Comparison and review of updated guidelines for advanced gastric cancer diagnosis and treatment in 2024: CSCO, NCCN and ESMO

doi:10.19401/j.cnki.1007-3639.2025.02.009

Abstract

Abstract:

Gastric cancer is a highly prevalent and aggressive malignancy worldwide, with generally poor prognosis. There are differences in epidemiology, clinicopathological characteristics, treatment modalities, and drug selection for gastric cancer between Eastern and Western populations. Recent advancements in targeted therapy and immunotherapy, the maturation of precision treatment concepts, and the promotion of multidisciplinary therapy have led to continuous updates in clinical research outcomes. Gastric cancer guidelines are annually updated to meet evolving diagnostic and therapeutic needs. This article compared the latest versions of three authoritative global gastric cancer guidelines [National Comprehensive Cancer Network (NCCN) clinical practice guidelines for gastric cancer 2024 version 5, European Society for Medical Oncology (ESMO) online guidelines for gastric cancer 2024, and Chinese Society of Clinical Oncology (CSCO) guidelines for gastric cancer diagnosis and treatment 2024], focusing on clinical treatment strategies for unresectable locally advanced or metastatic esophagogastric junction/gastric adenocarcinoma, and on the whole-process management and precise implementation guided by targets such as human epidermal growth factor receptor 2 (HER2) expression, programmed cell death ligand 1 (PD-L1) expression, mismatch repair (MMR) status,, and novel targets such as Claudin 18.2. Meanwhile, HER2-positive advanced gastric cancer has entered the era of full-line anti-HER2 treatment. Anti-HER2 antibody-drug conjugates (ADCs) has become a new option after first-line trastuzumab resistance. Immunotherapy combined with chemotherapy is regarded as a new standard for the first-line treatment of advanced gastric cancer. The diagnosis and treatment mode based on MMR status and PD-L1 expression promote the precision of immunotherapy. However, the detection of PD-L1 expression has difficulties in clinical promotion and implementation. The three guidelines in 2024 integrate the latest clinical study results, the new indication approval and the updated health care system. In particular, the CSCO gastric cancer guidelines are rewritten based on the rapid development of independently developed drugs in China and the approval of new indications. The three guidelines differ in the recommendation and adoption of targeted therapy and immunotherapy. This article showed different perspectives and focuses based on different guidelines, enriched the dimensions of clinical decision-making, helped the clinical adaptability of evidence-based guidelines to better enlightens clinical practice.

Key words: Gastric cancer, Diagnosis and treatment guidelines, CSCO, NCCN, EMSO

LAN Yu, WANG Fenghua. Comparison and review of updated guidelines for advanced gastric cancer diagnosis and treatment in 2024: CSCO, NCCN and ESMO[J]. China Oncology, 2025, 35(2): 219-227.

Figures/Tables 2

Tab. 1

Comparison of 2024 updated diagnosis and treatment guidelines for advanced gastric cancer: CSCO, NCCN and ESMO"

Patients types	The same recommendation	Different recommendation
First line treatment
HER2 overexpression (IHC3+ or 2+/ISH+)	Recommendations based on PD-L1 expressions: ① PD-L1 CPS≥1: chemotherapy+trastuzumab+pembrolizumab; ② PD-L1 CPS<1: chemotherapy+trastuzumab	-
HER2 overexpression (IHC3+ or 2+/ISH+)		-
HER2 negative	Recommendations based on PD-L1 expression levels in tumor tissues, should chemotherapy be further combined with immunotherapy and the selection of different ICIs ① PD-L1 CPS≥5: chemotherapy+nivolumab ② PD-L1 CPS≥1: chemotherapy+pembrolizumab	NCCN guideline ① PD-L1 CPS<5: consider chemotherapy+nivolumab in certain useful situations (Class 2B recommendation); ② PD-L1 CPS≥1 but<10: chemotherapy+pembrolizumab (Class 1 recommendation); ③ PD-L1 CPS 1-10: chemotherapy+pembrolizumab (Class 2B recommendation) ESMO guideline ① PD-L1 CPS 1-4: chemotherapy+nivolumab may be considered; ② PD-L1 CPS≥10: should receive chemotherapy+pembrolizumab; ③ PD-L1 CPS 1-9: chemotherapy+pembrolizumab may be considered CSCO guideline ① The selection of ICIs is more diverse. Including multiple PD-1 monoclonal antibodies (nivolumab, pembrolizumab, sintilimab, and tislelizumab), PD-L1 mAb (sugemalimab), and PD-1/CTL4 bispecific antibody (cadonilimab); ② Based on the different evaluation methods and expression levels of PD-L1 expression, the recommended immunotherapy regimen is more diversified; ③ For patients with lower PD-L1 expression or CPS-1<1 or whose testing is not accessible, first-line chemotherapy combined with immunotherapy may be considered as a Grade Ⅱ recommendation (Class 1B); ④ Consideration for inclusion in the population suitable for monotherapy immunotherapy: Grade Ⅲ recommendation for pembrolizumab monotherapy for those who have chemotherapy contraindications, refuse chemotherapy, or cannot tolerate chemotherapy (Class 2B)
dMMR/MSI-H	Immunotherapy is recommended regardless of PD-L1 or HER2 status	NCCN guideline Recommend pembrolizumab or dostarlimab, nivolumab combined with ipilimumab, nivolumab combined with chemotherapy, pembrolizumab combined with chemotherapy ESMO guideline Immunotherapy is recommended, but it is uncertain whether PD-1 mAb should be used alone or in combination with chemotherapy. If the patient with severe symptoms and metastases involving important organs, consider PD-1 mAb combination therapy CSCO guideline ① Recommended combination therapy of nivolumab and ipilimumab (Grade Ⅱ recommendation, Class 2B), pembrolizumab (Grade Ⅱ recommendation, Class 2B), nivolumab combined with chemotherapy (Grade Ⅲ recommendation, Class 2B), and pembrolizumab combined with chemotherapy (Grade Ⅲ recommendation, Class 2B); ② The use of ICIs alone is contraindicated or cannot be considered in a timely manner for chemotherapy alone
AFP-producing gastric cancer	-	CSCO guideline The CSCO guidelines focus for the first time on the treatment of subtypes of AFP producing gastric cancer and add a first-line treatment regimen of SOX+camrelizumab/apatinib (Grade Ⅱ recommendation)
CLDN 18.2-positive	For patients with pMMR and HER2 negative and CLDN18.2 positive (≥75% tumor cells CLDN18.2 membrane staining, IHC≥2+), chemotherapy combined with zolbetuximab is recommended	NCCN and ESMO guideline CLDN18.2 as a first-line treatment stratification for HER2 negative patients, chemotherapy+zolbetuximab (Class Ⅰ recommendation) is recommended CSCO guideline ① As the indications for zolbetuximab have not been approved in China and there is no recommendation, positive research results are presented in the form of annotations; ② Emphasize the importance of the CLND18.2 target, and other novel drugs targeting CLND18.2 such as ADC, bispecific antibodies, CAR-T, etc. Phase Ⅰ-Ⅱ trials have shown good efficacy, with confirmatory studies underway. Encourage patients to participate in clinical trials
Second line and posterior line treatment
HER2 positive	① Cross line therapy with trastuzumab is not recommended; ② For HER2 overexpression patients (IHC 3+or 2+/ISH+), T-DXd is recommended as a third line treatment	NCCN and ESMO guideline For individuals with HER2 overexpression (IHC test results of 3+or 2+and ISH+), second-line T-DXd is recommended, and HER2 expression status should be evaluated by biopsy as much as possible before treatment CSCO guideline ① Patients who have failed first-line chemotherapy and have not received trastuzumab are recommended to trastuzumab+chemotherapy (Grade Ⅱ recommendation, 2A evidence); ② Second line treatment does not recommend anti-HER2 ADC, and patients are encouraged to participate in clinical trials; ③ For HER2 patients with IHC test results of 2+or 3+, first-line treatment with disitamab vedotin is recommended (Grade Ⅰ recommendation, Class 2A)
dMMR/MSI-H	① If the first-line treatment has not yet received immunotherapy for patients, it is recommended to choose immunotherapy as the preferred option; ② If the first-line treatment contains immunotherapy, it is recommended to choose second-line and second-line treatment plans based on HER2 status	NCCN guideline Pembrolizumab, dostarlimab, nivolumab combined with ipilimumab are recommended ESMO guideline Pembrolizumab is recommended CSCO guideline Recommendation: envafolimab, tislelizumab and serplulimab (Grade Ⅰ recommendation, Class 2A), pembrolizumab (Grade Ⅱ recommendation, Class 2B)
No specific target	Remdesizumab is recommended in combination with paclitaxel or monotherapy chemotherapy (paclitaxel or irinotecan)	NCCN and ESMO guideline For patients with contraindications to chemotherapy, monotherapy with ramucirumab is also recommended as an option CSCO guideline ① Add data on the second-line treatment of advanced gastric cancer with fruquintinib combined with paclitaxel in the form of annotations; ② Apatinib third line treatment (Grade Ⅰ recommendation, Grade ⅠA evidence)
Specific target and relative detection		NCCN guideline ① Patients with NTRK gene fusion mutations are recommended to receive entrectinib and larotrectinib; ② For BRAF V600E mutation patients, dabrafenib+trametinib is recommended; ③ Patients with RET gene fusion mutations are recommended to use selpercatinib; ④ Recommend NGS testing for newly diagnosed gastric cancer patients ESMO and CSCO guideline ① Currently, there is no treatment recommendation provided for the rare patient with the gene mutations mentioned above; ②NGS is not necessary according to ESMO, while CSCO guidelines recommend NGS testing for patients who have failed standard treatment to identify potential therapeutic targets

Tab. 1

Tab. 2

References 26

[1]	BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2]	HAN B F, ZHENG R S, ZENG H M, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1): 47-53.
[3]	JANJIGIAN Y Y, KAWAZOE A, BAI Y X, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial[J]. Lancet, 2023, 402(10418): 2197-2208. doi: 10.1016/S0140-6736(23)02033-0 pmid: 37871604
[4]	RHA S Y, KAWAZOE A, BAI Y, et al. Final overall survival for the phase Ⅲ, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2⁺ advanced, unresectable or metastatic G/GEJ adenocarcinoma[J]. Ann Oncol, 2024, 35: S1453-S1454.
[5]	JANJIGIAN Y Y, SHITARA K, MOEHLER M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial[J]. Lancet, 2021, 398(10294): 27-40. doi: 10.1016/S0140-6736(21)00797-2 pmid: 34102137
[6]	RHA S Y, OH D Y, YAÑEZ P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial[J]. Lancet Oncol, 2023, 24(11): 1181-1195. doi: 10.1016/S1470-2045(23)00515-6 pmid: 37875143
[7]	KANG Y K, CHEN L T, RYU M H, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2022, 23(2): 234-247.
[8]	XU J M, JIANG H P, PAN Y Y, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial[J]. JAMA, 2023, 330(21): 2064-2074. doi: 10.1001/jama.2023.19918 pmid: 38051328
[9]	QIU M Z, OH D Y, KATO K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial[J]. BMJ, 2024, 385: e078876.
[10]	ZHANG X, WANG J, WANG G, et al. Prespecified progression-free survival (PFS) and overall survival (OS) final analyses of a phase Ⅲ study of sugemalimab plus chemotherapy vs placebo plus chemotherapy in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma[J]. Ann Oncol, 2023, 34: S1319.
[11]	JI J F, ZIYU LI, ZHANG X T, GAO X Y, et al. Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): a randomized, double-blind, phase 3 trial[C]. AACR, 2024.
[12]	SHITARA K, VAN CUTSEM E, BANG Y J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial[J]. JAMA Oncol, 2020, 6(10): 1571-1580.
[13]	WANG Y K, WANG C, CHEN X F, et al. Camrelizumab plus apatinib and SOX as first-line treatment in patients with alpha-fetoprotein-producing gastric or gastroesophageal junction adenocarcinoma: a single-arm, multi-center, phase 2 trial[J]. J Clin Oncol, 2024, 42(3_suppl): 351.
[14]	SHITARA K, LORDICK F, BANG Y J, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial[J]. Lancet, 2023, 401(10389): 1655-1668. doi: 10.1016/S0140-6736(23)00620-7 pmid: 37068504
[15]	SHAH M A, SHITARA K, AJANI J A, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial[J]. Nat Med, 2023, 29(8): 2133-2141. doi: 10.1038/s41591-023-02465-7 pmid: 37524953
[16]	SHITARA K, BANG Y J, IWASA S, et al. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial[J]. Nat Med, 2024, 30(7): 1933-1942. doi: 10.1038/s41591-024-02992-x pmid: 38745009
[17]	VAN CUTSEM E, DI BARTOLOMEO M, SMYTH E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study[J]. Lancet Oncol, 2023, 24(7): 744-756. doi: 10.1016/S1470-2045(23)00215-2 pmid: 37329891
[18]	THUSS-PATIENCE P C, SHAH M A, OHTSU A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study[J]. Lancet Oncol, 2017, 18(5): 640-653.
[19]	PENG Z, LIU T S, WEI J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase Ⅱ study[J]. Cancer Commun (Lond), 2021, 41(11): 1173-1182.
[20]	SHEN L, CHEN P, LU J, et al. Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2-positive locally advanced/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): primary efficacy and safety from the phase Ⅱ single-arm DESTINY-Gastric06 (DG06) trial[J]. Ann Oncol, 2023, 34: S1542-S1543.
[21]	SHEN L, LI J, DENG Y H, et al. Envafolimab (KN035) in advanced tumors with mismatch-repair deficiency[J]. J Clin Oncol, 2020, 38(15_suppl): 3021.
[22]	LI J, XU Y, ZANG A M, et al. A phase 2 study of tislelizumab monotherapy in patients with previously treated, locally advanced unresectable ormetastatic microsatellite instability-high/mismatch repair deficient solid tumors[J]. J Clin Oncol, 2021, 39(15_suppl): 2569.
[23]	QIN S, LI J, ZHONG H, et al. Efficacy and safety of HLX10, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors: a single-arm, multicenter, phase 2 study[J]. J Clin Oncol, 2022.
[24]	FUCHS C S, TOMASEK J, YONG C J, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial[J]. Lancet, 2014, 383(9911): 31-39. doi: S0140-6736(13)61719-5 pmid: 24094768
[25]	XU R H, WANG F, SHEN L, et al. Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): a randomized, multicenter, double-blind, placebo-controlled, phase 3 study[J]. J Clin Oncol, 2024, 42(36_suppl): 438780.
[26]	LI J, QIN S K, XU J M, et al. Randomized, double-blind, placebo-controlled phase Ⅲ trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction[J]. J Clin Oncol, 2016, 34(13): 1448-1454.