as rationale for our study) could potentially be explained by the different chemotherapy agents and a different trial design. In contrast to the pemetrexed study (28), our study was randomized for vitamin%u00a0suppletion. Today, more options are available for the treatment of advanced EC and GC. Doublet schedules are preferred over triplet chemotherapy regimens, since the latter do result in more toxicity and only a limited survival benefit (30). First-line treatment with capecitabine and oxaliplatin (CAPOX) is presently the most commonly employed approach for patients with advanced or metastatic esophageal cancer (31, 32). Biomarker testing of the HER2 receptor is standard of care since the Toga trial found OS benefit for the addition of the HER2 antibody trastuzumab to palliative chemotherapy in advanced HER2-positive gastric adenocarcinoma or gastroesophageal junction tumors (33). A new treatment approach involving the humanized monoclonal PD-1 antibody pembrolizumab has been linked to an OS benefit (HR: 0.62; p < 0.0001), with a median OS of 13.5 months compared to 9.4 months when pembrolizumab is added to 5-FU and cisplatin in patients with HER2-negative advanced esophageal carcinoma or adenocarcinoma of the gastroesophageal junction, and high PD-L1 expression (CPS score > 10) (34). Dual PD-1 and HER2 blockade has also increased the response rate in interim analyses of the Keynote 811 trial in HER2-positive gastric or gastroesophageal junction adenocarcinoma (35). Furthermore there is more interest in the differences and similarities between ESCC and EAC since these types of cancer originate from the same organ but differ in genomic profile (36). Currently after disease progression second-line therapy using paclitaxel and ramucirumab and third line therapy with trifluridine/tipiracil can be considered for patients with an adenocarcinoma of esophagogastric origin in a good clinical condition (37, 38). In our study the use of second-line chemotherapy was not documented but was at the time very limited and unlikely to substantially confound our OS data. Although the trial described in chapter 4 did not demonstrate a benefit with vitamin suppletion to palliative chemotherapy we want to point out some relevant aspects of the study. When we look at the chemotherapy backbone with cisplatin and gemcitabine in our phase 2 trial the median combined OS of 9.2 months and TTP of 5.4 months is comparable with current commonly used first-line palliative (doublet) chemotherapy regimens that are recommended for patients with advanced (CPS low) EC and GC. Cisplatin and gemcitabine are not used anymore in daily practice as first-line treatment, but these agents do have a different toxicity profile compared with now more commonly used 5-FU based chemotherapy regimens. Cisplatin and gemcitabine are in general