# Gastric Cancer

Stage gastric adenocarcinoma with cross-sectional imaging and selective laparoscopy, then direct care by resectability and tumor biology. Perioperative FLOT is central for localized advanced disease; metastatic treatment depends on HER2, MSI/MMR, PD-L1, and CLDN18.2 results.

**Clinical question:** How should gastric cancer be staged and treated according to resectability and predictive biomarker profile?

Updated: 2026-08-24T16:59:51.696729+00:00

## What matters in practice
- Obtain thoracic, abdominal, and pelvic CT for initial staging; use EUS for locoregional T/N assessment when disease appears resectable, and consider staging laparoscopy for cT3/cT4 or poorly cohesive tumors to detect occult peritoneal disease. [10]
- Very early cT1N0 gastric cancer may be managed with endoscopic or surgical resection alone; cT2 or node-positive localized disease generally warrants perioperative FLOT and D2 lymphadenectomy when resectable. [10][18]
- Before first-line treatment of unresectable or metastatic gastric/GEJ adenocarcinoma, determine HER2, MMR/MSI, PD-L1, and CLDN18.2 status because each can alter systemic-treatment selection. [2]
- For HER2-positive advanced disease, chemotherapy plus trastuzumab and pembrolizumab is a first-line standard approach; trastuzumab deruxtecan has activity after progression on at least two prior regimens including trastuzumab. [12][19]
- In HER2-negative, CLDN18.2-positive advanced gastric/GEJ adenocarcinoma, zolbetuximab plus chemotherapy is a first-line targeted option; selection between zolbetuximab and PD-1-based therapy is less certain when PD-L1 expression is high. [21][23]

## Define resectability before choosing therapy

Stage through a multidisciplinary gastric cancer pathway before initiating potentially curative therapy.

After diagnostic endoscopy establishes gastric cancer, obtain CT of the thorax, abdomen, and pelvis for initial staging and risk assessment. In apparently resectable disease, use endoscopic ultrasonography when locoregional T and N assessment will affect the choice between local resection, surgery, and perioperative therapy. [10]

Use staging laparoscopy to look for occult peritoneal metastases when imaging does not show distant disease but peritoneal risk is substantial, particularly with cT3/cT4 tumors or poorly cohesive histology. Occult peritoneal metastasis or positive cytology redirects management away from curative gastrectomy toward treatment for unresectable/metastatic disease. [3][10]

Make resectability the first therapeutic branch: cT1N0 disease may be treated by endoscopic or surgical resection alone, whereas cT2 and/or cN-positive disease should enter a perioperative-treatment and surgical-planning pathway. [10]
- Document tumor location and operative feasibility with an experienced gastric cancer surgeon before committing to perioperative treatment. [8][14]
- Discuss localized, unresectable, and metastatic presentations in a multidisciplinary team because imaging, endoscopic staging, laparoscopy, pathology, systemic treatment, and surgical candidacy must be integrated. [8][11][14]

*Staging findings that redirect initial gastric cancer management. [10]*

| Clinical finding | Next staging or treatment step | Management implication |
| --- | --- | --- |
| cT1N0 lesion | Assess for endoscopic versus surgical resection. [10] | Local resection alone may be appropriate. [10] |
| Apparently resectable lesion | Perform thoracic, abdominal, and pelvic CT; add EUS for locoregional staging when useful. [10] | Use clinical stage to select local therapy versus perioperative treatment. [10] |
| cT3/cT4 or poorly cohesive tumor without radiographic metastases | Perform laparoscopic exploration for occult peritoneal metastasis. [10] | Peritoneal metastatic disease changes intent from curative surgery to systemic management. [10] |
| Distant or peritoneal metastasis | Obtain predictive biomarker testing before systemic therapy. [2] | Treat as unresectable/metastatic gastric or GEJ adenocarcinoma. [2] |

## Use perioperative therapy for localized advanced resectable disease

Separate very early tumors from cT2 or node-positive disease before scheduling gastrectomy.

For cT1N0 gastric cancer, endoscopic or surgical resection alone is appropriate when local therapy can achieve oncologic control. Do not automatically expose this group to perioperative systemic therapy intended for clinically advanced disease. [10]

For localized cT2 and/or cN-positive gastric cancer, perioperative FLOT is the recommended standard approach in the cited guideline pathway. FLOT includes fluorouracil, leucovorin, oxaliplatin, and docetaxel; the cited NCCN regimen summary lists leucovorin 200 mg/m² IV on day 1 within FLOT. [10][18]

Plan radical gastrectomy with D2 lymphadenectomy after perioperative treatment in patients who remain operable and free of metastatic progression. D2 nodal dissection is the operative standard described across surgical gastric cancer trial and guideline materials. [5][6][7]
- Use the preoperative interval to reassess performance status, nutritional reserve, treatment tolerance, and interval evidence of unresectability before proceeding to gastrectomy. [8][14]
- Do not substitute postoperative therapy decisions for adequate initial staging; occult peritoneal disease detected by laparoscopy changes the treatment objective before a nonbeneficial gastrectomy. [3][10]
- For localized treatment planning, distinguish gastric cancer from esophageal squamous cell carcinoma and other gastroesophageal malignancies because biomarker and chemoradiation pathways differ. [2][16]

### Role of perioperative immunotherapy

A recent French intergroup guideline summary reports improved survival when durvalumab was added to perioperative FLOT and followed by 10 months of durvalumab maintenance. Incorporate this strategy only after confirming current U.S. regulatory status, local protocol, eligibility, and toxicity-management capacity. [10]

*Localized resectable gastric cancer treatment branch. [10][18]*

| Clinical stage | Primary strategy | Procedure/systemic-treatment decision |
| --- | --- | --- |
| cT1N0 | Endoscopic or surgical resection alone. [10] | Choose local modality according to lesion resectability and oncologic adequacy. [10] |
| cT2 and/or cN-positive, resectable | Perioperative FLOT. [10] | Proceed to radical gastrectomy with D2 lymphadenectomy when operable after preoperative therapy. [5][6][10] |
| Occult peritoneal metastasis identified at laparoscopy | Systemic-treatment pathway. [10] | Avoid curative-intent gastrectomy and complete metastatic biomarker testing. [2][10] |

## Order the biomarker panel before first-line metastatic therapy

Biomarker results are treatment-selection tests, not prognostic add-ons.

For unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, establish HER2 status, MMR/MSI status, PD-L1 expression, and CLDN18.2 expression before first-line systemic therapy. Regimen selection is driven by these results together with performance status and prior therapy. [2]

Assess PD-L1 by immunohistochemistry using the combined positive score or tumor proportion score, recognizing that PD-L1 expression is a predictive biomarker for immune checkpoint inhibitor treatment in gastroesophageal cancers. MSI-H/dMMR is also predictive for checkpoint-inhibitor benefit and can identify patients with activity from pembrolizumab independent of PD-L1 CPS in previously treated disease. [2][19]

Interpret HER2 as a therapeutic branch rather than a generic molecular descriptor. HER2 overexpression/amplification predicts HER2-directed treatment; the cited review defines HER2-positive disease as IHC 3+ or IHC 2+ with FISH positivity in the trastuzumab deruxtecan-treated advanced gastric/GEJ population. [19]

Use CLDN18.2 testing in HER2-negative advanced disease because CLDN18.2 positivity identifies patients eligible for first-line zolbetuximab plus chemotherapy. CLDN18.2 expression has little overlap with HER2 and high PD-L1 overexpression in reported trial commentary, which makes its early measurement clinically useful rather than a later-line reflex test. [21][22][23]
- Do not delay HER2 testing until progression if first-line trastuzumab-based therapy may be indicated. [12][19]
- Do not rely on pembrolizumab monotherapy for mismatch-repair-proficient disease on the basis of HER2 positivity alone; the cited review notes lack of monotherapy benefit in pMMR gastric cancer. [12]
- Cancer genome sequencing has less clearly established routine benefit in gastric cancer and should be limited to selected cases rather than replacing the core predictive biomarker panel. [2]

*Biomarker-directed branches in unresectable or metastatic gastric/GEJ adenocarcinoma. [2][12][19][21]*

| Biomarker result | Clinical interpretation | Treatment consequence |
| --- | --- | --- |
| HER2-positive | Predicts benefit from HER2-directed treatment. [19] | Use chemotherapy with trastuzumab and pembrolizumab as a first-line standard approach. [12] |
| MSI-H/dMMR | Predicts checkpoint-inhibitor sensitivity. [19] | Consider immunotherapy as a key systemic-treatment component; pembrolizumab has shown activity in previously treated MSI-H advanced gastric/GEJ cancer regardless of PD-L1 CPS. [19] |
| PD-L1 expression by CPS/TPS | Predictive biomarker for checkpoint-inhibitor treatment. [2] | Use with HER2, MSI/MMR, and clinical context to select a PD-1-based strategy. [2] |
| HER2-negative, CLDN18.2-positive | Defines a targetable first-line population. [21][23] | Consider zolbetuximab plus chemotherapy. [21][23] |

## Choose first-line treatment by HER2 and immune-target profile

Use combination therapy rather than a uniform chemotherapy-only approach when a predictive biomarker supports escalation.

For advanced HER2-positive gastric cancer, use chemotherapy plus trastuzumab and pembrolizumab as the cited first-line standard. This branch requires confirmation of HER2 positivity before treatment and should not be extrapolated to HER2-negative tumors. [12]

For HER2-negative advanced gastric/GEJ adenocarcinoma, fluoropyrimidine- and oxaliplatin-based chemotherapy remains the backbone of contemporary combination therapy. FOLFOX is identified as a typical first-line chemotherapy platform, with nivolumab or pembrolizumab used in combination in current practice discussions; the cited regimen summary lists leucovorin 400 mg/m² IV on day 1 for modified FOLFOX6. [18][21]

For HER2-negative, CLDN18.2-positive disease, zolbetuximab plus chemotherapy is an effective first-line alternative, particularly when immune checkpoint inhibitors are contraindicated or PD-L1 expression is low. When CLDN18.2 positivity coexists with PD-L1 CPS above 5%, the optimal choice among zolbetuximab, nivolumab, or pembrolizumab remains uncertain and should be individualized according to comorbidity and patient priorities. [13][21]

For MSI-H/dMMR disease, give immunotherapy substantial weight in first-line strategy selection because this phenotype predicts checkpoint-inhibitor responsiveness. In previously treated MSI-H gastric/GEJ cancer, pembrolizumab activity was reported regardless of PD-L1 CPS; this supports avoiding a PD-L1-only interpretation of an MSI-H result. [19][20]
- Before each cycle, reassess functional status, treatment-limiting toxicity, disease-related symptoms, and whether treatment goals remain prolongation of life, delay of progression, and preservation of quality of life. [21]
- For patients unable to receive immune checkpoint inhibitors, CLDN18.2-positive status provides a non-immunotherapy targeted first-line route with zolbetuximab plus chemotherapy. [13][21]
- Do not use a biomarker-directed regimen outside its defined molecular population: trastuzumab-based therapy requires HER2 positivity, and zolbetuximab-based therapy requires CLDN18.2 positivity in HER2-negative disease. [12][21]

*First-line systemic treatment selection for advanced gastric/GEJ adenocarcinoma. [12][13][19][21][23]*

| Disease profile | Preferred treatment direction | Key selection issue |
| --- | --- | --- |
| HER2-positive advanced disease | Chemotherapy plus trastuzumab and pembrolizumab. [12] | Confirm HER2 positivity before initiating HER2-targeted therapy. [19] |
| HER2-negative disease with immunotherapy eligibility | Fluoropyrimidine/oxaliplatin chemotherapy with PD-1-based therapy is a contemporary first-line approach. [21] | Integrate PD-L1 expression and MSI/MMR status. [2][19] |
| HER2-negative, CLDN18.2-positive disease | Zolbetuximab plus chemotherapy. [21][23] | Particularly relevant when immune checkpoint inhibitors are contraindicated or PD-L1 expression is low. [13][21] |
| MSI-H/dMMR disease | Prioritize checkpoint-inhibitor sensitivity in systemic-treatment planning. [19][20] | Do not use PD-L1 CPS as the sole determinant of immunotherapy relevance. [19] |

## Reassess biology and treatment fitness at progression

At progression, verify prior exposure and biomarker eligibility before selecting later-line therapy.

For HER2-positive locally advanced or metastatic gastric/GEJ cancer that has progressed after at least two prior regimens including trastuzumab, trastuzumab deruxtecan improved objective response and overall survival in the cited DESTINY-Gastric01 evidence summary. This is a later-line HER2-directed option rather than a substitute for first-line trastuzumab-based treatment. [19]

Nivolumab demonstrated overall-survival improvement as later-line treatment in unselected advanced gastric cancer in ATTRACTION-2 and as first-line therapy with chemotherapy in CheckMate-649. Apply checkpoint inhibition according to prior treatment exposure, tumor biomarkers, and regional regulatory indications rather than assuming all PD-1 regimens are interchangeable. [20]

At each radiographic or clinical progression, review whether HER2, MMR/MSI, PD-L1, and CLDN18.2 were obtained before first-line therapy; if a core result is missing, obtain it before bypassing an indicated targeted or immune-based branch. Broader genomic sequencing should be reserved for selected cases because its routine benefit in gastric cancer remains less clear. [2]
- Record prior trastuzumab exposure before considering trastuzumab deruxtecan. [19]
- Use performance status and prior therapies alongside biomarkers when selecting subsequent treatment. [2]
- Revisit goals of care at progression, including symptom control, expected benefit, toxicity burden, and quality-of-life priorities. [21]

*Later-line decision points in advanced gastric/GEJ adenocarcinoma. [2][19][20]*

| Progression scenario | Action | Rationale |
| --- | --- | --- |
| HER2-positive disease after at least two prior regimens including trastuzumab | Consider trastuzumab deruxtecan. [19] | The cited DESTINY-Gastric01 summary reported improved objective response and overall survival. [19] |
| Advanced disease after prior systemic therapy | Review checkpoint-inhibitor exposure and MSI/MMR status before selecting further therapy. [19][20] | Nivolumab showed later-line overall-survival benefit in ATTRACTION-2; MSI-H disease has demonstrated pembrolizumab activity. [19][20] |
| Incomplete first-line biomarker profile | Obtain HER2, MMR/MSI, PD-L1, and CLDN18.2 testing. [2] | Missing predictive testing can obscure a targeted or immune-treatment option. [2] |

## References
1. Curriculum Vitae: Jaffer A. Ajani, MD — www.fda.gov — https://www.fda.gov/media/130602/download
2. Digestive cancers: mechanisms, therapeutics and management | Signal Transduction and Targeted Therapy — www.nature.com — https://www.nature.com/articles/s41392-024-02097-4
3. Non-invasive liquid biopsy based on transcriptomic profiling for early diagnosis of occult peritoneal metastases in locally advanced gastric cancer | npj Precision Oncology — www.nature.com — https://www.nature.com/articles/s41698-025-00875-z
4. Exploring treatment options in cancer: tumor treatment strategies | Signal Transduction and Targeted Therapy — www.nature.com — https://www.nature.com/articles/s41392-024-01856-7
5. Multicenter, Prospective Phase II Clinical Trial — www.cell.com — https://www.cell.com/cms/10.1016/j.ccell.2026.06.015/attachment/814278fa-b3a8-4ea7-8399-74a5085ed143/mmc2.pdf
6. Neoadjuvant FLOT versus SOX phase II randomized ... — www.nature.com — https://www.nature.com/articles/s41467-020-19965-6
7. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer — www.sciencedirect.com — https://www.sciencedirect.com/science/article/pii/S2059702923014679
8. Gastric cancer: ESMO Clinical Practice Guideline for ... — www.sciencedirect.com — https://www.sciencedirect.com/science/article/pii/S0923753422018518
9. The Chinese Society of Clinical Oncology (CSCO ... — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/10.1002/cac2.12193
10. Gastric cancer: ESMO–ESSO–ESTRO Clinical Practice ... — www.sciencedirect.com — https://www.sciencedirect.com/science/article/pii/S0923753419315649
11. Gastric cancer: French intergroup clinical practice guidelines for diagnosis, staging, treatment and follow-up (TNCD, SNFGE, FFCD, UNICANCER, GERCOR, SFCD, SFED, AFEF, SFRO, SFP, SFR, ACHBPT, RENAPE, SNFCP) — www.sciencedirect.com — https://www.sciencedirect.com/science/article/pii/S0959804926004776
12. Overcoming resistance in HER2-positive gastric cancer: a... : Annals of Medicine and Surgery — journals.lww.com — https://journals.lww.com/annals-of-medicine-and-surgery/fulltext/2024/12000/overcoming_resistance_in_her2_positive_gastric.60.aspx
13. patient selection for zolbetuximab in advanced treatment-naïve ... — academic.oup.com — https://academic.oup.com/oncolo/article/30/7/oyaf185/8174925
14. ESMO Clinical Practice Guideline: Gastric Cancer — www.esmo.org — https://www.esmo.org/guidelines/esmo-clinical-practice-guideline-gastric-cancer
15. ESMO Clinical Practice Guidelines: Gastrointestinal Cancers — www.esmo.org — https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers
16. ESMO Clinical Practice Guideline: Oesophageal Cancer — www.esmo.org — https://www.esmo.org/guidelines/esmo-clinical-practice-guideline-oesophageal-cancer
17. ESMO Clinical Practice Guideline: Prevention of Chemotherapy and Radiotherapy induced Nausea and Vomiting — www.esmo.org — https://www.esmo.org/guidelines/esmo-clinical-practice-guideline-prevention-of-chemotherapy-and-radiotherapy-induced-nausea-and-vomiting
18. Table 8, Summary of Leucovorin Doses in Different Fluorouracil-Based Regimens - Leucovorin Dosing for Gastrointestinal Cancer - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/books/NBK599851/table/t08
19. Novel Biomarkers of Gastric Cancer: Current Research and Future Perspectives - PMC — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380533
20. The New Era of Immunotherapy in Gastric Cancer - PubMed — www.ncbi.nlm.nih.gov — http://www.ncbi.nlm.nih.gov/pubmed/35205802
21. Clinical Review - Zolbetuximab for Injection (Vyloy) - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/books/NBK616214
22. Zolbetuximab Succeeds Yet Again in CLDN18.2-Positive Advanced Gastric/Gastroesophageal Junction Cancer in First-Line Phase 3 GLOW Trial — dailynews.ascopubs.org — https://dailynews.ascopubs.org/do/zolbetuximab-succeeds-yet-again-cldn18-2-positive-advanced-gastric-gastroesophageal
23. New Claudin 18.2 approach shows promise in gastric cancer — dailyreporter.esmo.org — https://dailyreporter.esmo.org/esmo-asia-congress-2025/esmo-asia-congress/a-new-claudin-18.2-targeting-approach-appears-promising-in-gastric-cancers
24. HER2-targeted therapies in cancer: a systematic review — www.ccjm.org — https://www.ccjm.org/lookup/external-ref?access_num=10.1186%2Fs40364-024-00565-1&link_type=DOI

## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.