# Gastric and gastro-oesophageal junction adenocarcinoma

Source: https://nuclide.cc/indications/gastric-oesophageal-cancer/  
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## TL;DR

Cancer of the stomach or the junction where the gullet meets the stomach is common worldwide and still mostly found late, which is why survival is poor for most patients. Treatment now depends heavily on testing the tumour for a handful of markers that decide which targeted drugs and immunotherapies can be used.

## Summary

Gastric and gastro-oesophageal junction (GEJ) adenocarcinoma is a heterogeneous disease spanning intestinal and diffuse (signet-ring) histological subtypes and a spectrum from proximal junctional tumours to distal gastric tumours. GLOBOCAN 2024 estimates rank stomach cancer fifth worldwide for both incidence and mortality, with 980,286 new cases and 641,554 deaths a year. In the United States, SEER projects 31,510 new cases and 10,740 deaths for 2026, and five-year relative survival is 39.8% overall, but that figure conceals an enormous stage gradient: 78.1% for localised disease, which is 32% of cases, 39.0% for regional disease at 23%, and 8.1% for distant disease at 35%. Most Western patients present with regional or distant disease, which is why the field has organised itself around biomarker-directed systemic therapy rather than around early detection.

Treatment splits by resectability and, in the metastatic setting, by biomarker. Resectable gastric or GEJ adenocarcinoma is treated with perioperative FLOT chemotherapy, which the FLOT4 trial showed improves overall survival over ECF/ECX (median 50 versus 35 months), combined with D2 lymphadenectomy at surgery; the phase 3 MATTERHORN trial has since shown that adding durvalumab to FLOT improves event-free survival further and NCCN restricts the category-1 recommendation for that combination to PD-L1-positive tumours. Resectable oesophageal or junctional (Siewert I-II) adenocarcinoma has long been treated with neoadjuvant chemoradiotherapy per the CROSS trial, which gave a median overall survival of 49.4 versus 24.0 months and a 13 percentage point absolute ten-year survival benefit, but the newer ESOPEC trial reports perioperative FLOT outperforming CROSS in this population (median overall survival 66 versus 37 months), so practice is shifting. In the metastatic setting, first-line therapy is chosen by testing for HER2 (trastuzumab, with pembrolizumab added if PD-L1 CPS is at least 1), PD-L1 CPS in HER2-negative disease (nivolumab or pembrolizumab added to chemotherapy), CLDN18.2 positivity in HER2-negative disease (zolbetuximab), and mismatch-repair status, with pembrolizumab recommended second line for MSI-H/dMMR disease; trastuzumab deruxtecan is approved second line after trastuzumab progression.

Nuclear medicine's role is limited and this is the central problem the field is trying to solve. FDG PET/CT is an adjunct to CT rather than a replacement for staging laparoscopy, and NCCN guideline text records FDG-PET/CT accuracy of 68% in preoperative staging against 47% for FDG-PET alone and 53% for CT alone, while a Dutch prospective cohort found FDG-PET/CT sensitivity of only 33% for distant metastases against a specificity of 97%, and staging laparoscopy sensitivity of 82% for peritoneal disease against 78% specificity. FDG uptake is characteristically low in diffuse and signet-ring histology, a common subtype in gastric cancer, so the modality is weakest exactly where peritoneal spread most needs to be excluded; PET sensitivity for peritoneal carcinomatosis has been reported at only about 50%. This gap between what biomarker testing can select for systemically and what imaging can see anatomically, particularly for peritoneal disease, is the opening that new imaging targets such as CLDN18.2 and FAPI tracers are being explored to fill.

## Fields

- Kind: Indication
- Last checked: 2026-09-23
- Also known as: stomach cancer; gastric cancer; GEJ adenocarcinoma; oesophagogastric adenocarcinoma
- Tags: gastrointestinal; biomarker-selected; peritoneal staging
- Group: gastrointestinal
- Burden: GLOBOCAN 2024 estimates rank stomach cancer fifth worldwide for incidence, with 980,286 new cases a year (age-standardised rate 8.9 per 100,000), and fifth for mortality, with 641,554 deaths a year (age-standardised rate 5.6 per 100,000). SEER projects 31,510 new US cases and 10,740 US deaths in 2026. Five-year relative survival (SEER, 2016-2022) is 39.8% overall: 78.1% for the 32% of patients diagnosed with localised disease, 39.0% for the 23% with regional disease, and 8.1% for the 35% with distant disease.
- Subtypes: Gastric adenocarcinoma, intestinal type; Gastric adenocarcinoma, diffuse type (signet-ring cell); Gastro-oesophageal junction (Siewert I-II) adenocarcinoma; HER2-positive disease; CLDN18.2-positive, HER2-negative disease; Mismatch-repair deficient / microsatellite instability-high disease
- Biomarkers: HER2, by IHC with reflex FISH for IHC 2+ equivocal cases, positive in about 22.1% of gastric/GEJ cancers overall in the ToGA screening cohort, higher in GEJ (33.2%) and intestinal-type (32.2%) tumours; PD-L1 Combined Positive Score by IHC (28-8 or 22C3 pharmDx), with roughly 80% of patients CPS 1 or above, 60% CPS 5 or above and 50% CPS 10 or above in the CheckMate 649 population; CLDN18.2 by IHC (VENTANA CLDN18 43-14A RxDx Assay), positive when at least 75% of tumour cells show moderate to strong membranous staining, seen in about 38% of patients screened in the SPOTLIGHT and GLOW trials; Mismatch repair / microsatellite instability, by IHC for MLH1/MSH2/MSH6/PMS2 or PCR/NGS panels, pooled MSI-H prevalence around 11% overall and more common in early-stage tumours than in metastatic disease

## Standard of care

- Resectable gastric or GEJ adenocarcinoma: Perioperative FLOT chemotherapy with D2 lymphadenectomy at surgery; the MATTERHORN trial has shown that adding durvalumab to FLOT improves event-free survival, and NCCN restricts the category-1 recommendation for durvalumab-FLOT to PD-L1-positive (CPS or TAP at least 1) tumours.
- Resectable oesophageal/junctional (Siewert I-II) adenocarcinoma: Neoadjuvant chemoradiotherapy per the CROSS regimen has been standard, but the ESOPEC trial reports perioperative FLOT gives superior overall survival, so FLOT is emerging as preferred where feasible.
- Metastatic disease, first line, HER2-positive: Trastuzumab with fluoropyrimidine- and platinum-based chemotherapy, with pembrolizumab added when PD-L1 CPS is at least 1.
- Metastatic disease, first line, HER2-negative: Chemotherapy plus nivolumab (regardless of PD-L1 status) or pembrolizumab; zolbetuximab is added for CLDN18.2-positive tumours. Pembrolizumab alone is recommended second line for MSI-H/dMMR disease.

## State of the art

- The phase 3 MATTERHORN trial established that adding durvalumab to perioperative FLOT improves event-free survival over FLOT alone in resectable gastric/GEJ adenocarcinoma, and this durvalumab-FLOT combination is now described as the new standard of care for all-comers, though NCCN currently restricts its category-1 recommendation to PD-L1-positive tumours.
- The ESOPEC trial has reported that perioperative FLOT gives a median overall survival of 66 months versus 37 months for neoadjuvant CROSS chemoradiotherapy in resectable oesophageal/GEJ adenocarcinoma, challenging more than a decade of CROSS as the reference standard for that population.
- Biomarker testing at diagnosis now routes patients into distinct first-line regimens by HER2, PD-L1 CPS, CLDN18.2 and mismatch-repair status, so molecular characterisation has effectively become as important as anatomical staging for treatment selection.
- FDG PET/CT remains an adjunct to CT rather than a replacement for staging laparoscopy, with NCCN guideline text recording combined PET/CT accuracy of 68% in preoperative staging against 53% for CT alone, reflecting persistently limited sensitivity for peritoneal disease.

## Open problems

- Peritoneal metastases are missed by all cross-sectional and PET imaging and remain reliably detectable only by invasive staging laparoscopy with lavage cytology, and even that is imperfect: one Dutch study found tumour-guided cfDNA analysis detected peritoneal disease with 91% sensitivity against 64% for conventional cytology.
- Cytology interpretation at staging laparoscopy is not standardised between centres, with a multicentre Japanese survey finding more than a tenfold variation in cytology positivity rates, from 2.1% to 28.3%, tied to differences in laboratory methodology.
- Diffuse-type, signet-ring and mucinous histology is systematically under-staged by CT, PET and EUS alike, so a common histological subgroup has no noninvasive staging modality it can be confidently assessed with.
- Even a macroscopically negative staging laparoscopy misses disease: 13% of such patients have positive cytology, and 29% of cytology-negative patients still develop a peritoneal recurrence after apparently complete R0 resection.
- Emerging 68Ga-FAPI PET tracers have been proposed as a possible partial solution to the peritoneal and diffuse-histology staging gap, but this is not yet adopted into any guideline.

## Sources

- IARC GLOBOCAN 2024 stomach factsheet: https://gco.iarc.who.int/media/globocan/factsheets/cancers/7-stomach-fact-sheet.pdf
- SEER Cancer Stat Facts: stomach cancer: https://seer.cancer.gov/statfacts/html/stomach.html
- NCI PDQ: gastric cancer treatment, health professional version: https://www.cancer.gov/types/stomach/hp/stomach-treatment-pdq
- FLOT4 trial, Al-Batran et al., Lancet 2019 (PubMed): https://pubmed.ncbi.nlm.nih.gov/30982686/
- CROSS trial, van Hagen et al., NEJM 2012: https://www.nejm.org/doi/full/10.1056/NEJMoa1112088
- FDA approval of zolbetuximab-clzb (Vyloy) for CLDN18.2-positive gastric/GEJ adenocarcinoma: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma

## Connected records

- targets: [Claudin-18.2](https://nuclide.cc/targets/cldn18-2/), [FAP](https://nuclide.cc/targets/fap/), [HER2](https://nuclide.cc/targets/her2/)
- technologies: [FDG PET](https://nuclide.cc/technologies/fdg-pet/)
- opportunities: [Claudin-18.2 imaging when one biopsy says negative](https://nuclide.cc/opportunities/opp-cldn18-2-imaging-gastric/)

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