2022 ESMO临床实践指南：胃癌的诊断，治疗和随访

指南肿瘤内科· 消化道肿瘤 · 2022

Prevention

There is consistent evidence that eradication of H. pylori substantially reduces the incidence of gastric cancer in healthy individuals, patients with gastric atrophy and people with a family history of gastric cancer. 10 , 11 Non-cardia intestinal-type cancer d the most common histological subtype of gastric cancer d follows a pattern of stepwise progression (known as the Correa Cascade) from normal mucosa to non-atrophic gastritis, atrophic gastritis with or without intestinal metaplasia (IM), dysplasia and ﬁ nally cancer. 12 In high-risk East Asian countries (China, Japan and South Korea), population- and endoscopy-based screening programmes have been implemented. 13-15 These programmes have resulted in higher detection rates of earlystage gastric cancer, with substantially reduced mortality. In contrast, population-based endoscopic screening of asymptomatic individuals is not recommended in low incidence countries. 16 , 17 Since individuals with IM have an increased risk of gastric cancer, multidisciplinary European and UK endoscopy guidelines recommend that patients with IM as well as a family history of gastric cancer, incomplete-type IM or persistent H. pylori -associated

| gastric cancer6|||| |---|---|---|---| |Gene mutation||Associatedsyndrome|Associatedsyndrome| |APC||FAP|| |APCpromoter1B||GAPPS|| |CDH1,CTNNA1||HDGC|| |MLH1,MSH2,MSH6,PMS2||Lynch syndrome|| |SMAD4,BMPR1A|||Juvenile polyposis syndrome| |STK11|||Peutz-Jegherssyndrome| |TP53|||Li-Fraumeni syndrome|

FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; HDGC, hereditary diffuse gastric cancer. Adapted with permission. 6

gastritis should undergo endoscopic surveillance with guided biopsies every 3 years.

Recommendations

If a familial cancer syndrome is suspected, referral to a geneticist for assessment is recommended [V, A]. Population-based endoscopic screening of asymptomatic individuals is only recommended in regions with a very high incidence of gastric cancer [V, B].

## DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

Diagnosis

Gastric cancer is often asymptomatic in the early stages. In advanced disease, common signs and symptoms include dysphagia, asthenia, indigestion, vomiting, weight loss, early satiety and/or iron de ﬁ ciency anaemia. In many cases, however, these non-speci ﬁ c symptoms do not lead to urgent investigations. Overall, $\sim\!60\%$ of people with gastric cancer are not eligible for curative treatment owing to late presentation or comorbidities. 18

Endoscopic examination and forceps biopsies are the gold standard method for diagnosing gastric cancer. Multiple (5- 8) biopsies should be carried out to provide adequately sized material for histological and molecular interpretation, especially in the setting of ulcerated lesions. 19 , 20 Details of the mucosal surface can be evaluated by narrow-band imaging or chromoendoscopy in combination with magnifying endoscopy. Endoscopic ultrasonography (EUS) is also a helpful tool to identify in ﬁ ltrated regions of the gastric wall. 21 Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) may also be used for diagnosis. Both procedures can deliver reliable staging information and can also be used to treat super ﬁ cial lesions such as dysplasia or intramucosal carcinoma. 22

Pathology

Approximately $90\%$ of gastric cancers are adenocarcinomas (ACs). This Clinical Practice Guideline (CPG) does not apply to rarer gastric malignancies such as gastrointestinal stromal tumours, lymphomas and neuroendocrine tumours.

Based on macroscopic features, early gastric carcinomas are sub-classi ﬁ ed into three main types according to the Endoscopic Classi ﬁ cation Review Group (Paris classi ﬁ cation): 0-I (protruded); 0-II (super ﬁ cial); and 0-III (excavated). 23 Locally advanced gastric carcinomas are macroscopically sub-classi ﬁ ed according to the Borrmann classi ﬁ cation as polypoid/fungating without ulceration (type I), ulcerated with elevated borders and sharp margins (type II), ulcerated with diffuse in ﬁ ltration at the base (type III) and diffusely in ﬁ ltrative with thickening of the wall (type IV). 24

There are several gastric cancer histopathological classi ﬁ cation schemes. The most commonly used are the World Health Organization $(\mathsf{W H O})^{25}$ and Japanese Gastric Cancer Association 26 classi ﬁ cations, which are very similar, as well

as those proposed by Nakamura and colleagues 27 and Laurén, the latter of which recognises three main subtypes: intestinal, diffuse and mixed. 28 The WHO classi ﬁ cation is widely used in Western countries and recognises ﬁ ve main histological subtypes: tubular, papillary, poorly cohesive (including signet ring cell and other subtypes), mucinous and mixed ACs.

Molecular biology

The recently identi ﬁ ed molecular pro ﬁ les of gastric cancer are important for better understanding gastric cancer subtypes and may also be useful for identifying clinically relevant biomarkers and new therapeutic targets. Intratumoural and intertumoural heterogeneity is a feature of gastric carcinoma which leads to diagnostic and therapeutic challenges.

The Cancer Genome Atlas (TCGA) research network identi ﬁ ed four molecularly distinct gastric cancer subtypes: EBV positive, microsatellite instability-high (MSI-H), genomically stable (GS) and tumours with chromosomal instability (CIN). 4 Each subtype is enriched for selected molecular abnormalities, with some overlap. The CIN subtype is enriched for copy number changes in key receptor tyrosine kinase oncogenes such as human epidermal growth factor receptor 2 ( HER2) , epidermal growth factor receptor ( EGFR) , ﬁ broblast growth factor receptor 2 (FGFR2) and MET . Other genomic classi ﬁ cations, such as the Asian Cancer Research Group subtyping, show some overlap with TCGA classi ﬁ cation. 29

Based on positive phase III trial data, HER2 status and programmed death-ligand 1 (PD-L1) combined positive score (CPS) should be evaluated in patients with metastatic gastric cancer to tailor ﬁ rst-line treatment in combination with chemotherapy (ChT) [see the table of ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) scores for further details, Supplementary Table S1 , available at https://doi.org/10.1016/j.annonc.2022.07.004 ]. 30 , 31 Patients with HER2-overexpressing gastric cancer [HER2 immunohistochemistry (IHC) score $^{3+}$ or HER2 IHC $^{2+}$ and FISH positive] bene ﬁ t from treatment with the anti-HER2 antibody trastuzumab in addition to standard platinum e ﬂ uoropyrimidine ChT. 30 , 32 The prevalence of HER2 overexpression is $10\%–20\%$ , with higher prevalence in proximal/ OGJ cancers and in the intestinal subtype according to Laurén. 30 , 32 , 33 Ef ﬁ cacy of HER2-targeted treatment is hampered by the intratumoural heterogeneity of HER2 expression. Therefore, quantitative reporting of the proportion of tumour cells staining positive for HER2 by IHC and the gene ampli ﬁ cation ratio (if in situ hybridisation was carried out, especially in IHC $^{2+}$ patients) have been suggested. 33

Emerging data from clinical trials suggest that immunotherapies such as programmed cell death protein 1 (PD-1) inhibitors demonstrate ef ﬁ cacy in gastric cancer. Evaluation of PD-L1 expression in patients with gastric cancer using CPS has been proposed, where a cut-off ${\geq}1$ would indicate positive PD-L1 expression; the prevalence of PD-L1 CPS ' 1

tumours is between $50\%$ and $60\%$ . 34 , 35 A CPS cut-off ${\geq}5$ represents a validated threshold for overall survival (OS) bene ﬁ t of nivolumab given in addition to standard platinum e ﬂ uoropyrimidine ﬁ rst-line ChT. 31 Different antibodies for staining of PD-L1 in gastric cancer are used. In a recent study, PD-L1 22C3 and 28-8 pharmDx assays, both tested on the same platform (hardware), were highly comparable at CPS cut-offs of 1, 10 and 50, providing evidence for the potential interchangeability of the two PD-L1 assays in gastric cancer. 36 These results, however, were not con ﬁ rmed in another study, which suggested that scoring PD-L1 CPS with the 28-8 assay may result in higher PD-L1 scores and a higher proportion of PD-L1 positivity compared with the 22C3 and other assays. Until stronger evidence of inter-assay concordance is found, caution should be taken when treating the assays as equivalent. 37

MSI-H/mismatch repair de ﬁ ciency (dMMR) are associated with better prognosis in localised stages of gastric cancer. 38 There is an ongoing debate on whether microsatellite instability (MSI)/mismatch repair (MMR) status should be used in order to tailor peri-operative ChT. 39 , 40 As MSI-H/dMMR are associated with a high response rate and improved bene ﬁ t from immunotherapy compared with ChT in stage IV gastric cancer, 41 MSI/MMR status should be assessed for patients with locally advanced and unresectable or metastatic gastric cancer to tailor treatment accordingly. 32

Other molecular markers, such as FGFR2 ampli ﬁ cation/ overexpression, MET ampli ﬁ cation, claudin-18.2 overexpression and EBV, 32 are being investigated and their validation as predictive biomarkers in randomised controlled trials (RCTs) is awaited.

Recommendations

Diagnosis should be made from multiple (5-8) endoscopic biopsies to guarantee an adequate representation of the tumour [IV, B]. The histological diagnosis should be reported according to WHO criteria [V, B]. HER2 expression by IHC and/or ampli ﬁ cation by in situ hybridisation [I, A; ESCAT score: I-A], PD-L1 by IHC according to CPS [I, A] and MSI-H/dMMR [II, A; ESCAT score: I-B] are validated predictive biomarkers for drug therapy.

STAGING AND RISK ASSESSMENT

Careful tumour staging is essential to ensure patients are appropriately selected for treatment interventions. The recommended initial staging investigations are detailed in Table 2 .

The following characteristics are frequently demonstrated in malignant lymph nodes detected on computed tomography (CT) 42 :

Short axis diameter 6-8 mm in perigastric lymph nodes Round shape Central necrosis

Loss of the fatty hilum Heterogeneous or high enhancement

Nevertheless, the sensitivity of CT for lymph node staging is variable $\mathsf{\Gamma}62.5\%–91.9\%$ on systematic review 42 ) and global consensus is lacking on speci ﬁ c diagnostic criteria.

EUS is more sensitive for N staging compared with CT $(91\%$ versus $77\%$ , respectively). Additionally, for T1 staging, the sensitivity for EUS $(82\%)$ is higher than that for multidetector CT $(41\%)$ ; however, both EUS and CT show limited speci ﬁ city ( $49\%$ and $63\%$ , respectively). 43 [ 18 F]2-Fluoro-2-deoxy- D - glucose (FDG) positron emission tomography (PET) e CT imaging may improve staging by detecting involved lymph nodes or metastatic disease; however, FDG e PET may not be informative in patients with mucinous or diffuse tumours due to lower tracer uptake. 44 Therefore, FDG e PET e CT is not routinely recommended for staging of gastric cancer.

Laparoscopy and peritoneal washings for malignant cells are recommended in all stage IB-III gastric cancers which are considered potentially resectable, to exclude radiologically and macroscopically occult peritoneal metastatic disease. The bene ﬁ t is greater for patients with T3/T4 disease and poorly cohesive tumours. 44 The accuracy for detection of peritoneal metastases is good, with overall sensitivity of $84.6\%$ and speci ﬁ city of $100\%$ . 45 Peritoneal metastases should be documented according to the Peritoneal Carcinomatosis Index (PCI). 46 A lower PCI score has been associated with better prognosis, and patients with limited peritoneal metastases might be appropriate candidates for cytoreductive surgery and hyperthermic intraperitoneal ChT (HIPEC); however, evidence is still limited and risks must be balanced carefully against uncertain bene ﬁ ts. 47-49 The prognosis of patients with positive lavage cytology $(\mathsf{C Y}+)$ without gross peritoneal dissemination is poor. The survival

|Table 2. Diagnostic and staging investigations in gastric cancer.|| |---|---| |Procedure|Purpose| |FBC|Assess for iron deficiency anaemia| |Renal and liver function| Assess renal and liver function to determine appropriate therapeutic options | | Endoscopy and biopsy| Obtain tissue for diagnosis, histological classification and molecular biomarkers, e.g. HER2 status | ||| | CT of thorax + abdomen ± pelvis | Staging of tumour —to detect local/distant lymphadenopathy and metastatic disease or ascites | |EUS| Accurate assessment of T and N stage in potentially operable tumours Determine the proximal and distal extent of | ||| || Determine the proximal and distal extent of tumour | |Laparoscopy 十 washings | Exclude occult metastatic disease involving peritoneum/diaphragm | |PET, if available|| || May improve detection of occult metastatic disease in some cases. Often negative in diffuse- type gastric cancer | || Assessment of nutritional May detect relevant dietary and nutritional deficienciesinbothlocalised and advanced disease settings |

CT, computed tomography; EUS, endoscopic ultrasound; FBC, full blood count; HER2, human epidermal growth factor receptor 2; N, node; PET, positron emission tomography; T, tumour.

bene ﬁ t of gastrectomy for these patients has not been established. 50 , 51 A retrospective analysis, however, indicated a better prognosis if $\mathsf{C Y+}$ can be converted to negative lavage cytology during neoadjuvant ChT. 52 The additional value of HIPEC needs to be established in ongoing clinical trials. Cases involving $\mathsf{C Y+}$ should be discussed in a multidisciplinary tumour board, weighing up the risks and potential bene ﬁ t of surgery. Patients with $\mathsf{C Y+}$ peritoneal lavage should ideally be treated within a clinical trial.

Gastric cancer should be staged according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM (tumour e node e metastasis) 8th edition staging manual (see Supplementary Tables S2 and S3 , available at https://doi.org/10.1016/j. annonc.2022.07.004 ). 53 , 54

Patients should be tested for dihydropyrimidine dehydrogenase enzyme de ﬁ ciency before starting cancer treatment with 5- ﬂ uorouracil (5-FU) given by infusion, or with the related medicines capecitabine and tegafur. 55

Recommendations

Initial staging and risk assessment should include physical examination, full and differential blood count, liver and renal function tests, endoscopy and contrastenhanced CT scan of the thorax, abdomen $\pm$ pelvis ( Table 2 ) [V, A]. FDG e PET e CT is not routinely recommended [III, C]. Diagnostic laparoscopy and peritoneal washings for cytology are recommended for patients with resectable gastric cancer who are also candidates for perioperative ChT [III, B]. Patients with $\mathsf{C Y+}$ are uncertain candidates for curatively-intended surgical resection. The TNM stage should be recorded according to the 8th edition of the AJCC/UICC staging manual [IV, A].

MANAGEMENT OF LOCAL AND LOCOREGIONAL DISEASE

Multidisciplinary treatment planning before any treatment decision is mandatory. The core membership of the multidisciplinary team should include surgeons, medical and radiation oncologists, gastroenterologists, radiologists and pathologists, with dieticians and nurse specialists if available. 18 A proposed algorithm for the treatment of localised gastric cancer is shown in Figure 1 .

Resection

Surgical resection of operable gastric cancer is potentially curative; however, most patients relapse following resection; therefore, combined modality therapies are standard for stage $\geq\!|\mathsf{B}$ disease.

Endoscopic resection. Endoscopic resection is recommended for very early gastric cancers (T1a) if they are clearly (i) con ﬁ ned to the mucosa, (ii) well-differentiated G1-2, (iii) ${\leq}2$ cm and (iv) non-ulcerated. 56 Expanded endoscopic resection criteria concerning size, depth of submucosal

![Localised gastric cancer Stage IA Stage IB-II1 T1 NO MO >T1 and/or ≥N0 MO Endoscopica or surgical Multimodality resectionb treatment [1，B] No pre-operative ChT Pre-operative ChTc (staging issue or [I，A] emergency surgery)e Radical gastrectomyd Radical gastrectomyd D2 lymphadenectomy D2 lymphadenectomy [I， A] [I， A] Post-operative ChTc Post-operative ChTf,g.h [I， A] [I，A] ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-04-04/c8021a28-b389-4563-90a1-acd43fca42b2/c8021a28-b389-4563-90a1-acd43fca42b2.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1743759372%3B1743762972&q-key-time=1743759372%3B1743762972&q-header-list=host&q-url-param-list=&q-signature=0085a30d992c790d1ff1921308cfa5a053110b78) Figure 1. Treatment algorithm for localised gastric cancer. Purple: general categories or strati ﬁ cation; red: surgery; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; MSI-H, microsatellite instability-high; R1, microscopic tumour at the margin; RT, radiotherapy. a Endoscopic resection indicated if: (i) con ﬁ ned to mucosa; (ii) well-differentiated G1-2; (iii) ${\leq}2~\mathsf{c m},$ ; (iv) non-ulcerated. Endoscopic resection to be considered if no more than two expanded criteria are met according to Pimentel-Nunes et al. 56 b Lymph node dissection for T1 tumours may be con ﬁ ned to perigastric lymph nodes and include local N2 nodes $(\mathsf{D1+}$ lymphadenectomy, with variation in nodal groups dissected according to site of cancer). $^\mathrm{c}\mathsf{A}$ triplet ChT regimen including a ﬂ uoropyrimidine, a platinum compound and docetaxel should be given when possible. Recommended treatment duration is 2-3 months pre- and post-operatively. d Subtotal gastrectomy may be carried out if a macroscopic proximal margin of ${\geq}3$ cm can be achieved. For cancers of the poorly cohesive/diffuse subtype, a margin of ' 5 cm is advocated. For patients with stage $\geq\!|\mathtt{B}$ gastric cancer who have undergone surgery without administration of preoperative ChT. However, a peri-operative approach is preferred as adjuvant ChT is less well tolerated than neoadjuvant ChT and neoadjuvant therapy leads to tumour downsizing, allowing for more curative resections. f A doublet ChT for a total duration of 6 months containing a ﬂ uoropyrimidine plus oxaliplatin or docetaxel is recommended. g For patients with an R1 resection, adjuvant RT or ChT might be considered as an individual recommendation but is not standard. h For patients with MSI-H gastric cancers who have undergone surgery, adjuvant ChT cannot be recommended.

invasion and grade of differentiation [G1/G2-no ulceration, any diameter; G1/G2-ulceration, diameter ${\le}30~\mathsf{m m}$ ; G3-no ulceration, diameter ${\le}20~\mathsf{m m}$ ; SM1 tumours $({<}500~\upmu\mathsf{m})]$ have been published and endoscopic resection might be considered for early gastric cancers with fewer than two expanded criteria. 57 As some of the criteria (grading, invasion of the submucosa) require an exact histopathological workup, endoscopic resection can primarily be carried out for diagnostic purposes and a resection with no tumour at the margin (R0) should be aimed for. Two forms of endoscopic resection are used in clinical practice: EMR is acceptable for lesions smaller than 10-15 mm with a very low probability of advanced histology (Paris 0-IIa) 23 ; however, the European Society of Gastrointestinal Endoscopy (ESGE) recommends ESD as the treatment of choice for most gastric super ﬁ cial neoplastic lesions. 56

Endoscopic resection of early gastric cancer should be carried out en bloc and allow for a complete histological evaluation of the lateral and basal resection margins.

Surgery. The extent of surgical resection depends on tumour location, TNM category and histological subtype.

T1 tumours which do not meet the criteria for endoscopic resection require surgery, although less extensive surgery than other gastric cancers. Lymph node dissection for T1 tumours may be con ﬁ ned to perigastric lymph nodes and include local N2 nodes ${.01+}$ lymphadenectomy, with variation in nodal groups dissected according to the site of cancer).

For stage IB-III disease, radical gastrectomy is indicated. A proximal margin of ${\geq}3$ cm is recommended for tumours with an expansive growth pattern (including intestinal histotypes) and ${\geq}5$ cm for those with an in ﬁ ltrative growth pattern (including poorly cohesive/diffuse histotypes). When these rules cannot be satis ﬁ ed, it is advisable to examine the whole thickness of proximal resection margin by frozen section. Subtotal gastrectomy can be selected when a satisfactory proximal resection margin can be obtained. 58-60

The extent of nodal dissection accompanying radical gastrectomy has been extensively debated. D1 resection implies removal of the perigastric lymph nodes plus those along the left gastric artery. $\mathsf{D1+}$ and D2 implies removal of additional lymph nodes along the proper or common hepatic artery, splenic artery or coeliac axis. 60 The current AJCC/UICC TNM (8th edition) classi ﬁ cation recommends excision of a minimum of 15 lymph nodes for reliable staging. 53 , 54 In Asian countries, observational and randomised trials have demonstrated that D2 resection leads to superior outcomes compared with D1 resection. 60 In Western countries, patients with resectable disease should undergo D2 resection in specialised, high-volume centres with appropriate surgical expertise and post-operative care. 18 The Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland has stated that an ideal oesophagogastric unit would consist of four to six surgeons each carrying out a minimum of 15-20 oesophagogastric resections per year, serving a population of 1-2 million. The

German Cancer Society requires 30 gastric resections per year by two dedicated surgeons to qualify for certi ﬁ cation as a gastric cancer centre. 18 The concept of ‘ enhanced recovery ’ encompasses all aspects of optimal peri-operative care for patients undergoing gastrectomy; guidance is provided by relevant Enhanced Recovery After Surgery® Society guidelines on this topic. 61

Laparoscopic surgery has the potential bene ﬁ ts of decreased post-operative morbidity and reduced recovery time, with a lymph node yield comparable with open surgery. 62 Trials from East Asia in early and advanced (T2-T4a) gastric cancer have shown that laparoscopic distal gastrectomy is non-inferior with regard to oncological outcomes, with improved short-term outcomes. In Western countries, two small, randomised trials reported similar short-term outcomes between open versus laparoscopic gastrectomies, with non-inferior results regarding relapse-free survival. Today, laparotomy is an acceptable approach to achieve total or partial gastrectomy with D2 lymphadenectomy for gastric cancer. A laparoscopic approach may be selectively proposed in expert hands. Robot-assisted gastrectomy has shown similar oncological outcomes in terms of survival and lymph node yield compared with conventional laparoscopic gastrectomy. With technical advances, future gastric cancer surgery will most likely become increasingly minimally invasive and will probably take advantage of the rapidly developing robotic technologies. 32

Peri-operative ChT

The UK-based phase III MAGIC trial demonstrated an improvement in 5-year survival from $23\%$ to $36\%$ [hazard ratio (HR) for death 0.75; $95\%$ con ﬁ dence interval (CI) 0.60- 0.93; $P=0.009]$ in patients with resectable stage II and III gastric cancer treated with six cycles (three pre- and three post-operative) of epirubicin e cisplatin e 5-FU (ECF) compared with surgery alone. 63 These data are supported by a similarly designed but smaller French phase III trial that evaluated a regimen of peri-operative cisplatin e 5-FU, suggesting that anthracyclines may not be needed for optimal results. 64 Peri-operative ChT has therefore been adopted as the standard of care in Europe and many Western countries.

A German phase II-III study investigating eight cycles of peri-operative 5-FU e leucovorin e oxaliplatin e docetaxel (FLOT) versus six cycles ECF/epirubicin e cisplatin e capecitabine (ECX) reported a signi ﬁ cant improvement in the primary endpoint of OS (median 50 months with FLOT versus 35 months with ECF/ECX; HR 0.77; $95\%$ CI 0.63-0.94; $P=$ 0.012), with no major concerns for toxicity. 65 Based on these data, the peri-operative use of FLOT (four cycles preand four cycles post-operative) should be regarded as standard of care for patients who are able to tolerate a triple cytotoxic drug regimen. For patients un ﬁ t for triplet ChT, a combination of a ﬂ uoropyrimidine with cisplatin or oxaliplatin is recommended.

In all relevant trials, the post-operative ChT regimen was the same as the preoperative regimen. Whether a different treatment regimen should be used after poor response to

neoadjuvant ChT is currently unknown. Also, the potential bene ﬁ t of additional preoperative radiotherapy (RT) to perioperative ChT is currently unde ﬁ ned and is being explored in clinical trials.

Adjuvant treatment

Adjuvant ChT. Historically, a greater bene ﬁ t has been noted with adjuvant ChT in Asian studies, and uptake of adjuvant ChT in Europe for patients with resected gastric cancer remains limited due to a perceived lack of bene ﬁ t and routine use of peri-operative ChT. Nevertheless, a large individual patient-level meta-analysis of adjuvant ChT in gastric cancer has con ﬁ rmed a $6\%$ absolute bene ﬁ t in 5-year OS for 5-FUbased ChT compared with surgery alone (HR 0.82; $95\%$ CI 0.76-0.90; $P<0.001$ ) in all subgroups tested, including the group of Western patients. 66 A doublet ChT for a total duration of 6 months containing a ﬂ uoropyrimidine plus oxaliplatin or docetaxel is recommended. It is notable, however, that adjuvant ChT is less well tolerated than neoadjuvant ChT and neoadjuvant therapy leads to tumour downsizing, allowing for more curative resections; therefore, a peri-operative approach is preferred, if possible, so that more patients can bene ﬁ t from systemic treatment even if the post-operative component of treatment is unable to be delivered.

Adjuvant chemoradiotherapy. Recently, the randomised phase III CRITICS trial concluded that patients undergoing ChT followed by surgery with curative intent have similar OS and progression-free survival (PFS), regardless of whether they receive ChT or chemoradiotherapy (CRT) after surgery. 67 , 68 Additionally, the Korean ARTIST and ARTIST II studies did not demonstrate a survival bene ﬁ t for the addition of RT to adjuvant ChT in patients who had undergone gastrectomy with D2 lymphadenectomy. 69-71 Therefore, in patients who receive adequate surgery and have a high risk of relapse (e.g. positive nodal status), only adjuvant ChT should be given. The addition of postoperative CRT is not recommended following R0 resection, whereas for patients who have not received preoperative ChT and have not undergone an appropriate D2 lymphadenectomy, adjuvant CRT can be considered. 72 , 73 In current post-operative CRT regimens, RT should preferably be given as a concomitant regimen of ﬂ uoropyrimidinebased CRT to a total dose of 45 Gy in 25 fractions of 1.8 Gy ( ﬁ ve fractions per week) by intensity-modulated RT techniques.

In patients who have undergone gastrectomy with involved margins and are not candidates for more extended surgery, post-operative RT or CRT should be discussed by a multidisciplinary tumour board. Post-operative performance status, comorbidities and additional tumour risk factors, including nodal status, should be considered for decision making. A retrospective Dutch registry study suggested that adjuvant CRT was associated with a marginal improvement in survival compared with no further treatment in patients who had undergone a resection with microscopic tumour at the margin (R1). 74 As in the case of

R0 resections, tumour recurrence after R1 resections is mainly systemic rather than local. The potential bene ﬁ t of additive local post-operative therapies in R1-resected patients must be balanced against overall prognosis and therapy-speci ﬁ c morbidity and mortality. In conclusion, no speci ﬁ c and evidence-based recommendation can be made for patients with R1-resected gastric cancer.

MSI. Patients with MSI-H gastric cancers who have undergone radical resection have a better prognosis compared with patients with non-MSI-H subtypes of gastric cancer. There seems to be no added bene ﬁ t of adjuvant ChT in this population, according to retrospective analyses of prospectively conducted RCTs. 38 Although evidence is limited, adjuvant (post-operative) ChT should be avoided in resected MSI-H gastric cancers. 38 Regarding peri-operative treatment of MSI-H disease, combinatorial results from older clinical trials that did not use taxanes did not show a bene ﬁ t of peri-operative ChT for patients with MSI-H gastric cancer 38 ; however, data from a small number of MSI-H patients treated with FLOT demonstrated better response rates than historical rates with platinum e 5-FU. 75 Therefore, if a response is required to downstage an MSI-H tumour before surgery, FLOT is recommended. This does not, however, imply that FLOT is better than surgery alone as no control group was available to compare in the FLOT4 trial. In the future, it is likely that chemoimmunotherapy or immunotherapy alone 76 may be alternative treatment choices.

Recommendations

Multidisciplinary treatment planning before any treatment decision is mandatory [IV, B].

Resection

Endoscopic or surgical resection alone is appropriate for selected very early tumours (stage IA) [III, B]. For stage IB-III gastric cancer, peri-operative therapy and radical gastrectomy is recommended [I, A]. Patients should undergo D2 resection in a high-volume surgical centre [II, B].

Peri-operative ChT

Peri-operative (pre- and post-operative) ChT is recommended for patients with stage $\geq\!{\mathsf{B}}$ resectable gastric cancer [I, A]. A triplet ChT regimen including a ﬂ uoropyrimidine, a platinum compound and docetaxel should be given when possible [I, A]. Peri-operative use of FLOT is standard of care for patients who are able to tolerate a triple cytotoxic drug regimen [I, A; ESMO-Magnitude of Clinical Bene ﬁ t Scale (ESMO-MCBS) v1.1 score: A]. For patients un ﬁ t for triplet ChT, a combination of a ﬂ uoropyrimidine with cisplatin or oxaliplatin is recommended [II, B].

Adjuvant treatment

For patients with stage $\geq\!|\mathsf{B}$ gastric cancer who have undergone surgery without administration of preoperative ChT, adjuvant ChT is recommended [I, A]. For patients who have undergone surgery with clear margins (R0), post-operative RT has no added bene ﬁ t and should not be given [I, D]. For patients undergoing peri- or post-operative ChT, the addition of post-operative RT has no added bene ﬁ t and should not be given [I, E]. For patients who have not received preoperative ChT and have not undergone an appropriate D2 lymphadenectomy, adjuvant CRT can be considered [I, C]. For patients who have undergone surgery with involved margins (R1), adjuvant RT or CRT might be considered as an individual recommendation, but is not standard [IV, C]. For patients with MSI-H gastric cancer who have undergone curative surgery, adjuvant ChT cannot be recommended [IV, D], but if a response is required to downstage a tumour before surgery, FLOT is recommended.

MANAGEMENT OF ADVANCED AND METASTATIC DISEASE

Locally advanced unresectable or metastatic gastric cancer has a poor prognosis; survival in clinical trials assessing the value of ChT has historically been ${<}1$ year in non-Asian countries. 32 ChT improves survival in comparison to best supportive care, and combination ChT improves survival compared with single-agent 5-FU. 77 Additionally, the use of nivolumab with ChT has recently improved survival for patients with advanced/metastatic disease 31 and trastuzumab e ChT has improved survival in patients with HER2-positive advanced/metastatic disease. 30

First-line ChT, targeted therapy and immunotherapy

A proposed algorithm for the ﬁ rst-line treatment of advanced and metastatic gastric cancer is shown in Figure 2 .

ChT. Standard ﬁ rst-line ChT for gastric cancer is a platinum e ﬂ uoropyrimidine doublet. Oxaliplatin and cisplatin are the most commonly used platinum drugs, whereas ﬂ uoropyrimidines may be administered as an infusion (5-FU) or as oral treatment [capecitabine or tegafur e gimeracil e oteracil (S-1)]. Cisplatin and oxaliplatin were shown to be equally effective in RCTs. 78 , 79 In older patients (aged ${>}65$ years), oxaliplatin has a superior safety pro ﬁ le and may be associated with improved survival. 79 Oral capecitabine is at least as effective as infused 5-FU. Infused 5-FU may be favoured when dysphagia is a problem. S-1 is commonly used in Asian patients. 80 In non-Asian populations, pharmacogenetic differences require altered dosing and reduce S-1 tolerability. For older or frail patients, results from the phase III GO-2 trial support dose-reduced oxaliplatin-based

![Advanced/metastaticunresectablegastriccancer 1st-line treatment Platinum-fluoropyrimidine doublet ChT [I,A] HER2+b PD-L1+c Additionof trastuzumab Addition of nivolumab [1,A;MCBS 3;ESCATI-A]de [I, A; MCBS 4]d Radical resection to be considered inhighlyselected casesg.h ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-04-04/a8a37559-84a6-493c-88cc-4cec960656b4/a8a37559-84a6-493c-88cc-4cec960656b4.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1743759372%3B1743762972&q-key-time=1743759372%3B1743762972&q-header-list=host&q-url-param-list=&q-signature=3fce39266265f1491ddb15b46acaeaeea438c948) Figure 2. Treatment algorithm for ﬁ rst-line treatment of advanced/metastatic unresectable gastric cancer.

Purple: general categories or strati ﬁ cation; red: surgery; white: other aspects of management; blue: systemic anticancer therapy. 5-FU, 5- ﬂ uorouracil; ChT, chemotherapy; CPS, combined positive score; EMA, European Medicines Agency; ESCAT, ESMO Scale for Clinical Actionability of Molecular Targets; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; MCBS, ESMO-Magnitude of Clinical Bene ﬁ t Scale; PD-L1, programmed death-ligand 1; S-1, tegafur e gimeracil e oteracil. a Recommended platinum compounds are oxaliplatin or cisplatin. Oxaliplatin is preferred, especially for older patients. Recommended ﬂ uoropyrimidines are intravenous 5-FU, oral capecitabine or oral S-1. Irinotecan e 5-FU can be considered an alternative option for patients who do not tolerate platinum compounds. b c PD-L1 status should be reported according to the CPS. HER2 IHC 3 þ or IHC 2 þ /FISH-positive. d ESMO-MCBS v1.1 112 was used to calculate scores for therapies/indications approved by the EMA or FDA. The scores have been calculated by the ESMOMCBS Working Group and validated by the ESMO Guidelines Committee ( https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms ). e ESCAT scores apply to genomic alterations only. These scores have been de ﬁ ned by the guideline authors and validated by the ESMO Translational Research and Precision Medicine Working Group. 111 f Nivolumab e ChT is recommended for advanced, untreated gastric cancer with a PD-L1 CPS ${\tt\ge}5$ (FDA approved without PD-L1 CPS restriction, EMA approved g for PD-L1 CPS Gastrectomy is not recommended in metastatic gastric cancer unless required $\mathsf{C P S}\ge5$ ' 5). for palliation of symptoms. h Resection of metastases cannot be recommended in general, but might be considered as an individual approach in highly selected cases with oligometastatic disease and response to ChT.

ChT, demonstrating lower toxicity and comparable survival outcomes versus standard dosing. 81

The addition of a taxane to a platinum doublet increased radiological response rates and OS in one older phase III randomised trial, but was associated with substantially increased toxicity. 82 Phase II trials evaluating taxane-based triplets showed higher toxicity but did not provide level I evidence of higher ef ﬁ cacy. 83-85 In the large phase III JCOG1013 study, Japanese patients with advanced gastric cancer were randomly assigned to receive either cisplatin e S-1 or cisplatin e S-1 e docetaxel. 86 No differences in radiological response rate, PFS or OS were demonstrated between the treatment groups. Due to higher levels of toxicity and uncertain survival bene ﬁ t over recommended doublet regimens, ﬁ rst-line taxane-based triplet ChT is not recommended as a standard approach.

Irinotecan e 5-FU has been evaluated in comparison to cisplatin e 5-FU and to ECX in randomised phase III trials and demonstrated superior time to treatment failure compared with ECX (HR 0.77; $95\%$ CI 0.63-0.93; log-rank $P=0.008\}$ ). Irinotecan e 5-FU can be considered an alternative option for patients who do not tolerate platinum compounds. 87 , 88

HER2-positive tumours. Adding trastuzumab to ChT is recommended for patients with HER2-overexpressing (HER2 IHC $^{3+}$ or IHC 2 þ /FISH positive) gastric cancer, based on the phase III ToGA study, which demonstrated higher response rates and longer OS (HR 0.74; $95\%$ CI 0.60-0.91; $P\,=\,0.0046\%$ ) with trastuzumab e ChT compared with ChT alone; additional toxicity was low and manageable. 30

Immunotherapy. The phase III CheckMate 649 study evaluated the addition of nivolumab to ChT (either capecitabine e oxaliplatin or 5-FU e leucovorin e oxaliplatin) in patients with treatment-naive gastric, OGJ or oesophageal cancer. 31 Nivolumab e ChT resulted in signi ﬁ cant improvements in OS (HR 0.71; $98.4\% $ CI 0.59-0.86; $\textit{P}<\ 0.0001\}$ and PFS (HR 0.68; $98\%$ CI 0.56-0.81; $P<0.0001)$ ) versus ChT alone in patients with a PD-L1 CPS ${\geq}5$ (minimum follow-up 12.1 months).

In the phase III KEYNOTE-062 trial, pembrolizumab monotherapy was non-inferior to cisplatin e ﬂ uoropyrimidine ChT for OS in patients with PD-L1 CPS ' 1, but was associated with lower response rates and inferior PFS, and is therefore not recommended. 89 Pembrolizumab is approved for patients with AC of the oesophagus and OGJ expressing PD-L1 ${\mathsf{C P S}}\geq\!10,$ , based on the results of the phase III KEYNOTE-590 trial 90 ; however, KEYNOTE-590 included relatively few patients with AC.

Patients with MSI-H gastric cancer have high response rates and excellent long-term outcomes when treated with anti-PD-1 monotherapy. 41 , 91

Second- and later-line treatment

A proposed algorithm for the second-line treatment of advanced and metastatic gastric cancer is shown in Figure 3 . In previously treated gastric cancer, treatment options often follow clinical trials which have enrolled patients with

gastric and OGJ cancer. The standard ChT options are paclitaxel, docetaxel and irinotecan, which have equivalent ef ﬁ cacy but different toxicity pro ﬁ les. 77 , 92 5-FU e leucovorin e irinotecan (FOLFIRI) is also used, but there are limited data to support this regimen. 88 The addition of the anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, ramucirumab, to paclitaxel improves overall response rate (ORR), PFS and OS, based on the results of the phase III RAINBOW trial. 93 In the phase III REGARD trial, ramucirumab monotherapy demonstrated limited response rates but improved OS compared with placebo. 94 In the phase III KEYNOTE-061 trial, pembrolizumab monotherapy did not improve survival compared with ChT in second-line gastroesophageal cancer, 95 but an exploratory subgroup analysis suggested a bene ﬁ t in advanced MSI-H gastric cancer. 41 In the phase II KEYNOTE-158 trial, pembrolizumab monotherapy was highly active in patients with previously treated advanced MSI-H gastric cancer, demonstrating an ORR of $45.8\%$ and a median PFS of 11 months, with median OS and median duration of response not yet reached. 96 Such results have never been reported with ChT. If available, pembrolizumab should therefore be the preferred treatment in this setting.

Trials evaluating second-line trastuzumab combinations, lapatinib and trastuzumab emtansine have been negative in patients with HER2-positive gastric cancer who have progressed on trastuzumab 32 ; however, a recent phase II Asian randomised trial evaluating the HER2-targeting antibody drug conjugate, trastuzumab deruxtecan, compared with ChT in HER2-positive pre-treated gastric cancer reported a survival bene ﬁ t for trastuzumab deruxtecan-treated patients. 97 Con ﬁ rmatory global trials have demonstrated comparable response rates in nonAsian populations. 98

In the third-line setting for patients with gastric cancer, treatment with tri ﬂ uridine e tipiracil has the strongest evidence base following the phase III TAGS trial. 99 Alternative treatments in chemorefractory gastric cancer include a taxane or irinotecan. 77 A proposed algorithm for the thirdline treatment of advanced and metastatic gastric cancer is shown in Figure 4 .

Surgery for metastatic gastric cancer

The randomised phase III REGATTA trial demonstrated that gastrectomy in addition to ChT without resection of metastases for oligometastatic gastric cancer did not improve survival compared with ChT alone. 100 The phase II AIOFLOT3 trial reported favourable outcomes in patients with oligometastatic disease after FLOT induction followed by gastrectomy plus resection of the metastatic site, but this study was not randomised. 101 The potential bene ﬁ t of surgery in oligometastatic gastric cancer is currently being explored in two ongoing randomised phase III trials [RENAISSANCE (NCT0257836) and SURGIGAST (NCT03042169)], but at the present time, data to support routine resection or ablation of oligometastases are limited. 102 In case of limited peritoneal carcinomatosis, addition of HIPEC to

![Advanced/metastatic unresectable gastric cancer 2nd-line treatment Nocontraindicationsfor Contraindications Contraindications for MSI-H/dMMR ChT or antiangiogenictx for ChT antiangiogenic tx Ramucirumab-paclitaxel Ramucirumab monotherapy Taxane or irinotecan Pembrolizumab monotherapy [1, A; MCBS 2]a [I, B; MCBS 1]a [I，A] [II, A; MCBS 3; ESCAT I-B]ab ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-04-04/04e96c74-4dfd-45ac-a83d-e009ce65a578/04e96c74-4dfd-45ac-a83d-e009ce65a578.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1743759372%3B1743762972&q-key-time=1743759372%3B1743762972&q-header-list=host&q-url-param-list=&q-signature=f651f42faef10dc70ca76ac011daa02be7076c46) Figure 3. Treatment algorithm for second-line treatment of advanced/metastatic unresectable gastric cancer. Purple: general categories or strati ﬁ cation; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; dMMR, mismatch repair de ﬁ cient; EMA, European Medicines Agency; ESCAT, ESMO Scale for Clinical Actionability of Molecular Targets; FDA, Food and Drug Administration; MCBS, ESMO-Magnitude of Clinical Bene ﬁ t Scale; MSI-H, microsatellite instability-high; tx, treatment. a ESMO-MCBS v1.1 112 was used to calculate scores for therapies/indications approved by the EMA or FDA. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee ( https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms ). b ESCAT scores apply to genomic alterations only. These scores have been de ﬁ ned by the guideline authors and validated by the ESMO Translational Research and Precision Medicine Working Group. 111

cytoreduction has been reported to be safe and may be associated with some improved oncological outcomes, but is yet to be con ﬁ rmed in larger trials. 47-49 Peri-operative ChT with or without HIPEC may also be a strategy for patients with $\mathsf{C Y+}$ without gross peritoneal metastases, but the prognostic bene ﬁ t of gastrectomy in this situation is currently not established. 50-52

Pressurised intraperitoneal aerosol ChT (PIPAC) is a recently developed technique that allows homogeneous locoregional application of intraperitoneal ChT during a laparoscopic procedure. This technique could offer a valuable alternative for patients with unresectable peritoneal disease. Results from the randomised, controlled, multicentre phase II PIPAC EstoK 01 trial evaluating PIPAC in addition to intravenous ChT are awaited. 103

Supportive care and nutrition

Supportive care is critical for the well-being of patients with gastric cancer. A recent randomised phase III trial demonstrated an increase in survival of 3 months for patients who received multidisciplinary supportive care compared with those who received standard ChT. 104 Supportive care includes both palliation of symptoms and nutritional support.

Weight loss is multifactorial and may be due to obstruction of the gastrointestinal tract, anorexia, malabsorption or hypermetabolism. In clinical trial datasets, ﬁ weight loss of rst cycle of treatment is associated with reduced OS. ${\geq}10\%$ before treatment and ${\geq}3\%$ during the 105 Dysphagia due to proximal gastric tumours may be relieved by RT or stent placement. 106 Single-dose brachytherapy may be a preferred option even after external RT, since it provides better long-term relief of dysphagia with fewer complications than metal stent placement. Stenting is warranted in patients with severe dysphagia, especially with short life expectancy, since the effect on swallowing is immediate, whereas RT (both brachytherapy and external beam) takes around 4-6 weeks for relief of dysphagia. 107 Options for patients who are not suitable for RT or stent placement include enteral feeding using nasojejunal or nasogastric tubes, or placement of percutaneous feeding tubes. Distal gastric outlet obstruction may be treated by pyloric stenting or bypass surgery.

Recommendations

First-line ChT, targeted therapy and immunotherapy

First-line ChT with a platinum and ﬂ uoropyrimidine is recommended. Oxaliplatin is preferred, especially for

![Advanced/metastatic unresectable gastric cancer 3rd-line treatment ChT Oral therapy possible i.v.therapypreferred Trifluridine-tipiracil Taxaneoririnotecanb [1, A; MCBS 3]a [I，B] ](https://venus-llm-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-04-04/fa2485b2-bcba-4874-8253-3ef3a3ca4dc0/fa2485b2-bcba-4874-8253-3ef3a3ca4dc0.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1743759372%3B1743762972&q-key-time=1743759372%3B1743762972&q-header-list=host&q-url-param-list=&q-signature=a6dfffe01e92a5d9a54b8ff52a24aa8df545be2f) Figure 4. Treatment algorithm for third-line treatment of advanced/metastatic unresectable gastric cancer. Purple: general categories or strati ﬁ cation; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; ${\mathsf{i}}.{\mathsf{v}}.,$ intravenous; MCBS, ESMO-Magnitude of Clinical Bene ﬁ t Scale. a ESMO-MCBS $\tt V1.1^{\mathrm{112}}$ was used to calculate scores for therapies/indications approved by the European Medicines Agency or Food and Drug Administration. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee ( https://www.esmo.org/guidelines/ esmo-mcbs/esmo-mcbs-evaluation-forms ). b If not given previously for advanced/metastatic disease.

older patients [I, A]. S-1 is commonly used in Asian patients [I, A]. Due to higher levels of toxicity and uncertain survival bene ﬁ t over recommended doublet regimens, ﬁ rst-line taxane-based triplet ChT is not recommended as a standard approach [I, C]. Irinotecan e 5-FU can be considered an alternative option for patients who do not tolerate platinum compounds [II, B]. Trastuzumab e ChT is recommended in patients with HER2-positive tumours [I, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-A]. Nivolumab e ChT is recommended for advanced, untreated gastric, OGJ and oesophageal cancer with a PD-L1 $\mathsf{C P S}\geq\!5$ [I, A; ESMO-MCBS v1.1 score: 4]. Pembrolizumab is approved for patients with AC of the oesophagus and OGJ expressing PD-L1 CPS ${\geq}10$ [II, C; ESMO-MCBS v1.1 score: 4].

Second- and later-line treatment

Ramucirumab e paclitaxel is recommended for secondline treatment of gastric cancer [I, A; ESMO-MCBS v1.1 score: 2]. Ramucirumab monotherapy is also an option [I, B; ESMO-MCBS v1.1 score: 1]. Where ramucirumab is not available, paclitaxel, docetaxel or irinotecan monotherapy [I, A] or FOLFIRI [II, B] are recommended. Treatment with trastuzumab is not recommended after ﬁ rst-line therapy in HER2-positive advanced gastric cancer [I, D], but trastuzumab deruxtecan may be considered [II, B; ESMO-MCBS v1.1 score: 4; Food and Drug Administration (FDA) approved, not EMA approved]. Pembrolizumab is recommended for second-line treatment of patients with MSI-H/dMMR gastric cancer [II, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-B]. For patients previously treated with two lines of therapy, tri ﬂ uridine e tipiracil is recommended [I, A; ESMO-MCBS v1.1 score: 3]. Alternative treatments include a taxane or irinotecan [II, B].

Surgery for metastatic gastric cancer

Gastrectomy is not recommended in metastatic gastric cancer unless required for palliation of symptoms [I, D]. Resection of metastases cannot be recommended in general, but might be considered as an individual approach in highly selected cases with oligometastatic disease and response to ChT [V, C].

Supportive care and nutrition

Care for patients with gastric cancer should include an early palliative care referral and nutritional support [I, A].

FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

In the setting of resectable gastric cancer, the complexity of treatment frequently induces symptoms that adversely affect health-related quality of life. Regular follow-up may allow investigation and treatment of symptoms, psychological support and early detection of recurrence, though there is no evidence that it improves survival outcomes. Follow-up should be tailored to the individual patient and stage of disease. 108 Dietary support is recommended, with attention to vitamin and mineral de ﬁ ciencies. 109 , 110

In the advanced disease setting, regular follow-up is recommended to detect symptoms of disease progression before signi ﬁ cant clinical deterioration. If disease progression is suspected, then a clinical history, physical examination and directed blood tests should be carried out. Radiological investigations should be carried out in patients who are candidates for further cancer-speci ﬁ c therapies. For patients receiving cancer-speci ﬁ c therapies such as ChT, CT of the thorax/abdomen plus speci ﬁ c body regions of

interest, if necessary, are typically recommended every 6-12 weeks in order to avoid futile therapy and to switch to alternative treatment options, if available.

The aggressive nature of gastric cancer and historically poor outcomes even in the setting of resectable disease mean that the concept of survivorship is only now beginning to evolve. Long-term implications, late effects of therapy and the psychosocial impact of treatment have been poorly studied to date.

Recommendations

Regular follow-up is recommended for investigation and treatment of symptoms, psychological support and early detection of recurrence [III, B]. Follow-up should be tailored to the individual patient and stage of disease [V, B]. Dietary support is recommended with attention to vitamin and mineral de ﬁ ciencies [V, B]. In the advanced disease setting, regular follow-up is recommended to detect symptoms of disease progression before signi ﬁ cant clinical deterioration [IV, B]. Radiological investigations, speci ﬁ cally CT of the thorax and abdomen, should be carried out every 6-12 weeks in patients who are candidates for further cancerspeci ﬁ c therapies [IV, B].

METHODOLOGY

This CPG was developed in accordance with the ESMO standard operating procedures for CPG development ( http://www.esmo.org/Guidelines/ESMO-GuidelinesMethodology ). The relevant literature has been selected by the expert authors. An ESCAT table with ESCAT scores is included in Supplementary Table S1 , available at https:// doi.org/10.1016/j.annonc.2022.07.004 . ESCAT scores have been de ﬁ ned by the authors and validated by the ESMO Translational Research and Precision Medicine Working Group. 111 An ESMO-MCBS table with ESMO-MCBS scores is included in Supplementary Table S4 , available at https:// doi.org/10.1016/j.annonc.2022.07.004 . ESMO-MCBS $\mathsf{v}1.1^{112}$ was used to calculate scores for therapies/indications approved by the EMA or FDA ( https://www.esmo. org/Guidelines/ESMO-MCBS ). The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. The FDA/EMA or other regulatory body approval statuses of new therapies/indications are reported at the time of writing this CPG. Levels of evidence and grades of recommendation have been applied using the system shown in Supplementary Table S5 , available at https://doi.org/10.1016/j.annonc.2022.07. 004 . 113 , 114 Statements without grading were considered justi ﬁ ed standard clinical practice by the authors. Future updates to this CPG will be published on esmo.org as a Living Guideline version or an eUpdate, to be made available at: https://www.esmo.org/guidelines/gastrointestinalcancers/gastric-cancer .

ACKNOWLEDGEMENTS

Manuscript editing support was provided by Jennifer Lamarre (ESMO Guidelines staff) and Angela Corstorphine and SianMarie Lucas of Kstor ﬁ n Medical Communications Ltd (KMC); this support was funded by ESMO. Nathan Cherny, Chair of the ESMO-MCBS Working Group, Urani Dafni ESMO-MCBS Working Group Member/Frontier Science Foundation Hellas and Giota Zygoura of Frontier Science Foundation Hellas provided review and validation of the ESMO-MCBS scores. Nicola Latino (ESMO Scienti ﬁ c Affairs staff) provided coordination and support of the ESMO-MCBS scores and Angela Corstorphine and Sian-Marie Lucas of KMC provided medical writing and editing support in the preparation of the ESMOMCBS table; this support was funded by ESMO. Dr Benedikt Westphalen, Dr Noelia Tarazona (members of the ESMO Translational Research and Precision Medicine Working Group) and Dr Svetlana Jezdic (ESMO Medical Affairs Advisor) provided validation support for ESCAT scores.

FUNDING

No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO, Switzerland from central funds.

DISCLOSURE

FL reports personal fees for advisory board membership of Amgen, Astellas Pharma, Bristol Myers Squibb (BMS), Bayer, Beigene, BioNTech, Eli Lilly, Merck Sharp & Dohme (MSD), Novartis, Roche and Daiichi-Sankyo; personal fees as an invited speaker for AstraZeneca, BMS, Eli Lilly, Imedex, Incyte, MedUpdate, Medscape, Merck Serono, MSD, Roche, Servier and StreamedUp!; personal fees from BioNTech and Elsevier for expert testimony; personal fees for writing engagements for Deutscher Ärzteverlag, Iomedico and Springer-Nature and a research grant paid to his institute from BMS. SC reports personal fees as an invited speaker from Amgen, Lilly and Servier and personal fees for advisory board membership of BMS, Daiichi, Lilly, MSD and Servier. TF reports personal fees as an invited speaker from Amgen, Bayer, Bristol and Servier; non-remunerated activities as principal investigator (PI) for Adapt Immune, BeiGene and Daiichi Sankyo. KH reports personal fees as for an editorial role as Clinical Editor for Radiotherapy & Oncology. GP reports personal fees as an invited speaker from Amgen and Roche; personal fees for advisory board membership from Astellas, BMS and MSD; personal fees for writing engagement and participation in a study on immunonutrition from Nestle; institutional funding as a local PI for Bard, BMS and MSD; non-remunerated advisory role on the French board on colorectal surgery of Johnson & Johnson and participation in the Medtronic-sponsored European group of upper GI surgeons dedicated to minimally invasive surgery. AV reports personal fees for speaker, consultancy and advisory roles for AstraZeneca, Amgen, Basilea, BeiGene, Bayer, Boehringer Mannheim, BMS, BTG, Daiichi-Sankyo, Eisai, GlaxoSmithKline (GSK), Imaging Equipment Ltd (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicine, MSD, Pierre Fabre,

Roche, Sano ﬁ , Servier, Sirtex, Tahio and Terumo; research funding from Incyte and Servier; and participation in educational activities for OncLive and Oncowissen.de. ECS reports personal fees as an invited speaker from Amgen, BMS, Imedex, Merck, Novartis, Prova Education, Servier and touchIME; personal fees for advisory board membership of Astellas, AstraZeneca, BMS, My Personal Therapeutics, Novartis, Roche and Zymeworks; other personal fees from Amgen Trial Steering Group (TSC), BeiGene and Zymeworks for Independent Data Monitoring Committee (IDMC) membership, BMS for expert testimony, Everest Clinical Research as IDMC chair; institutional funding as a local or coordinating PI for clinical trial research from AstraZeneca, Basilea, Daiichi Sankyo, Roche, Merus and MSD and a research grant to her institute from BMS. FC has declared no con ﬂ icts of interest.

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表 1
gastric cancer6
Gene mutation	Associatedsyndrome	Associatedsyndrome
APC	FAP
APCpromoter1B	GAPPS
CDH1,CTNNA1	HDGC
MLH1,MSH2,MSH6,PMS2	Lynch syndrome
SMAD4,BMPR1A		Juvenile polyposis syndrome
STK11		Peutz-Jegherssyndrome
TP53		Li-Fraumeni syndrome

表 2
Table 2. Diagnostic and staging investigations in gastric cancer.
Procedure	Purpose
FBC	Assess for iron deficiency anaemia
Renal and liver function	Assess renal and liver function to determine appropriate therapeutic options
Endoscopy and biopsy	Obtain tissue for diagnosis, histological classification and molecular biomarkers, e.g. HER2 status

CT of thorax + abdomen ± pelvis	Staging of tumour —to detect local/distant lymphadenopathy and metastatic disease or ascites
EUS	Accurate assessment of T and N stage in potentially operable tumours Determine the proximal and distal extent of

	Determine the proximal and distal extent of tumour
Laparoscopy 十 washings	Exclude occult metastatic disease involving peritoneum/diaphragm
PET, if available
	May improve detection of occult metastatic disease in some cases. Often negative in diffuse- type gastric cancer
	Assessment of nutritional May detect relevant dietary and nutritional deficienciesinbothlocalised and advanced disease settings

图示：CHECR FOR IPDATES

引用 / 出处

2022 ESMO临床实践指南：胃癌的诊断，治疗和随访. 2022.