These investigated chemo-immunotherapy in the first-line setting of EC/GC. However, the big breakthrough of ICIs for EC and GC in 2020, was based on positive results from four randomized phase III trials ( Table 1). 25ġL, first-line 2L, second-line 3L, third-line adeno, adenocarcinoma BSC, best supportive care CPS, combined positive score CRT, chemoradiotherapy GEJ, gastroesophageal junction HER2, human epidermal growth factor receptor 2 peri-op, perioperative Tmab, trastuzumab. 22,23 Recently, phase III studies have provided insights into the possible efficacy of ICIs with second-line nivolumab in ESCC, 24 as well for pembrolizumab in programmed death-ligand 1 (PD-L1)-overexpressing ESCC or AEC. To date, doublet combinations for fit patients in first-line and single-agent therapies, or as best supportive care, are appropriate considerations for unfit patients. 22,23 The evidence for the optimal palliative treatment of advanced esophageal squamous cell carcinoma (ESCC) is missing. 11,19–21 In general, fit patients with advanced esophageal adenocarcinoma (AEC) will be treated according to guidelines of advanced GC. In some Asian and American countries, immunotherapy with nivolumab 17 or pembrolizumab 18 would be a possible option in refractory EC or GC, whereas for the subgroup of microsatellite instability (MSI)-high or tumor mutational burden (TMB)-high tumors, pembrolizumab is available from the start, according to the FDA label. ![]() 15 Treatment plans for third-line and later line treatments can consider evidence-based options with trifluridine/tipiracil (TAS-102), 16 as well as irinotecan and taxanes, if not previously used 11 ( Figure 1). 7,10,11 The options for second-line treatment include ramucirumab, 12 irinotecan, 13 taxane, 14 and ramucirumab monotherapy. To date, the standard therapy for fit patients with advanced GC has included the first-line fluoropyrimidine–platinum doublet regimen, combined with trastuzumab in HER2-positive patients. 7–9 First-line ICI and chemotherapy combinations in advanced EC and GC 5,6 For HER2-positive patients, first-line treatment with trastuzumab plus platinum and 5-FU in advanced EC and GC has been defined, but the outlook for combinations in first-line and further-line treatments have remained poor. Immune checkpoint inhibitor (ICI) monotherapies in first-line and second-line settings have had disappointing results, especially for adenocarcinoma. 4 Thus, in this field, new treatment combinations and new strategies are urgently needed. 2,3 Thus, the median overall survival (OS) for patients with inoperable human epidermal growth factor receptor 2 (HER2)-negative EC/GC was approximately 1 year using the systemic treatment regimens at that time. Before 2020, in advanced stage EC and GC, the prognosis with the available systemic options was poor. Historically, the median overall survival (OS) for advanced EC and GC did not exceed 12 months irrespective of the applied regimen. 1 Patient prognosis remains poor, although improvements have been exclusively observed with novel perioperative treatments for resectable EC, mainly due to the perioperative 5-fluorouracil (5-FU), leucovorin, oxaliplatin, docetaxel (FLOT) regimen in GC. ![]() Esophageal (EC) and gastric (GC) cancers account for more than 1,200,000 deaths every year, and therefore these cancers are considered to be a global public health problem.
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