Initial systemic therapy for metastatic esophageal and gastric adenocarcinoma

The selection of initial systemic therapy for advanced unresectable and metastatic esophageal and gastric adenocarcinoma is presented here. Our general approach is to select a backbone chemotherapy regimen and then decide whether to pair it with additional systemic agents (immunotherapy and/or targeted therapy), based on tumor biomarker status. Listed treatments are preferred options, although alternative agents that are not listed may also be effective. Patients who are ineligible for or unable to tolerate the suggested regimens should be evaluated for other better-tolerated therapies or best supportive care. Clinical trials are encouraged if available. For further details on evidence, refer to UpToDate content on systemic therapy for advanced and metastatic esophageal and gastric cancer.

CAPOX: capecitabine plus oxaliplatin; CLDN18.2: claudin18.2; CPS: combined positive score; dMMR: mismatch repair deficiency; ECOG: Eastern Cooperative Oncology Group; FOLFIRI: fluorouracil, leucovorin, irinotecan; FOLFOX: fluorouracil, leucovorin, oxaliplatin; HER2: human epidermal growth factor receptor 2; modified FLOT: fluorouracil, leucovorin, oxaliplatin, and docetaxel; MSI-H: microsatellite instability high; MSS: microsatellite stable; pMMR: mismatch repair proficiency.

* Other options for chemotherapy include the following regimens, which are administered alone without additional agents:

Modified FLOT is an option for patients who require a robust initial treatment response due to malignant obstruction, visceral crisis, or other significant symptoms. Patients may switch to the appropriate initial systemic therapy (chemotherapy plus immunotherapy and/or targeted therapy) based on their biomarker status once their disease has stabilized on modified FLOT.
FOLFIRI is an acceptable alternative for those unable to receive oxaliplatin (eg, due to peripheral neuropathy).

¶ Options include infusional fluorouracil plus leucovorin, capecitabine, oral S-1 (where available), irinotecan, paclitaxel, docetaxel, or dose-reduced CAPOX. Patients who are unable to tolerate these regimens should be evaluated for best supportive care.

Δ Tumor-specific criteria for determining HER2 expression are used for esophageal and gastric cancer. Refer to UpToDate content on pathology and molecular pathogenesis of gastric cancer.

◊ Patients who are ineligible for or unable to tolerate immunotherapy and/or targeted therapy may be offered chemotherapy alone.

§ For patients with CPS <5, we do not typically incorporate immunotherapy given that the overall survival benefits are limited in this population and may not outweigh the risks. However, we acknowledge that others may prefer to offer chemotherapy plus immunotherapy. We emphasize a risk-benefit discussion and encourage shared-decision making on a case-by-case basis.

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Initial systemic therapy for metastatic esophageal and gastric adenocarcinoma