Gastric Cancer
Compliance rules
1Summary
Gastric cancer is one of the more common malignant diseases. As in other parts of the western world, the age-standardized incidence in Germany, Austria and Switzerland has been steadily decreasing in recent decades. Men are affected twice as often as women. A subgroup of patients has a hereditary risk. One of the acquired risk factors is a Helicobacter pylori infection of the gastric mucosa. Population-based endoscopic screening for the detection of early gastric carcinomas is currently not recommended in Germany.
The patient's prognosis is primarily determined by the stage, but also by histology, general condition and comorbidity. In early and localized stages, the treatment approach is curative; in metastatic stages, it is palliative. The main treatment modalities are surgery and systemic tumor therapy. Despite some progress in the last 10 years, the cancer-specific mortality rate is very high at 70%.
This guideline refers to adenocarcinoma of the stomach. Recommendations on localized tumors of the esophago-gastric junction can be found in Onkopedia Esophageal cancer. The recommendations for the treatment of advanced adenocarcinomas of the esophago-gastric junction and esophagus largely correspond to those for gastric cancer. Recommendations for less common, non-epithelial tumors of the stomach can be found in Onkopedia Gastrointestinal Stromal Tumors (GIST) or Onkopedia Extranodal Marginal Zone Lymphomas (Guideline exists in German language only).
2Basics
2.1Definition and basic information
Gastric cancer arises in the proximal sections of the stomach (subcardial), in the middle third (fundus and corpus) and in the distal stomach (antrum). Subcardial gastric carcinomas often have an anatomic connection to the esophago-gastric junction and are then also referred to as adenocarcinomas of the esophago-gastric junction type III (according to Siewert).
The guideline presented here refers to gastric carcinomas according to the current 8th edition of the TNM/UICC classification. The special features of adenocarcinomas of the esophago-gastric junction type I and type II according to Siewert, which are categorized as esophageal carcinomas according to the current TNM/UICC classification, are only addressed cursorily here, as the clinical algorithms must be differentiated from gastric carcinoma.
2.2Epidemiology
Every year, around 9,500 new cases of gastric cancer are diagnosed in men and around 6,000 new cases in women in Germany. This makes gastric cancer the tenth most common cancer in men, accounting for around 3.5% of all malignancies, and the ninth most common malignancy in women, accounting for around 2.4%. In terms of cancer mortality, the relevance of gastric cancer is even higher. It accounts for around 3.5% of all cancer deaths in women and 4.2% in men. The average age of onset is 71 years for men and 76 years for women, which is higher than for cancer as a whole (70 for men, 69 for women). The average age at death is 74 years (men) and 78 years (women) (cancer overall: 75 and 77 years). It can be assumed that there are around 33,000 patients living in Germany who were diagnosed no more than five years ago and 52,000 patients who were diagnosed in the last 10 years.
The age-standardized incidence rates, as well as the age-standardized mortality rates, have been declining for years for both sexes, see Figure 1. The age-standardized incidence rate for men has fallen by an average of 2.2% per year over the past 16 years - the mortality rate has declined by an average of 3.4% per year. The incidence rate for women has declined by an average of 2.7% per year over the last 16 years - the mortality rate by an average of 3.7% per year. Case numbers and (crude) rates for men are around 60% higher than for women.
The decline in incidence was also confirmed by data from the Dutch cancer registry. Here, the incidence fell from 20.3 to 6.1 per 100,000 between 1989 and 2021, with a simultaneous improvement in relative survival rates [143].
While the age-standardized new-case rates represent a measure of the probability of disease and are largely independent of the population structure, the number of new cases of disease reflects not only the probability of disease but also the age structure and population size. Due to the shift in the age structure towards an older society and the fact that the “baby boomers” are reaching the age cohorts most likely to develop the disease, the trends in new cases and deaths differ from the trends in rates. This shift is particularly evident in men. Although the number of cases is falling, this is only by an average of 0.2% per year, despite a significant long-term decline in disease rates. The situation is similar for the number of deaths. Here, the number of male patients is falling by an average of 1.2% per year, which is also lower than the decline in mortality rates (3.4%). For women, the decline in the number of new cases (2.1% per year), and deaths (2.7% per year) is also lower than the corresponding rates. However, the difference is not quite as great (Figure 2).
Most gastric cancers in men are diagnosed in men between 75 and 79, see Figure 3 (bar). From the age of 40 until the age of 80, the number of new cases rises steadily. After that, it drops significantly. In women, the number increases almost continuously up to the highest age group. The highest risk of disease - i.e., the number of cases in relation to the underlying population per age group, see Figure 3 (lines) - is found in the highest age group 85 years and older for both sexes. Case numbers and incidence rates for men are higher than for women in all age groups.
The prognosis for gastric cancer is relatively unfavorable, especially during the first two years after diagnosis. Around 40% of patients die in the first year after diagnosis. The small difference between the absolute survival rate - i.e., the percentage of patients who survive for a certain time - and the relative survival rate - i.e., the ratio of absolute survival to the expected survival in the general population - shows the excess mortality caused by the cancer. From the fifth year after diagnosis, the gap between the absolute and relative survival rates increases, while the relative survival rate remains largely constant. This means that after about five years there are hardly any additional cancer-related deaths. Figure 4 shows the absolute and relative survival rates for the first 10 years after diagnosis. There are hardly any differences in survival between the sexes.
Based on the current incidence of the disease and the 14th coordinated population projection of the Federal Statistical Office (G2L2W2, moderate development), the number of cases can be expected to increase by around 30% to around 20,000 new cases (2050) over the next 30 years, solely due to the shift in the age structure of the population. In reality, however, the increase is likely to be lower due to falling disease rates.
2.3Pathogenesis
Gastric cancers - in analogy to carcinomas of the rest of the digestive tract - develop in many cases sequentially in multistage processes via precancerous intermediate stages and histologically defined lesions [2]. Unlike for Laurén's diffuse type, this stepwise process is well characterized for the intestinal type [3]. The clinical observation that gastric cancers are histologically heterogeneous in up to 30%, i.e., have both intestinal and diffuse components, underscores the importance of local factors of cellular microenvironment and genetic or epigenetic heterogeneity. Generally accepted, histologically graspable components of the sequential development of gastric cancer are: Helicobacter pylori infection, atrophic gastritis, intestinal metaplasia, intraepithelial neoplasia (low- and high-grade), and gastric adenoma, which is rare in the Western hemisphere.
2.4Risk factors
The risk of developing gastric carcinoma is associated with the presence of the following risk factors [4]:
Genetic
Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome [5]
Hereditary diffuse gastric cancer (HDGC) with mutations in the cadherin 1 (CDH-1) or catenin alpha-1 (CTNNA1) gene [6, 7]
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), with autosomal dominant inheritance and involvement of the promoter region of the APC gene [97, 154]
Peutz-Jeghers syndrome (mutation in the serine-threonine kinase gene [STK11])
First-degree relatives with gastric carcinoma
Male gender (incidence in men:women approximately 2:1)
Blood group A
Acquired
Helicobacter (H.) pylori infection of the gastric mucosa
Epstein-Barr virus infection of the gastric mucosa
Dietary factors: high intake of salt-preserved foods, high intake of processed meat, low consumption of fruit
Tobacco inhalation
Atrophic gastritis
Partial gastrectomy
Ménétrier's disease
Gastroesophageal reflux disease and trunk-predominant obesity
Risk factors differ for the various anatomical localizations and histological subtypes. Distal gastric carcinomas are frequently found associated with Helicobacter pylori infection of the gastric mucosa, high-salt and low fruit and vegetable intake. Carcinomas of the intestinal subtype are more frequently associated with an H. pylori infection than carcinomas of the diffuse subtype. The risk of gastric carcinoma is particularly high if there is a genetic predisposition and an H. pylori infection [141]. Carcinomas of the esophago-gastric junction are more commonly associated with obesity and gastroesophageal acid reflux.
3Prevention and early detection
3.1Prevention
H. pylori eradication with the aim of preventing gastric cancer is recommended for people at risk; see also Chapter 3.2.2. It is currently assumed that the timing of treatment is crucial for the effectiveness of H. pylori eradication in preventing gastric cancer. This should be done in adulthood at a time when no pre-neoplastic changes have yet developed [8]. Data from Japan show a particularly high rate of H. pylori-associated gastric carcinomas in individuals with germline mutations in genes of particular relevance to homologous recombination capacity (ATM, BRCA1, BRCA2, and PALB2), who showed a 40-fold increased risk of developing gastric carcinoma in the presence of H. pylori colonization [141]. Results from prospective and controlled intervention studies are not yet available. In a large US population, H. pylori eradication was associated with a significantly lower incidence of gastric cancer after 8 years compared to no treatment. After an observation period of 7-10 years, the risk in treated individuals was lower than in the general population. The results show that eradication of H. pylori has the potential to significantly reduce the risk of gastric cancer [139].
There is currently insufficient evidence for chemoprevention of gastric cancer, for example with non-steroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, or acetyl salicylic acid [9].
3.2Early detection
3.2.1Population
Since Germany/Austria/Switzerland are not high-incidence regions for gastric cancer, it seems unlikely that population-based endoscopic screening would be cost-effective. However, no study has yet been conducted explicitly examining cost-effectiveness under the conditions in German-speaking Central Europe. Population-based endoscopic screening for the detection of early gastric cancer is currently not recommended in the countries mentioned.
3.2.2Persons-at-risk
If more than one first-degree relative has stomach cancer, the risk is approximately tenfold increased [10]. However, it is not possible to provide a scientifically sound recommendation for screening endoscopy in individuals with a positive family history. Risk groups have been defined in accordance with the recommendations of the DGVS-S2k guideline on H. pylori and gastroduodenal ulcer disease [8]. The group of persons-at-risk include first-degree relatives of patients with gastric cancer, persons residing/born in high-prevalence areas, and patients who already have advanced, corpus-predominant atrophic gastritis with or without intestinal metaplasia and patients with previous gastric neoplasms (adenoma, early carcinoma) after endoscopic resection or partial gastric resection [11]. At least these individuals should be screened for H. pylori infection and, if the infection is detected, undergo eradication treatment.
Since individuals with a pathogenic CDH1 germline mutation have a lifetime risk around 10-40% of developing invasive hereditary diffuse gastric carcinoma, a careful family history should be taken. Regular endoscopy is recommended. Previous standard recommendation for gastrectomy in cases of signet ring cells is no longer valid without restrictions. Instead, individuals affected should be offered differentiated genetic, endoscopic, and histopathological diagnostics and counseling. The indication for gastrectomy is based on family history and the individual risk constellation of genetic, endoscopic, and histopathological findings. In many cases, endoscopic monitoring in designated expert centers is now considered an alternative to gastrectomy in young adults [14, 131, 156, 157, 158]. The level of knowledge about the penetrance of pathogenic CTNNA1 mutations is low, so that a clear recommendation for prophylactic gastrectomy cannot be given at present. At the very least, close endoscopic monitoring in a designated center is recommended. Consultation in a specialized center is recommended [13, 14].
Furthermore, gastric carcinomas can occur more frequently in other hereditary tumor disorders, such as Lynch syndrome (hMLH1, hMLH2) and microsatellite instability (MSI).
4Clinical characteristics
4.1Symptoms
Early gastric carcinoma is usually asymptomatic. The following symptoms often only occur in locally advanced or metastatic carcinomas [15]:
Dysphagia
Dyspepsia
Recurrent vomiting
Loss of appetite
Early feeling of satiety
Weight loss
Signs of gastrointestinal bleeding
Epigastric pain
Symptoms from metastatically affected organs (such as liver capsule pain, ileus/subileus from peritoneal metastasis, etc.)
Vitamin B12 deficiency of undetermined origin
Gastric cancer can be associated with various paraneoplastic syndromes, with cutaneous manifestations being observed more frequently than others [16].
5Diagnosis
5.1[Chapter not relevant]
5.2Diagnostics
5.2.1Initial diagnosis
Endoscopy is considered the most sensitive and specific diagnostic method. Using high-resolution video-assisted endoscopy, it is possible to detect even discrete changes in color, mucosal surface, and architecture of the gastric mucosa. Endoscopic detection of early lesions can be improved by chromoendoscopy.
The aims of further diagnostics are to determine the stage of the disease and to guide therapy, see Table 1.
2 Laparoscopy with cytological examination of the lavage fluid helps to detect clinically occult metastasis of the peritoneum in locally resectable tumors. The detection of macroscopic peritoneal metastasis has a direct impact on treatment planning [17]. Cytological detection of malignant cells in the lavage fluid is an unfavorable prognostic factor, but outside of clinical studies, it has not yet been shown to have a definite impact on treatment recommendations. Abnormal laparoscopic findings are more common in tumors classified as T3/T4 [18].
5.2.2Histology and subtypes
The histological diagnosis of gastric cancer should be made on the basis of a biopsy, evaluated by two experienced pathologists [11]. Biomarker diagnostics from tumor tissue are now standard practice, at least in case of stage IV gastric cancer. Immunohistochemically determined biomarker diagnostics should be performed on the basis of 5 tumor-bearing biopsies [51, 132]. In case of non-endoscopically resectable and advanced gastric neoplasms, sufficient samples should include 8-10 biopsies. This makes it possible to obtain vital tumor tissue in 4-5 tissue samples in order to determine molecular biomarkers important for treatment planning, apart from confirming the diagnosis.
Standard diagnostics currently include the determination of the HER2 status, PD-L1 combined positive score (CPS) and tumor area positivity (TAP), mismatch repair enzymes (or microsatellite instability), and Claudin 18.2. In the near future, routine immunohistochemical determination of fibroblast growth factor receptor 2B (FGFR2B) is also likely to become routine standard [159].
In addition to describing HER2 positivity according to established criteria [51], the precise specification of the proportion of HER2-positive tumor regions [52] and the description of a HER2-low status is an option with possible therapeutic consequences in the future. The high rate of discrepancies in findings between different investigators of around 25% must also be taken into account [138, 142]. The routine determination of Epstein-Barr virus association by in situ hybridization (EBER-FISH) is under discussion, as it occurs very rarely [22].
5.2.2.1Laurén classification
Histologically, gastric carcinoma is characterized by a high degree of heterogeneity, with several different histological elements often present in a single tumor. Over the last few decades, histological classification has been based on the Laurén classification [19]:
intestinal type, approximately 54%
diffuse type, approx. 32%
unclassifiable, approx. 15%
The diffuse subtype is found more frequently in women and younger people, while the intestinal type is more common in men and older people and is associated with intestinal metaplasia and Helicobacter pylori infection [20].
5.2.2.2World Health Organization (WHO) classification
The World Health Organization (WHO) classification distinguishes between four main types of gastric carcinoma [21].
Tubular
Papillary
Mucinous
Poorly cohesive (including signet ring cell carcinoma)
The classification is based on the predominant histological pattern of the carcinoma, which often coexists with less dominant features or other histological patterns.
5.2.2.3The Cancer Genome Atlas (TCGA) classification
Molecular genetic studies divide gastric cancer into molecular subtypes based on genomic, transcriptomic, epigenetic and proteomic analyses. The molecular genetic heterogeneity of gastric carcinoma is the subject of extensive genome-wide sequencing studies [133]. The best-known molecular subtyping according to the TCGA distinguishes four subtypes [22].
Chromosomal instable – CIN
Epstein-Barr virus-associated – EBV
Microsatellite instable – MSI
Genomically stable – GS
5.2.3Stages and staging
5.2.3.1TNM staging
The extent of the primary tumor and metastasis is classified based on the UICC/AJCC TNM criteria [19, 21, 23]. The 8th edition has been in use in Europe since January 1, 2017 [21]. The TNM criteria are summarized in Table 2 and the staging in Table 3.
Classification | Tumor | |
|---|---|---|
T | Primary tumor | |
T | Superficially invading tumor | |
T1a | Tumor invades lamina propria or muscularis mucosae | |
T1b | Tumor invades submucosa | |
T2 | Tumor invades muscularis propria | |
T3 | Tumor invades subserosa without invasion of the visceral peritoneum | |
T4a | Tumor invades subserosa (visceral peritoneum) | |
T4 | Tumor invades adjacent structures | |
N | Regional lymph nodes | |
N | No regional lymph node metastases | |
N1 | Metastasis in 1-2 lymph nodes | |
N2 | Metastases in 3-6 lymph nodes | |
N3a | Metastases in 7-15 lymph nodes | |
N3b | Metastases in 16 or more lymph nodes | |
M | Distant metastases | |
M0 | No distant metastases | |
M1 | Distant metastases or positive peritoneal cytology | |
UICC stage | Primary tumor | Lymph nodes | Distant metastases |
|---|---|---|---|
0 | Tis | N0 | M0 |
IA | T1a T1b | N0 N0 | M0 M0 |
IB | T2 T1 | N0 N1 | M0 M0 |
IIA | T3 T2 T1 | N0 N1 N2 | M0 M0 M0 |
IIB | T4a T3 T2 T1 | N0 N1 N2 N3a | M0 M0 M0 M0 |
IIIA | T4b T4a T3 T2 | N0 N1/N2 N2 N3a | M0 M0 M0 M0 |
IIIB | T4b T4a T3 T2/T1 | N1/N2 N3a N3a | M0 M0 M0 M0 |
IIIC | T4b T4a/T3 | N3a/N3b N3b | M0 M0 |
IV | Any T | Any N | M1 |
Endosonography (EUS) is particularly suitable for determining the clinical T category, as it can visualize the different layers of the gastric wall better than other examination techniques. EUS should therefore be part of primary staging in a patient with a curative therapeutic approach.
The following characteristics are used to identify malignant lymph nodes in CT imaging [24]:
Diameter ≥ 6-8 mm (short axis) of perigastric lymph nodes
Round shape
Central necrosis
Loss of the fat hilus
Heterogeneous or enhanced contrast agent uptake
The sensitivity of CT for lymph node staging is estimated to be variable, ranging from 62.5- 91.9% in systematic reviews [25].
EUS improves the accurate determination of the T and N categories and can help to determine the proximal and distal ends of the tumor. EUS is less accurate for tumors of the antrum. EUS complements CT in the diagnosis of malignant lymph nodes.
Signs of malignancy in EUS include [26]:
Hypoechoic
Round shape
Blurred demarcation from the surrounding tissue
Longest diameter >1 cm
In locally advanced gastric cancer (clinical cT3, cT4) that is classified as potentially resectable, diagnostic laparoscopy with peritoneal lavage and examination for malignant cells should be performed before the start of neoadjuvant therapy in order to rule out occult peritoneal metastasis. Since the treatment concept changes significantly if peritoneal carcinomatosis is detected, it should be performed before neoadjuvant therapy and conducted according to a standardized protocol specifying the PCI (Peritoneal Carcinomatosis Index) according to Sugarbaker [160].
6Therapy
6.1Treatment structure
Multidisciplinary planning is required for any initial treatment recommendation. It should be developed by a qualified multidisciplinary tumor board. The core members of the multidisciplinary board include the following disciplines: medical oncology, visceral surgery, radiation oncology, gastroenterology, radiology, and pathology. In addition to determining the best possible standard therapy, possible inclusion in clinical trials should be part of the discussion in the tumor board.
Treatment is stage-adapted. An algorithm for first-line treatment is shown in Figure 5.
1 see Table 4
2 Best supportive care
6.1.1Stage IA – T1a (early-stage cancer)
Since the probability of lymph node metastasis in mucosal gastric carcinoma (T1a) is very low, endoscopic resection (ER) is considered sufficient [27]. If histopathological examination after endoscopic resection reveals that the tumor has invaded more than 500µm into the submucosa (T1b), surgical resection with systematic lymphadenectomy should be performed, as lymph node metastasis is already present in up to 30% of cases.
Gastric carcinomas classified as pT1a cN0 cM0 should be treated with endoscopic resection in accordance with the adapted Japanese criteria if the following criteria are met [11, 28], see Table 4:
|
Early gastric carcinomas with a maximum of one "extended criterion" can also be resected endoscopically in a curative approach [11]. Endoscopic submucosal dissection (ESD) should be used for resection. If more than one extended criterion is present, oncological surgical resection should be performed. The extended criteria are defined as follows:
Differentiated mucosal carcinoma (G1/G2) without ulceration and size >2 cm
Differentiated mucosal carcinoma (G1/G2) with ulceration and size <3 cm
Well-differentiated carcinomas (G1/G2) with submucosal invasion <500μm and size <3cm
Undifferentiated mucosal carcinoma (G3/G4) <2 cm in diameter (provided that no tumor cells are detected by biopsy at a distance of ≤1 cm [11]).
ER of early gastric cancer is performed as an en-bloc resection. It allows complete histological assessment of the lateral and basal margins. The recommended endoscopic control intervals are 3 months in the first and 6 months in the second year of follow-up. Thereafter, controls should be performed annually. Local recurrences after ER of early gastric cancer can be treated endoscopically if relapse is confined to the mucosal (rT1a cN0 cM0). A (limited) surgical approach is an alternative.
6.1.2Stage IA - T1b
In stage IA gastric carcinomas with submucosal invasion (T1b), the risk of lymph node metastases is 25-28%. The 5-year survival rate in the SEER database for the entire stage IA is 70.8% [29], and the cancer-specific survival rate after 10 years in the Italian IRGGC analysis is 93%. The treatment of choice in stage IA (T1 N0 M0) is radical surgical resection (subtotal, total, or transhiatal extended gastrectomy). Limited resection can only be recommended in exceptional cases due to the limited accuracy of pre-treatment staging. A benefit from perioperative or adjuvant chemotherapy has not been established for stage IA patients.
6.1.3Stage IB to III
In stage IB to III, resection should consist of radical resection (subtotal, total, or transhiatal extended gastrectomy) in combination with D2 lymphadenectomy. Subtotal gastrectomy can be performed, if safe free tumor margins can be achieved. The previously recommended resection margins of 5 cm for intestinal tumor growth and 8 cm for diffuse tumor growth are no longer universally accepted. There scientific evidence for definitive recommendations is low. A negative oral resection margin in the intraoperative frozen section is crucial.
Perioperative chemotherapy based on a platinum derivative and a fluoropyrimidine in patients with resectable gastric carcinoma led to a significant improvement in overall survival [30, 31]. Treatment according to the FLOT regimen (5-fluorouracil/folinic acid/oxaliplatin/docetaxel) led to a further improvement in progression-free survival [PFS] (hazard ratio [HR] 0.75) and overall survival [OS] (HR 0.77) in patients with stage ≥cT2 and/or cN+; see also chapter 6.2.3.1. The higher efficacy of FLOT was consistent across relevant subgroup analyses such as age, histology, and tumor location. The rate of perioperative complications was comparable [32].
Additional treatment with a PD-L1- or PD-1-targeted immune checkpoint inhibitor in combination with FLOT chemotherapy resulted in an increased histopathological response rate [34, 136, 140]. Recently, the phase III MATTERHORN study demonstrated an improvement in event-free survival [EFS] when the PD-L1 inhibitor durvalumab was added to perioperative FLOT chemotherapy and continued to be administered for up to a total of one year following combined chemoimmunotherapy. The two-year EFS rate (Kaplan-Meier estimate) was 67.4% in participants in the durvalumab group and 58.5% in participants in the placebo group (HR for event or death: 0.71; 95% confidence interval [CI] 0.58-0.86; p < 0.001). The two-year OS rate, which has not yet been finalized, was 75.7% in the durvalumab group and 70.4% in the placebo group. The final evaluation of OS requires a longer follow-up period [136]. The benefit in terms of EFS also appeared to be achieved in the subgroup of PD-L1-negative tumors. The addition of durvalumab to perioperative therapy with FLOT is currently not approved, but should be applied for as off-label use.
There is currently no indication outside of clinical trials for perioperative immunotherapy alone without chemotherapy in microsatellite-stable tumors. Adjuvant immunotherapy proved to be insufficiently effective in the EORTC1707 VESTIGE study (nivolumab and ipilimumab) and in the Asian ATTRACTION-5 study (nivolumab and chemotherapy) [147, 148].
For patients with gastric cancer ≥ stage IB who underwent resection without prior chemotherapy (e.g., due to incorrect tumor staging prior to surgery), adjuvant chemotherapy may be considered, see chapter 6.2.3.1.
In HER2-positive tumors, the benefit of combining perioperative chemotherapy with a HER2 antibody in the perioperative setting in terms of OS has not yet been proven. The AIO-Petrarca phase 2 study shows a higher histopathological remission rate when FLOT chemotherapy is combined with trastuzumab + pertuzumab and a trend toward better PFS and OS [121]. The multinational EORTC1203-INNOVATION study shows promising response rates with the combination of FLOT + trastuzumab and good feasibility of the regimen, while FLOT + trastuzumab + pertuzumab did not prove to be effective due to increased toxicity. According to currently available data, neither trastuzumab alone nor trastuzumab + pertuzumab led to improved survival [144].
Based on retrospective data analyses, there are doubts about the effectiveness of perioperative chemotherapy in microsatellite-instable [MSI] localized gastric carcinomas [35]. Data from the DANTE study show that complete and subtotal tumor remissions can also be achieved with FLOT chemotherapy in gastric carcinomas of the MSI subtype. However, the response rate is significantly higher with the combination of chemotherapy and immunotherapy, and there is a significant risk of non-response and progression with chemotherapy alone [35, 36]. The identification of the best approach for resectable MSI-high gastric carcinomas is the subject of ongoing studies. A clear recommendation cannot be given at this time. Several studies show that the addition of an immune checkpoint inhibitor to neoadjuvant chemotherapy in cases of deficient DNA mismatch repair/microsatellite instability [dMMR/MSI] leads to significantly increased remission rates [34, 136]. In addition, exploratory subgroup analyses also show that EFS and OS are significantly improved when perioperative chemotherapy is supplemented with an immune checkpoint inhibitor in MSI-high gastric carcinomas [140]. The FFCD-NEONIPIGA phase 2 study shows a high histopathological remission rate after 12 weeks of therapy with nivolumab + ipilimumab without chemotherapy in resectable MSI carcinomas [122]. The same observation was reported in the GONO Infinity study in a small group of patients who received neoadjuvant treatment with durvalumab + tremelimumab [146]. The data still need to be validated in larger and independent cohorts. Nevertheless, preoperative immunotherapy - currently most likely in combination with FLOT chemotherapy, as tested in the randomized and controlled studies Dante, Keynote-585, and Matterhorn in terms of safety, response rate, and EFS (Matterhorn) - can be considered in cases of confirmed MSI-high status, regardless of the approval status of the drugs.
There is currently no established indication for pre- or postoperative radiotherapy, regardless of the underlying tumor subtype. Following publication of the ESOPEC and TOPGEAR studies, this applies to subcardial gastric carcinomas and adenocarcinomas of the esophagogastric junction [149, 150]. Adjuvant chemoradiotherapy may only be considered after R1 resection; see chapter 6.2.2.1.
*Currently off-label (as of August 2025), but significant benefit in event-free survival demonstrated in randomized placebo-controlled phase III Matterhorn trial.
6.1.4Stage IV
In stage IV gastric cancer, the goal of therapy is generally non-curative. Systemic drug therapy is the first line of treatment, supplemented by local therapeutic measures in individual cases. Active symptom control and supportive measures such as nutritional counseling, psychosocial support, and palliative care are an integral part of treatment. The prognosis for patients with locally advanced and unresectable or metastatic (here: "advanced") gastric cancer is poor. Studies evaluating the value of chemotherapy have shown a median survival time of less than one year in the past [35]. However, it has been proven that chemotherapy can prolong the survival of patients with advanced gastric cancer compared to best supportive care alone, while maintaining quality of life for longer [36]. Long-term survival rates have improved significantly with the introduction of HER2- and Claudin18.2-targeted therapies and the introduction of immune checkpoint inhibitors.
6.1.4.1Systemic tumor therapy – Stage IV
The currently recommended algorithms for systemic tumor therapy in patients with advanced gastric cancer are shown in Figure 7, Figure 8 and Figure 9.
1Nivolumab is approved in Europe for PD-L1 CPS ≥ 5 according to the Checkmate 649 study;
2Pembrolizumab is approved in Europe for adenocarcinoma of the esophagus with PD-L1 CPS ≥ 10 according to the Keynote-590 study and for HER2-negative and HER2-positive adenocarcinoma of the stomach and esophagogastric junction with PD-L1 CPS ≥ 1 according to the Keynote-859study and Keynote 811 study;
3Tislelizumab is approved in Europe for adenocarcinoma of the stomach and esophagogastric junction with PD-L1 TAP≥ 5%.
2 5-FU/folinic acid-irinotecan is also used in some cases due to higher response rates compared to irinotecan monotherapy
3 Pembrolizumab in second line therapy only if no PD-1/PD-L1 inhibitor was administered first-line
6.1.4.1.1First-line chemotherapy, targeted therapy, and immunotherapy
The standard first-line chemotherapy for advanced gastric cancer is a platinum-fluoropyrimidine doublet. Oxaliplatin and cisplatin are comparably effective, with oxaliplatin offering advantages in terms of its side effect profile. This can contribute to a tendency toward better efficacy, especially in older patients (>65 years) [23, 37]. Fluoropyrimidines can be administered as an infusion (5-FU) or orally (capecitabine or S-1). Oral fluoropyrimidines are comparable in efficacy to infused 5-FU [38, 41]. Capecitabine is approved in combination with a platinum derivative and has been tested with both cisplatin and oxaliplatin in Europeans. S-1 is established as the standard in Japan and is approved in Europe for first-line palliative therapy in combination with cisplatin. Infused 5-FU should be preferred over oral medications in cases of dysphagia or other nutritional problems. In elderly or frail patients, the results of the phase III GO-2 study support the use of dose-reduced oxaliplatin-fluoropyrimidine chemotherapy (at 80% or 60% of the standard dose from the start), which achieved comparable efficacy with fewer side effects [42].
The addition of docetaxel to a platinum-fluoropyrimidine combination (three-weekly DCF regimen) improved the radiological response rate and prolonged overall survival in an older phase-III-study, but at the same time led to significantly increased side effects [43]. Further phase II studies investigated modified docetaxel-platinum-fluoropyrimidine triplets. Some of these showed reduced toxicity compared to DCF [46, 49]. In the phase III JCOG1013 study, patients with advanced gastric cancer received either cisplatin/S-1 or cisplatin/S1/docetaxel. There were no differences in radiological response, PFS or OS [48]. However, the subgroup of patients who had already received adjuvant fluoropyrimidine-based chemotherapy after gastrectomy benefited significantly from the addition of the taxane in palliative therapy. The investigators also discuss that 79% of patients had received second-line therapy after the study, which may have influenced OS. A recently published French investigator-initiated phase III study showed significantly prolonged PFS and significantly prolonged OS for a platinum-fluoropyrimidine-docetaxel triplet (modified FLOT, called T-FOX) compared to the FOLFOX doublet. Median OS was improved from 12 to 15 months (HR 0.76, 95% CI 0.62-0.93; p=0.008) [145]. It should be noted that all patients were docetaxel-naive and that these effects were not observed in patients over the age of 65, in patients with an ECOG performance status worse than 0, and in patients with Laurén intestinal-type carcinomas. The toxicity rate was increased in numerous categories (hematological, gastrointestinal, neurological) with mFLOT/T-FOX. Nevertheless, the time to deterioration in quality of life was significantly prolonged in the mFLOT/T-FOX group. Given the increased toxicity and uncertain effects on OS, no general recommendation can be made for first-line therapy with docetaxel-platinum-fluoropyrimidine. mFLOT/TFOX triplet chemotherapy is an individually applicable regimen for patients with high remission pressure, who have not been treated with docetaxel and who do not have the option of biomarker-based targeted or immune therapy. The standard remains a platinum-fluoropyrimidine doublet.
Irinotecan-5-FU was compared with cisplatin-5-FU and with epirubicin/cisplatin/capecitabine in randomized phase III studies and showed comparable survival times with controllable side effects [49, 50]. Irinotecan-5-FU (FOLFIRI) can therefore be considered a treatment alternative to platinum-fluoropyrimidine doublets according to scientific evidence, even though irinotecan is not approved for gastric cancer in Europe.
HER2 positivity in gastric cancer is defined as the presence of protein expression with immunohistochemistry (IHC) score 3+ or IHC 2+ and simultaneous gene amplification in situ hybridization (ISH) HER2/CEP17 ratio ≥2.0. HER2 diagnostics should be subject to quality control [51, 52]. Trastuzumab should be added to chemotherapy in patients with HER2-positive advanced gastric cancer [36, 53]. This recommendation is based on data from the phase III ToGA study, which showed a higher response rate and prolonged survival for trastuzumab-cisplatin-fluoropyrimidine chemotherapy versus chemotherapy alone in patients meeting the above selection criteria; the additional trastuzumab side effects are minor and controllable [53]. Combinations of trastuzumab and oxaliplatin plus fluoropyrimidine lead to comparable results to the historical cisplatin-containing ToGA regimen [54, 56]. Based on the randomized phase III Keynote-811 study [137], the EMA approved the combination of pembrolizumab plus trastuzumab and chemotherapy as first-line therapy for HER2-positive advanced gastric or esophagogastric (GEJ) adenocarcinomas with PD-L1 expression of CPS≥1 in September 2023 [134]. 698 patients with HER-2 positive advanced carcinomas of the stomach or esophagogastric junction were randomized between platinum, fluoropyrimidine, trastuzumab with pembrolizumab, or placebo. In the 85% of patients whose tumors showed PD-L1 overexpression (PD-L1 CPS≥1), PFS was significantly prolonged in the pembrolizumab arm (HR 0.70; 95% CI 0.58-0.85). Median OS was prolonged from 15.7 to 20.1 months (HR 0.79; 95% CI 0.66-0.95) [137]. Patients with PD-L1-negative tumors do not benefit from the addition of pembrolizumab. In HER2- and PD-L1-positive tumors, pembrolizumab should therefore now be added to the chemo-trastuzumab combination.
The phase III CheckMate 649 study investigated the addition of nivolumab to chemotherapy (capecitabine–oxaliplatin or 5-FU/folinic acid-oxaliplatin) in patients with untreated advanced gastric, esophagogastric junction, or esophageal adenocarcinoma [57]. The study included patients regardless of tumor PD-L1 status; the dual primary endpoints were OS and PFS. Approximately 60% of the study population had tumors with a PD-L1 CPS ≥ 5. Nivolumab plus chemotherapy resulted in a significant improvement in OS compared to chemotherapy alone (14.4 vs. 11.1 months, HR 0.71 [98.4% CI 0.59-0.86]; p<0.0001) and in PFS (7.7 vs. 6.0 months, HR 0.68 [98% CI 0.56-0.81]; p<0.0001) in patients with a PD-L1 CPS ≥ 5. Long-term data confirm these results [135].
The Asian phase II/III ATTRACTION-04 study also showed a significant improvement in PFS with nivolumab added to first-line chemotherapy [58].
The multinational randomized phase III Keynote-859 study included 1,589 patients with advanced incurable gastric cancer. Patients received either platinum-fluoropyrimidine and pembrolizumab or the same chemotherapy and placebo intravenously every 3 weeks. OS was prolonged in the pembrolizumab group (HR 0.78 [95% CI 0.70-0.87], p< 0.0001). The effect was particularly pronounced in the subgroup with PD-L1 CPS ≥ 10 (HR 0.64). With PD-L1 CPS ≥ 1, there was a 26% reduction in the risk of death (HR 74 [95% CI 0.65-0.85], p<0.0001) [123].
The results thus complement the positive data from the phase III Keynote-590 study, which led to EU approval of pembrolizumab in combination with platinum-fluoropyrimidine chemotherapy for adenocarcinoma of the esophagus and a CPS ≥ 10 [124]. In January 2024, pembrolizumab was also approved in combination with first-line platinum-fluoropyrimidine chemotherapy for PD-L1 CPS ≥ 1.
In the phase III Rationale 305 study, tislelizumab prolonged OS in combination with platinum-fluoropyrimidine or platinum-investigator's choice chemotherapy in patients with a positive PD-L1 score (TAP ≥ 5%). TAP stands for tumor area proportion and is expressed as a percentage of the PD-L1-positive tumor area [126].
Patients with carcinomas with weak PD-L1 expression benefit only marginally in terms of OS from the addition of an immune checkpoint inhibitor to first-line chemotherapy. A combined analysis of the studies relevant for approval in Europe (CheckMate 649, Keynote-859, and Rationale-305) showed minimal efficacy: PD-L1 CPS 1-9, median survival 12.4 vs. 11.9 months, HR 0.84, p=0.002; PD-L1 CPS 1-4, median survival 12.1 vs. 12.0 months, HR 0.87, p=0.018; PD-L1 CPS 5-9, median survival 13.1 vs. 12.2 months, HR 0.87, p=0.18 [125].
Due to the convincing effectiveness of PD-1/PD-L1 inhibitors in carcinomas with DNA mismatch repair deficiency (dMMR/MSI type), all patients with MSI-high gastric carcinomas or adenocarcinomas of the esophagogastric junction should be administered one of the approved PD-1 immune checkpoint inhibitors as first-line therapy. The subgroup analyses in all studies relevant to approval (CheckMate 649, Keynote-859) and also in studies that could not be used for approval (including Keynote-062) are convincingly positive for the administration of an immune checkpoint inhibitor plus chemotherapy. Based on the currently available data, it is uncertain whether the additional administration of chemotherapy can generally be dispensed with in this situation, and this should be investigated in studies.
Data from the multinational phase III Spotlight study show that in patients with advanced unresectable gastric cancer and tumor Claudin18.2 expression in ≥ 75% of tumor cells, zolbetuximab, a chimeric monoclonal IgG1 antibody directed against Claudin18.2, in combination with FOLFOX chemotherapy prolongs OS (median 18.23 vs. 15.54 months, HR 0.750, p = 0.0053). The main side effects of zolbetuximab are nausea and vomiting, especially during the first few applications [127]. The results of the phase III Spotlight study are largely confirmed by the multinational phase III GLOW study, in which the chemotherapy doublet was used as a control therapy or combination partner for zolbetuximab [128]. The aggregated data from Spotlight and Glow show an improvement in PFS (median 9.2 versus 8.2 months, HR 0.71 (95% CI 0.61–0.83) and an improvement in OS (median 16.4 versus 13.4 months, HR 0.77 (95% CI 0.67–0.89) [128].
Zolbetuximab was approved in September 2024 for the following indication: in combination with chemotherapy containing a fluoropyrimidine and a platinum analogue, for the first-line treatment of adult patients with locally advanced, unresectable, or metastatic HER2-negative adenocarcinoma of the stomach or esophagogastric junction whose tumors are Claudin18.2-positive.
Due to the high emetogenicity of zolbetuximab, special attention must be paid to consistent antiemetic prophylaxis and patient care. Current recommendations for highly emetogenic therapies suggest the use of a four-drug antiemetic prophylaxis regimen comprising a 5-HT3 antagonist (setron), an NK-1 antagonist, dexamethasone, and olanzapine. Sufficient time must be planned for the first infusions of zolbetuximab, so that, if nausea and vomiting occur, infusion breaks can be taken. After recovery, restarting at a lower infusion rate is possible [152, 153].
6.1.4.1.2Second- and third-line therapy
Figures 8 and 9 show the algorithm for second- and third-line therapy in patients with advanced gastric cancer. The evidence-based chemotherapy options in this situation are paclitaxel, docetaxel, and irinotecan, which have comparable efficacy with different substance-specific toxicities [59, 62]. Irinotecan may be preferred in cases of pre-existing neuropathy, even though it is still not approved in the EU for this indication. 5-FU/folinic acid–irinotecan (FOLFIRI) is also used occasionally, but the scientific evidence for this is limited [63]. Ramucirumab plus paclitaxel is the recommended standard therapy in the second line of treatment and is approved in the EU. The addition of the anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody ramucirumab to paclitaxel increased the tumor response rate and prolonged PFS and OS in the phase III RAINBOW study [64]. In the phase III REGARD study, ramucirumab monotherapy already had shown prolonged survival compared to placebo, albeit with a low radiological response rate [65].
In the phase III KEYNOTE-061 study, pembrolizumab monotherapy did not show prolonged OS compared to chemotherapy [64]. However, an exploratory subgroup analysis identified a very clear benefit for anti-PD-1 immunotherapy in patients with MSI-H gastric carcinomas [67]. PD-1 inhibition is therefore indicated in advanced MSI carcinomas at the latest in the second line of treatment. Pembrolizumab has a European approval for this indication based on the Keynote-061 and Keynote-158 studies [68]. Other biomarkers, in particular EBV and tumor mutation burden, are also being discussed as predictive factors for the efficacy of PD-1 immune checkpoint inhibitors [69, 71]. However, the evidence is not yet sufficient to make a positive recommendation for immunotherapy based on the presence of these biomarkers.
Studies investigating trastuzumab, lapatinib, and trastuzumab emtansine as second-line treatments in patients with HER2-positive carcinomas yielded negative results [72, 75]. These drugs should therefore not be used in gastric carcinoma outside of clinical trials for this indication.
A randomized phase II study showed that the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) improved tumor response rates and OS compared to standard chemotherapy in patients with pretreated HER2-positive advanced gastric cancer [76]. The prerequisites for inclusion in the Destiny-GC-01 study were at least two previous lines of therapy, previous treatment with a platinum derivative, a fluoropyrimidine, and trastuzumab, as well as previously confirmed HER2 positivity. The study was recruited exclusively in East Asia. The results of Destiny GC-01 were largely confirmed in the non-randomized phase II Destiny GC-02 study, which included non-Asian patients in the second line of therapy. Platinum-fluoropyrimidine-trastuzumab pretreatment and confirmed HER2 positivity of the tumor in a recent re-biopsy were mandatory before T-DXd therapy was initiated [129]. Most recently, the Destiny GC-04 study demonstrated the superiority of T-DXd over ramucirumab plus paclitaxel in terms of OS (median 14.7 vs. 11.4 months; HR for death 0.70; 95% CI 0.55-0.90; p = 0.004) in patients with HER2-positive metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction confirmed by re-biopsy after disease progression during trastuzumab-based therapy [161]. The EU approval includes the following use of T-DXd: monotherapy for the treatment of adult patients with advanced HER2-positive adenocarcinoma of the stomach or esophagogastric junction who have already received a previous trastuzumab-based therapy regimen.
In accordance with the classic established HER2 diagnostic criteria, we recommend checking the HER2 status before therapy with T-DXd, especially if it is to be used as a second-line therapy, where a valid alternative with paclitaxel-ramucirumab is available. This recommendation is based on the inclusion criteria of the Destiny-GC-02 study and the knowledge that approximately 30% of gastric carcinomas lose their HER2-positive status during first-line therapy with trastuzumab [72].
There is evidence of the efficacy of T-DXd in cases of low HER2 expression [130]. However, this evidence is not yet sufficient to recommend its use.
In the treatment of patients with advanced gastric cancer in the third line and beyond, the best evidence for trifluridine–tipiracil (FTD/TPI; TAS-102) is based on the phase III TAGS study. Median OS with FTD/TPI versus placebo was significantly improved in the overall group, in the third-line cohort, and in the fourth-line cohort [77, 79]. If oral therapy is feasible, trifluridine–tipiracil (FTD/TPI) should therefore be used. Alternatively, if intravenous therapy is preferred, irinotecan or a taxane can be given if not already used in a previous line of therapy. As shown above, T-DXd is a very effective third-line therapy for HER2-positive carcinomas after trastuzumab pretreatment. Nivolumab has also proven to be effective; however, the data from the ATTRACTION-03 study were obtained exclusively from Asian patients [80], meaning that nivolumab is not approved by the EMA for third-line treatment in patients with advanced gastric cancer and therefore cannot be recommended.
Following the recommendation from a molecular tumor board, an unapproved treatment option may also be preferable in select cases, especially if the recommendation is based on a level of evidence corresponding to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) level I or II [81].
6.1.4.1.3Surgery for metastatic gastric cancer
The randomized phase III REGATTA study showed that gastrectomy in addition to chemotherapy in metastatic disease does not provide a survival advantage compared to chemotherapy alone [84]. International data collection shows that surgical therapy is increasingly being considered as a treatment option for oligometastasis [83, 85]. The AIO-FLOT3 phase II study reported results on the feasibility of resections in stage IV gastric cancer and survival times in highly selected patients with oligometastatic disease who were receiving FLOT chemotherapy without primary progression [86]. The randomized phase III RENAISSANCE study failed to show a survival benefit for surgical resection of the primary tumor and metastases in patients with stage IV gastric cancer [151].
A definition for oligometastasis was determined in a Delphi procedure by a European expert group (OMEC). According to this definition, the following phenotypes can be referred to as oligometastasis: 1-2 metastases in either the liver, lungs, retroperitoneal lymph nodes, adrenal glands, soft tissue, or bones [85]. In selected cases of oligometastasis, the tumor board may agree on the concept of primary systemic tumor therapy and, in case of remission, subsequent resection of the primary tumor with resection or ablation of metastases, provided that all tumor manifestations can be completely removed.
The current data do not allow for a recommendation for radical tumor resection in stage IV. Any decisions are individual approaches with an unclear survival benefit. Possible complications of surgery possibly resulting in shortening of life must be taken into account and should not be excluded from the consultation. Other local ablative procedures (stereotactic radiotherapy, radiofrequency ablation, etc.) have not yet been evaluated in this regard and therefore cannot be assessed.
6.1.4.1.4Supportive care and nutrition
It is recommended that all patients with advanced gastric cancer undergo regular nutritional and symptom screening using appropriate instruments, and that adequate supportive care be derived from this. A study from China showed that early integration of supportive palliative care is effective and suggests a survival benefit in patients with advanced gastric cancer [87]. Weight loss is a multifactorial phenomenon and may be due to obstruction of the digestive tract, malabsorption, or hypermetabolism. Clinical data show that weight loss of ≥10% before chemotherapy or ≥3% during the first cycle of chemotherapy is associated with reduced survival times [88]. A change in body composition with a reduction in muscle quality has also been shown to be prognostically unfavorable in patients with advanced gastric cancer [79]. The modified Glasgow Prognostic Score (serum CRP and albumin) can be used to assess the extent of sarcopenia and the prognosis of patients with advanced gastric cancer [90]. It can therefore be concluded that all patients with advanced gastric cancer should undergo nutritional screening (e.g., using Nutritional Risk Screening, NRS) [91] and, if there are signs of nutritional deficiency, professional nutritional medical advice and support should be offered.
Dysphagia in proximal gastric cancer can be improved by radiotherapy or stent insertion [92]. Single-dose brachytherapy is the preferred option at some centers and leads to longer-lasting symptom control and fewer complications than stent insertion. Stenting is necessary in cases of severe dysphagia, especially in patients with limited life expectancy, as the effects of the stent are immediate, whereas dysphagia symptoms only improve after approximately 4-6 weeks with radiotherapy [93]. If radiotherapy or a stent are not an option, enteral nutrition via a nasogastric, nasojejunal, or percutaneously placed feeding tube can provide relief [94]. The indication for parenteral nutrition follows generally accepted guidelines.
6.2Treatment modalities
6.2.1Surgical resection
6.2.1.1Endoscopic resection
Endoscopic resection (ER) is a minimally invasive procedure for the resection of early-stage carcinomas. The criteria for ER are outlined above (chapter 6.1.1). The methods used are endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). EMR of early gastric carcinomas is performed as en-bloc resection. It allows complete histological assessment of the lateral and basal margins. The recommended endoscopic follow-up intervals are 3 months in the first year and 6 months in the second year. After that, follow-ups should take place annually. Local recurrences after ER of early gastric cancer can be treated endoscopically if there is again solely mucosal involvement (rT1a cN0 cM0). A (limited) surgical procedure is an alternative, see Table 4.
6.2.1.1.1Gastrectomy and lymphadenectomy
Surgery of the primary tumor is a central element of curative therapy. The goal is to achieve an R0 situation. Surgical therapy has a significant impact on the patient's prognosis. Depending on the location of the tumor, the standard procedures are total, subtotal, or transhiatal extended gastrectomy, each with systematic D2 lymphadenectomy. If the tumor has directly invaded adjacent organs/structures (spleen, diaphragm, pancreas), resection of these organs/structures is indicated. Diffusely invading carcinomas and early-stage carcinomas differ significantly in terms of resection strategy and the necessary safety margin. The passage is usually restored by Roux-Y reconstruction.
With regard to lymphadenectomy, a consensus has been reached in the Western world that patients with normal surgical risks should undergo D2 lymphadenectomy. D1 resection involves the removal of the perigastric lymph nodes; while D2 lymphadenectomy additionally removes the lymph nodes along the left gastric artery, common hepatic artery, splenic artery, and celiac axis [95]. Long-term results from a randomized study in the Netherlands showed a lower local recurrence rate and better cancer-specific survival after D2 versus D1 lymphadenectomy [96]. The current UICC/AJCC TNM (8th edition) classification recommends the resection and histopathological examination of at least 15 lymph nodes for reliable staging [21]. In the current German AWMF S3 guideline on gastric cancer, the removal of at least 25 lymph nodes is considered adequate [11]. The surgery should be performed at a certified high-volume center with sufficient surgical expertise and perioperative care [11]. Numerous studies demonstrate better short-term and long-term survival rates for patients treated at centers with proven expertise [98;100]. Perioperative morbidity and mortality should not exceed 15% and 3%, respectively [101]. The concept of "enhanced recovery" is presented in the Enhanced Recovery After Surgery (ERAS®) Society Guidelines and covers all aspects of optimized perioperative care [102].
Patients who have undergone gastrectomy require regular vitamin B12 supplementation for the rest of their lives. Pancreatic enzyme supplementation is indicated after Roux-Y reconstruction.
6.2.2Radiotherapy
6.2.2.1Adjuvant radiochemotherapy
The North American Intergroup 0116 study showed that adjuvant therapy with 5-FU/folinic acid plus conventionally fractionated radiotherapy (45 Gy in 25 fractions) improves OS compared to surgery alone (50% vs. 41% 3-year survival [66, 103]). This therapy was therefore recommended as a standard treatment in North America. In Germany and Europe, it was not universally accepted due to the inadequate surgical quality within the INT-0116 study. This reluctance is justified by the randomized controlled phase III CRITICS study, which suggested that adjuvant chemoradiotherapy reduces the local recurrence rate after D1 lymphadenectomy, but has no benefit after D2 lymphadenectomy [104]. The results presented in the Dutch-Scandinavian CRITICS study show that adjuvant chemoradiotherapy after neoadjuvant chemotherapy and quality-assured surgery does not provide a survival benefit [105]. The ARTIST-2 study conducted in Korea also failed to find any significance for adjuvant chemoradiotherapy compared to adjuvant chemotherapy with a platinum-fluoropyrimidine doublet in adequately (D2 lymphadenectomy) and curatively (R0) resected patients with gastric cancer and positive nodal tumor status [106].
The multinational TOPGEAR study investigated whether preoperative chemoradiotherapy plus perioperative chemotherapy improves survival in patients with resectable gastric cancer or cancer of the esophagogastric junction compared to perioperative chemotherapy without preoperative chemoradiotherapy. The study did not achieve its primary endpoint. The median OS was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (HR for death 1.05; 95% CI 0.83-1.31), and the median PFS was 31 months and 32 months, respectively [150].
In patients with R1 resection, retrospective studies suggest that adjuvant chemoradiotherapy may improve the prognosis [100, 107]. Therefore, in individual cases, adjuvant chemoradiotherapy may be considered in the presence of R1 status after weighing the benefits against the risks and burdens.
6.2.3Systemic tumor therapy
6.2.3.1Systemic tumor therapy – anticancer agents
6.2.3.1.1Cisplatin
In combination with other cytostatic drugs, cisplatin is part of the standard drug therapy in perioperative and palliative care. In palliative therapy, cisplatin in combination with fluoropyrimidines achieves remission rates of up to 30%. Specific severe side effects (grade 3 / 4) include nausea and vomiting, nephrotoxicity, polyneuropathy, ototoxicity, hematotoxicity, electrolyte dysbalance, and diarrhea.
6.2.3.1.2Docetaxel
Docetaxel belongs to the taxane family and is an effective combination partner for fluoropyrimidines and platinum derivatives in perioperative and palliative therapy, e.g., as part of the FLOT regimen [32, 45, 111]. Severe grade 3 / 4 side effects include infections, nail changes, stomatitis, and diarrhea, while grade 2 side effects include alopecia. Particularly burdensome is polyneuropathy, which can be irreversible in some cases. Common side effects such as nausea/vomiting and allergic reactions can be prevented with adequate supportive care; see Onkopedia Antiemesis (Guideline exists in German language only).
6.2.3.1.3Fluoropyrimidines: 5-fluorouracil / capecitabine / tegafur (S-1)
5-fluorouracil is used in almost all forms of systemic tumor therapy for patients with gastric cancer. Its effectiveness is increased when combined with folinic acid. Severe side effects include diarrhea and stomatitis. Patients with functionally relevant polymorphisms of the 5-FU degradation genes have an increased risk of severe side effects.
Capecitabine is an oral fluoropyrimidine that is metabolized to 5-FU. In comparative clinical studies, it is at least as effective as 5-FU/folinic acid. It can be used in palliative therapy instead of 5-fluorouracil. In combination with platinum derivatives, remission rates of up to 45% are achieved. Severe side effects (grade 3 / 4) occurring in more than 5% of patients in the approval studies include diarrhea and hand-foot syndrome. Patients with functionally relevant polymorphisms of the 5-FU degradation genes have an increased risk of severe side effects.
Another orally bioavailable fluoropyrimidine, consisting of tegafur in combination with two modulators of the activity of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, in a molar ratio of 1:0, 4:1, is S-1. Tegafur is a prodrug of 5-fluorouracil, an antimetabolite that inhibits thymidylate synthase, DNA synthesis, and cell division and competes with uridine triphosphate, thereby inhibiting RNA and protein synthesis. CDHP is a reversible inhibitor of dihydropyrimidine dehydrogenase (DPD), which is responsible for the rapid degradation of 5-FU to inactive metabolites. Potassium oxonate localizes preferentially in the intestine and inhibits the enzyme orotate phosphoribosyl transferase (OPRT), thereby reducing the activation of 5-FU in the intestine and the gastrointestinal toxicity associated with 5-FU.
Since 2020, the European Medicine Agency has recommended that all patients taking the above-mentioned fluoropyrimidines be tested for dihydropyrimidine dehydrogenase (DPD) deficiency prior to initiation of therapy in order to prevent severe side effects caused by 5-fluorouracil, capecitabine, or tegafur (https://www.ema.europa.eu/en/news/ema-recommendations-dpd-testing-prior-treatment-fluorouracil-capecitabine-tegafur-flucytosine).
6.2.3.1.4Irinotecan
Irinotecan is a topoisomerase I inhibitor. In combination with fluoropyrimidines, remission rates of up to 40% may be achieved. FOLFIRI is at least as effective as cisplatin-fluoropyrimidine-based therapies in terms of PFS and OS. Severe side effects (grade 3 / 4) that occurred in more than 5% of patients in the approval studies include diarrhea, nausea/vomiting, neutropenia, and neutropenic fever. The substance can be administered as monotherapy weekly, biweekly, or triweekly.
6.2.3.1.5Oxaliplatin
This platinum derivative is effective in combination with fluoropyrimidines (5-FU/folinic acid, capecitabine). In first-line therapy in stage IV, it increases remission rates to 45%. Severe side effects (grade 3 / 4) that occurred in more than 5% of patients in the approval studies include nausea/vomiting, diarrhea, mucositis, and polyneuropathy. Oxaliplatin is part of the preferred perioperative FLOT regimen.
6.2.3.1.6Paclitaxel
Paclitaxel belongs to the taxane family and is effective as monotherapy in palliative second-line therapy. Severe side effects (grade 3 / 4) include infections, stomatitis, diarrhea, and allergic reactions to the solvent Cremophor. Alopecia is one of the more distressing grade 2 side effects. Particularly burdensome is polyneuropathy, which can be irreversible in some cases. Frequent side effects such as allergic reactions can be prevented in some cases by adequate supportive care.
6.2.3.1.7Ramucirumab
Ramucirumab is a VEGF receptor 2 antibody that inhibits neoangiogenesis. In combination with paclitaxel, ramucirumab leads to a prolongation of PFS (HR 0.64; median 1.5 months) and OS (HR 0.81; median 2.2 months) and increases the remission rate. In patients who are not suitable for paclitaxel therapy, monotherapy with ramucirumab also prolongs PFS (HR 0.48; median 0.8 months) and OS (HR 0.78; median 1.4 months) compared with placebo. The only CTCAE grade 3 / 4 adverse event that occurred in more than 5% of patients receiving ramucirumab monotherapy was arterial hypertension. More common adverse events in combination therapy were fatigue (12%), neuropathy (8%), and abdominal pain (6%).
6.2.3.1.8Trastuzumab
Trastuzumab is the first monoclonal antibody that specifically interferes with the HER2/neu receptor and has been approved for the treatment of patients with HER2 overexpression or gene amplification. It is effective in palliative situations. In HER2-positive gastric cancer, trastuzumab in combination with a fluoropyrimidine and cisplatin leads to a prolongation of OS (HR 0.74; median 2.7 months) compared to chemotherapy alone. Severe side effects (grade 3 / 4) in this treatment setting are rare.
6.2.3.1.9Trastuzumab deruxtecan (T-DXd)
Trastuzumab deruxtecan is an antibody-drug conjugate that contains a humanized monoclonal anti-HER2 IgG1 antibody (mAb) with the same amino acid sequence as trastuzumab, which is covalently bound to DXd, an exatecan derivative and topoisomerase I inhibitor, via a tetrapeptide-based cleavable linker. Approximately 8 DXd molecules are bound to each antibody molecule. T-DXd is used as monotherapy for the treatment of adult patients with advanced HER2-positive adenocarcinoma of the stomach or esophagogastric junction who have already received a previous trastuzumab-based therapy regimen. Patients treated with T-DXd must have documented HER2-positive tumor status, defined either immunohistochemically (IHC) by a score of 3+ or by a gene copy number ratio relative to CEP17 of ≥ 2 measured by in situ hybridization (ISH). The recommended dose of T-DXd for gastric cancer (in contrast to breast cancer) is 6.4 mg/kg and is administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity occurs. The initial dose should be administered as a 90-minute intravenous infusion. If the first infusion was well tolerated, T-DXd can subsequently be administered as a 30-minute infusion. If the patient shows infusion-related symptoms, the infusion rate of T-DXd must be reduced or the infusion interrupted. In case of severe reactions to the infusion, T-DXd must be permanently discontinued. Particular attention must be paid to the possible occurrence of lung toxicity in terms of interstitial lung disease or pneumonitis. It should also be noted that trastuzumab deruxtecan has a moderate to high acute and delayed emetogenic potential. Therefore, prophylaxis with 3 antiemetics (dexamethasone, 5-HT3 antagonist, NK-1 antagonist) is recommended.
6.2.3.1.10Trifluridine/tipiracil (FTD/TPI; TAS-102)
The combination drug FTD/TPI consists of the nucleoside thymidine analogue trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil (TPI). The molar ratio of trifluridine to tipiracil is 1:0.5 (exact mass ratio: 1:0.471). TF is phosphorylated intracellularly by the enzyme thymidine kinase to monophosphate (TF-MP) and subsequently by the enzyme thymidylate kinase to diphosphate (TF-DP) and triphosphate (TF-TP). TF-TP is incorporated into DNA as a false building block. This incorrect incorporation results in long-lasting DNA damage and DNA strand breaks. TF-MP, in turn, binds covalently to tyrosine-146 in the active center of the enzyme thymidylate synthetase (TS, also thymidylate synthase) and inhibits its activity. TS is responsible for the conversion of uracil nucleotides into thymidine nucleotides and is therefore of vital importance for DNA synthesis by maintaining sufficient amounts of thymidine. TAS-102 proved superior to placebo in the third line of treatment for metastatic gastric cancer, prolonging OS (HR 0.69; p<0.001) and was tolerated satisfactorily: Grade ≥3 adverse events occurred in 267 (80%) patients in the trifluridine/tipiracil group and in 97 (58%) in the placebo group.
6.2.3.1.11Durvalumab
Durvalumab is a monoclonal anti-PD-L1 antibody that belongs to the substance class of immune checkpoint inhibitors (ICI). At the time of publication of this guideline, it is not yet approved for the treatment of gastric cancer, but it is approved for the treatment of small cell and non-small cell lung cancer, biliary tumors, and hepatocellular carcinoma (HCC). Durvalumab is administered as an intravenous infusion and, according to the study data on gastric cancer, can be administered perioperatively in combination with oxaliplatin plus 5-fluorouracil plus docetaxel (FLOT) chemotherapy and also, after a pre- and postoperative combined therapy phase, as subsequent monotherapy for a total duration of one year. The side effects are specific to the substance class. In the course of ICI-based therapy, immune-related adverse events (irAE) may occur due to autoimmune inflammation of various tissues or organs. For detection and management, we refer to current guidelines. After irAE have subsided, and after weighing the benefits as antitumor therapy against the risks of renewed, higher-grade irAE, ICI therapy may be continued in certain settings.
6.2.3.1.12Nivolumab
Nivolumab is an immune checkpoint inhibitor. It is a fully human monoclonal antibody of the immunoglobulin G4 (IgG4) class that binds to the PD-1 receptor on T cells and prevents interaction with the PD1 receptor ligand that normally binds here. This indirectly stimulates the cellular immune system by suppressing the inhibitory influence of the PD1 ligand/PD1 receptor interaction. Nivolumab is indicated in combination with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of HER2-negative advanced or metastatic adenocarcinomas of the stomach, esophagogastric junction, or esophagus in adults whose tumors express PD-L1 (combined positive score [CPS] ≥ 5). The recommended dose is 360 mg of nivolumab administered intravenously over 30 minutes in combination with fluoropyrimidine and platinum-based chemotherapy every 3 weeks, or 240 mg of nivolumab administered intravenously over 30 minutes in combination with fluoropyrimidine and platinum-based chemotherapy every 2 weeks. Treatment with nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
6.2.3.1.13Pembrolizumab
Pembrolizumab is an immune checkpoint inhibitor. It is a fully human monoclonal antibody of the immunoglobulin G4 (IgG4) class that binds to the PD-1 receptor on T cells and prevents interaction with the PD1 receptor ligand that normally binds here. In this way, the cellular immune system is indirectly stimulated by suppressing the inhibitory influence of the PD1 ligand/PD1 receptor interaction. Pembrolizumab is indicated in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative adenocarcinoma of the stomach and esophagogastric junction in adults with PD-L1-expressing tumors (CPS ≥ 1). Pembrolizumab is also indicated as monotherapy for the treatment of gastric cancer with MSI-H or dMMR in adults after at least one prior line of therapy.
6.2.3.1.14Tislelizumab
Tislelizumab is a drug from the group of monoclonal antibodies for the treatment of adult patients with esophageal cancer (squamous cell carcinoma of the esophagus), lung cancer (non-small cell lung cancer), and gastric cancer or tumors of the gastroesophageal junction. As a PD-1 inhibitor, tislelizumab is classified as an immune checkpoint inhibitor. The active ingredient is a humanized monoclonal IgG4 antibody modified in the Fc region and was developed with the aim of minimizing binding to Fcγ receptors on macrophages and increasing the functional activity of T cells, which has been demonstrated in cell-based in vitro tests. Tislelizumab is indicated in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative adenocarcinoma of the stomach and esophagogastric junction in adults with PD-L1-expressing tumors (TAP ≥ 5%).
6.2.3.1.15Zolbetuximab
Zolbetuximab is a monoclonal antibody approved in combination with 5-fluorouracil and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced, unresectable, or metastatic HER2-negative adenocarcinoma of the stomach or esophagogastric junction. Patients with a Claudin-18.2-positive tumor (≥75% of tumor cells stain positive with an ICH score of 2+ or 3+) are eligible for therapy with zolbetuximab. Claudin-18.2 is a transmembrane protein that is expressed in approximately 38% of patients with the aforementioned types of cancer. Zolbetuximab is administered as an intravenous infusion. Prior to the infusion of zolbetuximab, premedication with antiemetics is recommended:
Antiemesis with zolbetuximab should be based on the guideline recommendations for highly emetogenic substances [152, 153].
The focus of prophylaxis and management is on the first two doses, as studies have shown that nausea and vomiting occur most frequently during these doses. Patients should be made aware of the efficacy of zolbetuximab and it should be emphasized that nausea and vomiting occur less frequently from the second cycle onwards.
It is particularly important to actively ask patients about side effects during and after the first dose. Nursing staff play an important role in monitoring and managing side effects.
6.3Special settings
6.3.1Peritoneal metastasis
Several smaller randomized studies from Asia suggest a survival advantage for adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with curatively resected gastric carcinomas with a high risk of recurrence [109, 110]. The ongoing randomized GASTRICHIP study is attempting to clarify the efficacy of this approach in a European patient population [111]. For patients with peritoneal metastasis, there are also smaller randomized studies from Asia that suggest a benefit for cytoreductive surgery and HIPEC [112]. A larger multicenter case series from France showed a median survival for surgery plus HIPEC of 9.2 months, with a 5-year survival rate of 13% for all patients and 23% for patients with complete cytoreduction [113]. The approach of peritonectomy plus HIPEC plus perioperative chemotherapy was compared with peritonectomy without HIPEC plus perioperative chemotherapy in Germany in the multicenter, prospective, randomized GASTRIPEC study. The study had to be terminated prematurely after 105 patients due to slow recruitment and showed no survival benefit [114]. Based on current knowledge, adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) and peritonectomy are not standard therapies.
6.3.2Signet ring cell carcinoma in locally advanced stages
Gastric carcinomas with signet ring cells are associated with a poorer prognosis. This is at least partly due to late diagnosis with higher tumor stages at initial diagnosis [115]. Retrospective case series suggest that signet ring carcinomas respond less well to chemotherapy and chemoradiotherapy [116, 117]. A retrospective study from a French national registry, albeit without a central histopathological review of the findings, suggests a poorer prognosis for patients with signet ring cell carcinoma who receive perioperative chemotherapy in addition to resection [118]. However, the evidence from these studies is insufficient for specific treatment recommendations. A French study (PRODIGE 19 - FFCD1103 - DCI002) addressed the question of perioperative chemotherapy for resectable signet ring cell carcinomas of the stomach and compared this standard with adjuvant chemotherapy alone [119]. An evaluation published as an abstract showed that perioperative chemotherapy was sufficiently effective in patients with signet ring cell carcinoma [120]. In the FLOT-4 study, the remission rate was the same under FLOT and under ECF/ECX, but in a subgroup analysis, the OS in the FLOT arm was also significantly prolonged in patients with signet ring cell carcinoma [32]. Therefore, based on current knowledge, the same perioperative treatment recommendations apply to patients with locally advanced signet ring cell carcinoma as to patients with non-signet ring cell carcinomas.
7Rehabilitation
Gastric carcinoma and the treatments, both surgical and medicinal, can lead to considerable secondary disorders such as weight loss, tumor cachexia, maldigestion and neuropathy. In addition, patients are often psychologically stressed and suffer from fatigue syndrome. Targeted rehabilitative measures are therefore necessary. When selecting the rehabilitation facility, the approval of the clinic for gastric carcinoma patients by the health insurance (pension insurance, health insurance) is a prerequisite; in addition, the patient's right of wish and choice according to §9 of the German SGB IX should be taken into account. During rehabilitation, comprehensive nutritional advice should be given, patients should be included in the training kitchen, and there should be the possibility of administering all scientifically recognized diets, from normal whole foods to complete parenteral nutrition. All patients should be offered psycho-oncological care. Rehabilitation facilities should be able to continue ongoing drug therapies, including chemotherapy and immunotherapy, in accordance with the pre-treatment centers. Patients who have not yet reached the statutory retirement age should be informed about benefits for participation in working life as part of medical-occupational rehabilitation (German MBOR). Social-medical issues and any further care that the patient may require should be clarified during rehabilitation.
8Monitoring and follow-up
8.1Monitoring
During ongoing chemotherapy, patients’ general condition and vital body functions should generally be checked once a week, or more frequently if indicated [11]. Imaging follow-up examinations, preferably by computed tomography, are indicated every 6-12 weeks in order to timely detect an unfavorable course of the disease in time and not to expose patients to ineffective therapies for an unnecessarily long time, or to maintain the chance of more effective therapies.
8.2Follow-up
There are no prospective data on which a recommendation for a specific follow-up regimen could be based. The AWMF S3 guideline recommends offering patients structured follow-up care after curative therapy, including clinical monitoring, endoscopic monitoring, and imaging monitoring. The follow-up should be repeated at least every six months for the first two years and then at least annually until the fifth year. In past and ongoing studies, the regimen shown in Table 5 has become established.
9References
Center for Cancer Registry Data at the Robert Koch Institute: Database query with estimates of the incidence, prevalence, and survival of cancer in Germany based on epidemiological state cancer registry data. Mortality data provided by the Federal Statistical Office. https://www.krebsdaten.de/abfrage (Cancer in Germany), last updated: December 21, 2021, date of access: (June 15, 2022) . RKI - Center for Cancer Registry Data
Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 333:32-41, 1995. DOI:10.1056/NEJM199507063330107
Correa P. Gastric cancer: overview. Gastroenterol Clin North Am 42:211-217, 2013. DOI:10.1016/j.gtc.2013.01.002
Forman D, Burley VJ. Gastric cancer: global pattern of the disease and an overview of environmental risk factors. Best Pract Res Clin Gastroenterol 20:633-649, 2006. DOI:10.1016/j.bpg.2006.04.008
Petrovchich I, Ford JM. Genetic predisposition to gastric cancer. Semin Oncol 43:554-559, 2016. DOI:10.1053/j.seminoncol.2016.08.006
Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121:1348–1353, 2001. PMID:11729114
Van der Post RS, Vogelaar IP, Carneiro F et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 52:361-374, 2015. DOI:10.1136/jmedgenet-2015-103094
Fischbach W, Bornschein J, Hoffmann JC et al. Update S2k guideline Helicobacter pylori and gastroduodenal ulcer disease of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). Z Gastroenterol 62:261-321, 2024. doi: 10.1055/a-2181-2225.
Allum WH, Blazeby JM, Griffin SM et al. Guidelines for the management of esophageal and gastric cancer. Gut 60:1449-1472, 2011. DOI:10.1136/gut.2010.228254
Shin CM, Kim N, Yang HJ et al. Stomach cancer risk in gastric cancer relatives: interaction between Helicobacter pylori infection and family history of gastric cancer for the risk of stomach cancer. J Clin Gastroenterol 44:e34–e39, 2010. DOI:10.1097/MCG.0b013e3181a159c4
Guideline Program Oncology (German Cancer Society, German Cancer Aid, AWMF): S3 Guideline Diagnosis and Treatment of Adenocarcinomas of the Stomach and Esophagogastric Junction, Long Version 3.0, 2025. https://register.awmf.org/assets/guidelines/032-009oll_s3_magenkarzinom_diagnostik_therapie_adenokarzinome_oesophagogastraler_uebergang_2025-05
Choi IJ, Kim CG, Lee JY et al. Family history of gastric cancer and Helicobacter pylori treatment. N Engl J Med 382:427-436, 2020. DOI:10.1056/NEJMoa1909666
Clark DF, Michalski ST, Tondon R et al. Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer. Genet Med 22:840-846, 2020. DOI:10.1038/s41436-020-0753-1
Blair VR, McLeod M, Carneiro F et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 21:e386-e397, 2020. DOI:10.1016/S1470-2045(20)30219-9
Witzig R, Schönberger B, Fink U et al. Delays in diagnosis and therapy of gastric cancer and esophageal adenocarcinoma. Endoscopy 38:1122-1126, 2006. DOI:10.1055/s-2006-944847
Hejna M, Wöll E, Tschandl P, Raderer M. Cutaneous paraneoplastic disorders in stomach cancer: Collaboration between oncologically active dermatologists and clinical oncologists. Crit Rev Oncol Hematol 103:78-85, 2016. DOI:10.1016/j.critrevonc.2016.04.013
Jamel S, Markar SR, Malietzis G et al. Prognostic significance of peritoneal lavage cytology in staging gastric cancer: systematic review and meta-analysis. Gastric Cancer 21:10-18, 2018. DOI:10.1007/s10120-017-0749-y
Lauwers GY, Carneiro F, Graham DY. Gastric carcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds.). WHO Classification of Tumors of the Digestive System. Lyon: IARC; 2010
Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31-34, 1965. DOI:10.1111/apm.1965.64.1.31
Parsonnet J, Vandersteen D, Goates J et al.: Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 83:640-643, 1991. DOI:10.1093/jnci/83.9.640
Brierley JD, Gospodarowicz MK, Wittekind C (eds). TNM Classification of Malignant Tumors, 8th Edition, Wiley-Blackwell 2016. ISBN: 978-1-119-26357-9
The Cancer Genome Atlas. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202-209, 2014. DOI:10.1038/nature13480
Al-Batran SE, Hartmann JT, Probst S et al: Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 26:1435-1442, 2008. DOI:10.1200/JCO.2007.13.9378
Chen CY, Hsu JS, Wu DC et al. Gastric cancer: preoperative local staging with 3D multi-detector row CT - correlation with surgical and histopathologic results. Radiology 242:472-482, 2007. DOI:10.1148/radiol.2422051557
Kwee R, Kwee T. Imaging in assessing lymph node status in gastric cancer. Gastric Cancer 12:6-22, 2009. DOI:10.1007/s10120-008-0492-5
Catalano MF, Sivak MV Jr, Rice T et al. Endosonographic features predictive of lymph node metastasis. Gastrointest Endosc 40:442-446, 1994. DOI:10.1016/s0016-5107(94)70206-3
Bennett C, Wang Y, Pan T. Endoscopic mucosal resection for early gastric cancer. Cochrane Database Syst Rev 4:CD004276, 2009. DOI:10.1002/14651858.CD004276.pub3
Tada M, Tanaka Y, Matsuo N et al. Mucosectomy for gastric cancer: current status in Japan. J Gastroenterol Hepatol 15 Suppl: D98-102, 2000. DOI:10.1046/j.1440-1746.2000.02137.x
National Cancer Institute: Surveillance, Epidemiology and End Results. https://seer.cancer.gov/statfacts/html/stomach.html
Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006. DOI:10.1056/NEJMoa055531
Ychou M, Boige V, Pignon JP et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29:1715-21, 2011. DOI:10.1200/JCO.2010.33.0597
Al-Batran SE, Homann N, Pauligk C et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet 393:1948-1957, 2019. DOI:10.1016/S0140-6736(18)32557-1
Pietrantonio F, Miceli R, Raimondi A et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J Clin Oncol 37:3392-3400, 2019. DOI:10.1200/JCO.19.01124
Lorenzen S, Götze TO, Thuss-Patience P et al. Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: interim results from the randomized, multicenter, phase II/III DANTE/IKF-s633 trial. J Clin Oncol 42:410-420, 2024. DOI:10.1200/JCO.23.00975
Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet 396:635-648, 2020. DOI:10.1016/S0140-6736(20)31288-5
Wagner AD, Syn NL, Moehler M et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 8:Cd004064, 2017. DOI:10.1002/14651858.CD004064.pub4
Cunningham D, Starling N, Rao S et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36-46, 2008. DOI:10.1056/NEJMoa073149
Okines AFC, Norman AR, McCloud P et al. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced esophagogastric cancer. Ann Oncol 20:1529-1534, 2009. PMID:19474114
Cassidy J, Saltz L, Twelves C et al. Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann Oncol 22:2604-2609, 2011. DOI:10.1093/annonc/mdr031
Ajani JA, Abramov M, Bondarenko I et al. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol 28:2142-2148, 2017. DOI:10.1093/annonc/mdx275
Koizumi W, Narahara H, Hara T et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9:215-221, 2008. DOI:10.1016/S1470-2045(08)70035-4
Hall PS, Swinson D, Cairns DA et al. Efficacy of reduced-intensity chemotherapy with oxaliplatin and capecitabine on quality of life and cancer control among older and frail patients with advanced gastroesophageal cancer: the GO2 phase 3 randomized clinical trial. JAMA Oncol 7:869-877, 2021. DOI:10.1001/jamaoncol.2021.0848
Van Cutsem E, Moiseyenko VM, Tjulandin S et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991-4997, 2006. DOI:10.1200/JCO.2006.06.8429
Lorenzen S, Hentrich M, Haberl C et al. Split-dose docetaxel, cisplatin and leucovorin/fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: results of a phase II trial. Ann Oncol 18:1673-1679, 2007. DOI:10.1093/annonc/mdm269
Al-Batran SE, Hartmann JT, Hofheinz R et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 19:1882-1887, 2008. DOI:10.1093/annonc/mdn403
Shah MA, Janjigian YY, Stoller R et al. Randomized multicenter phase II study of modified docetaxel, cisplatin, and fluorouracil (DCF) versus DCF plus growth factor support in patients with metastatic gastric adenocarcinoma: a study of the US Gastric Cancer Consortium. J Clin Oncol 33:3874-3879, 2015. DOI:10.1200/JCO.2015.60.7465
Van Cutsem E, Boni C, Tabernero J et al. Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: a randomized phase II study. Ann Oncol 26:149-156, 2015. DOI:10.1093/annonc/mdu496
Yamada Y, Boku N, Mizusawa J et al. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomized controlled trial. Lancet Gastroenterol Hepatol 4:501-510, 2019. DOI:10.1016/S2468-1253(19)30083-4
Thanks to M, Zaluski J, Barone C et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy-naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol 19:1450-1457, 2008. DOI:10.1093/annonc/mdn166
Guimbaud R, Louvet C, Ries P et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol 32:3520-3526, 2014. DOI:10.1200/JCO.2013.54.1011
Lordick F, Al-Batran SE, Dietel M et al. HER2 testing in gastric cancer: results of a German expert meeting. J Cancer Res Clin Oncol 143:835-841, 2017. DOI:10.1007/s00432-017-2374-x
Haffner I, Schierle K, Raimúndez E et al. HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: results from the prospective multicenter VARIANZ study. J Clin Oncol 39:1468-1478, 2021. DOI:10.1200/JCO.20.02761
Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet 376:687-697, 2010. DOI:10.1016/S0140-6736(10)61121-X
Ryu MH, Yoo C, Kim JG et al. Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer 51:482-488, 2015. DOI:10.1016/j.ejca.2014.12.015
Rivera F, Romero C, Jimenez-Fonseca P et al. Phase II study to evaluate the efficacy of trastuzumab in combination with capecitabine and oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial. Cancer Chemother Pharmacol 83:1175-1181, 2019. DOI:10.1007/s00280-019-03820-7
Takahari D, Chin K, Ishizuka N et al. Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naïve, HER2-positive advanced gastric cancer. Gastric Cancer 22: 1238-1246, 2019. DOI:10.1007/s10120-019-00973-5
Janjigian YY, 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. Lancet 398:27-40, 2021. DOI:10.1016/S0140-6736(21)00797-2
Kang YK, Chen LT, Ryu MH 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 randomized, multicenter, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23:234-247, 2022. DOI:10.1016/S1470-2045(21)00692-6
Thuss-Patience PC, Kretzschmar A, Bichev D et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 47:2306-2314, 2011. DOI:10.1016/j.ejca.2011.06.002
Hironaka S, Ueda S, Yasui H et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 31:4438-4444, 2013. DOI:10.1200/JCO.2012.48.5805
Ford HE, Marshall A, Bridgewater JA et al. Docetaxel versus active symptom control for refractory esophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomized controlled trial. Lancet Oncol 15:78-86, 2014. DOI:10.1016/S1470-2045(13)70549-7
Wagner AD, Syn NL, Moehler M et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 8:Cd004064, 2017. DOI:10.1002/14651858.CD004064.pub4
Brown J, Liepa AM, Bapat B et al. Clinical management patterns of advanced and metastatic gastro-oesophageal carcinoma after fluoropyrimidine/platinum treatment in France, Germany, Spain and the United Kingdom. Eur J Cancer Care (Engl) 29:e13213, 2020. DOI:10.1111/ecc.13213
Wilke H, Muro K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomized phase 3 trial. Lancet Oncol 15:1224-1235, 2014. DOI:10.1016/S1470-2045(14)70420-6
Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomized, multicenter, placebo-controlled, phase 3 trial. Lancet 383:31-39, 2014. DOI:10.1016/S0140-6736(13)61719-5
Shitara K, Özgüroğlu M, Bang YJ et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomized, open-label, controlled, phase 3 trial. Lancet 392:123-133, 2018. DOI:10.1016/S0140-6736(18)31257-1
Chao J, Fuchs CS, Shitara K et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol 7:895-902, 2021. DOI:10.1001/jamaoncol.2021.0275
Marabelle A, Fakih M, Lopez J et al. Association of tumor mutational burden with outcomes in patients with advanced solid tumors treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21:1353-1365, 2020. DOI:10.1016/S1470-2045(20)30445-9
Kim St, Cristescu R, Bass AJ et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 9:1449-1458, 2018. DOI:10.1038/s41591-018-0101-z
Gu L, Chen M, Guo D et al. PD-L1 and gastric cancer prognosis: A systematic review and meta-analysis. PLoS One 12:e0182692, 2017. DOI:10.1371/journal.pone.0182692
Massetti M, Lindinger M, Lorenzen S. PD-1 blockade elicits ongoing remission in two cases of refractory Epstein-Barr Virus associated metastatic gastric carcinoma. Oncol Res Treat 45:375-379, 2022. DOI:10.1159/000523754
Makiyama A, Sukawa Y, Kashiwada T et al. Randomized, phase II study of trastuzumab beyond progression in patients with HER2-positive advanced gastric or gastroesophageal junction cancer: WJOG7112G (T-ACT study). J Clin Oncol 38:1919-1927, 2020. DOI:10.1200/JCO.19.03077
Satoh T, Xu RH, Chung HC et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase III study. J Clin Oncol 32:2039-2049, 2014. DOI:10.1200/JCO.2013.53.6136
Lorenzen S, Riera Knorrenschild J, Haag GM et al. Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Eur J Cancer 51:569-576, 2015. DOI:10.1016/j.ejca.2015.01.059
Thuss-Patience PC, Shah MA, 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 randomized, open-label, adaptive, phase 2/3 study. Lancet Oncol 18:640-653, 2017. DOI:10.1016/S1470-2045(17)30111-0
Shitara K, Bang YJ, Iwasa S et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020. DOI:10.1056/NEJMoa2004413
Shitara K, Doi T, Dvorkin M et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19:1437-1448, 2018. DOI:10.1016/S1470-2045(18)30739-3
Ilson DH, Tabernero J, Prokharau A et al. Efficacy and safety of trifluridine/tipiracil treatment in patients with metastatic gastric cancer who had undergone gastrectomy: subgroup analyses of a randomized clinical trial. JAMA Oncol 6:e193531, 2020. DOI:10.1001/jamaoncol.2019.3531
Tabernero J, Shitara K, Zaanan A et al. Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study. ESMO Open 6:100200, 2021. DOI:10.1016/j.esmoop.2021.100200
Kang YK, Boku N, Satoh T et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 390:2461-2471, 2017. DOI:10.1016/S0140-6736(17)31827-5
Mateo J, Chakravarty D, Dienstmann R et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol 29:1895-1902, 2018. DOI:10.1093/annonc/mdy263
Fujitani K, Yang HK, Mizusawa J et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomized controlled trial. Lancet Oncol 17:309-318, 2016. DOI:10.1016/S1470-2045(15)00553-7
Markar SR, Mikhail S, Malietzis G et al. Influence of surgical resection of hepatic metastases from gastric adenocarcinoma on long-term survival: systematic review and pooled analysis. Ann Surg 263:1092-1101, 2016. DOI:10.1097/SLA.0000000000001542
Kataoka K, Kinoshita T, Moehler M et al. Current management of liver metastases from gastric cancer: what is common practice? New challenge of EORTC and JCOG. Gastric Cancer 20:904-912, 2017. DOI:10.1007/s10120-017-0696-7
Kroese TE, van Hillegersberg R, Schoppmann S et al; OMEC working group. Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumor boards in Europe. Eur J Cancer 164:18-29, 2022. DOI:10.1016/j.ejca.2021.11.032
Al-Batran SE, Homann N, Pauligk C et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 Trial. JAMA Oncol 3:1237-1244, 2017. DOI:10.1001/jamaoncol.2017.0515
Lu Z, Fang Y, Liu C et al. Early interdisciplinary supportive care in patients with previously untreated metastatic esophagogastric cancer: a phase III randomized controlled trial. J Clin Oncol 39:748-756, 2021. DOI:10.1200/JCO.20.01254
Mansoor W, Roeland EJ, Chaudhry A et al. Early weight loss as a prognostic factor in patients with advanced gastric cancer: analyses from REGARD, RAINBOW, and RAINFALL phase III studies. Oncologist 26:e1538-e1547, 2021. DOI:10.1002/onco.13836
Hacker UT, Hasenclever D, Linder N et al. Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial. J Cachexia Sarcopenia Muscle 11:135-144, 2020. DOI:10.1002/jcsm.12484
Hacker UT, Hasenclever D, Baber R et al. Modified Glasgow prognostic score (mGPS) is correlated with sarcopenia and dominates the prognostic role of baseline body composition parameters in advanced gastric and esophagogastric junction cancer patients undergoing first-line treatment from the phase III EXPAND trial. Ann Oncol 33:685-692, 2022. DOI:10.1016/j.annonc.2022.03.274
Kondrup J, Allison SP, Elia M, Vellas B, Plauth M; Educational and Clinical Practice Committee, European Society of Parenteral and Enteral Nutrition (ESPEN). ESPEN guidelines for nutrition screening 2002. Clin Nutr 22:415-421, 2003. DOI:10.1016/s0261-5614(03)00098-0
Dai Y, Li C, Xie Y et al. Interventions for dysphagia in esophageal cancer. Cochrane Database Syst Rev 2014(10):Cd005048, 2014. DOI:10.1002/14651858.CD005048.pub4
Bergquist H, Wenger U, Johnsson E et al. Stent insertion or endoluminal brachytherapy as palliation of patients with advanced cancer of the esophagus and gastroesophageal junction. Results of a randomized, controlled clinical trial. Dis Esophagus 18:131-139, 2005. DOI:10.1111/j.1442-2050.2005.00467.x
Mulazzani GEG, Corti F, Della Valle S, Di Bartolomeo M. Nutritional support indications in gastroesophageal cancer patients: from perioperative to palliative systemic therapy. A comprehensive review of the last decade. Nutrients 13:2766, 2021. DOI:10.3390/nu13082766
Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2021 (6th edition). Gastric Cancer 26:1-25, 2023. DOI:10.1007/s10120-022-01331-8
Songun I, Putter H, Meershoek-Klein Kranenbarg E et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomized nationwide Dutch D1D2 trial. Lancet Oncol 11:439-449, 2010. DOI:10.1016/S1470-2045(10)70070-X
Worthley DL, Phillips KD, Wayte N et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut 61:774-779, 2012. DOI:10.1136/gutjnl-2011-300348
Begg CB, Cramer LD, Hoskins WJ, Brennan MF. Impact of hospital volume on operative mortality for major cancer surgery. JAMA 280:1747-1751, 1998. PMID:9842949
Bennett C, Wang Y, Pan T. Endoscopic mucosal resection for early gastric cancer. Cochrane Database Syst Rev 4:CD004276, 2009. DOI:10.1002/14651858.CD004276.pub3
Dikken JL, Jansen EP, Cats A et al. Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence patterns in gastric cancer. J Clin Oncol 28:2430-2436, 2010. DOI:10.1200/JCO.2009.26.9654
Degiuli M, Sasako M, Ponti A et al. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg 101:23-31, 2014. DOI:10.1002/bjs.9345
Mortensen K, Nilsson M, Slim K et al. Consensus guidelines for enhanced recovery after gastrectomy: Enhanced Recovery After Surgery (ERAS) Society recommendations. Br J Surg 101:1209-1229, 2014. DOI:10.1002/bjs.9582
Macdonald JS, Smalley SR, Benedetti J et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001. DOI:10.1056/NEJMoa010187
Dikken JL, van Sandick JW, Allum WH et al. Differences in outcomes of esophageal and gastric cancer surgery across Europe. Br J Surg 100:83-94, 2013. DOI:10.1002/bjs.8966
Verheij M, Jansen EPM, van Grieken NCT et al. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomized phase 3 trial. Lancet Oncol 19:616-628, 2018. DOI:10.1016/S1470-2045(18)30132-3
Park SH, Lim DH, Sohn TS et al. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol 32:368-374, 2021. DOI:10.1016/j.annonc.2020.11.017
Stiekema J, Trip AK, Jansen EP et al. The prognostic significance of an R1 resection in gastric cancer patients treated with adjuvant chemoradiotherapy. Ann Surg Oncol 21:1107-1114, 2014. DOI:10.1245/s10434-013-3397-4
Al-Batran SE, Pauligk C, Homann N et al. The feasibility of triple-drug chemotherapy combination in older adult patients with esophagogastric cancer: a randomized trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+). Eur J Cancer 49:835-842, 2013. DOI:10.1016/j.ejca.2012.09.025
Fujimoto S, Takahashi M, Mutou T et al. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. Cancer 85:529-534, 1999. PMID:10091726
Fujimura T, Yonemura Y, Muraoka K et al. Continuous hyperthermic peritoneal perfusion for the prevention of peritoneal recurrence of gastric cancer: randomized controlled study. World J Surg 18:150-155, 1994. DOI:10.1007/BF00348209
Glehen O, Gilly FN, Arvieux C et al. Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Ann Surg Oncol 17:2370-2377, 2010. DOI:10.1245/s10434-010-1039-7
Xiang XJ, Zhang L, Qiu F et al. A phase II study of capecitabine plus oxaliplatin as first-line chemotherapy in elderly patients with advanced gastric cancer. Chemotherapy 58:1-7, 2012. DOI:10.1159/000335585
Glehen O, Passot G, Villeneuve L et al. GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. BMC Cancer 14:183, 2014. DOI:10.1186/1471-2407-14-183
Rau B, Lang H, Königsrainer A et al. Effect of hyperthermic intraperitoneal chemotherapy on cytoreductive surgery in gastric cancer with synchronous peritoneal metastases: the phase III GASTRIPEC-I trial. J Clin Oncol 42:146-156, 2023. DOI:10.1200/JCO.22.02867
Pernot S, Voron T, Perkins G et al. Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol 21:11428-11438, 2015. DOI:10.3748/wjg.v21.i40.11428
Charalampakis N, Nogueras Gonzalez GM, Elimova E et al. The proportion of signet ring cell component in patients with localized gastric adenocarcinoma correlates with the degree of response to pre-operative chemoradiation. Oncology 90:239-247, 2016. DOI:10.1159/000443506
Heger U, Blank S, Wiecha C et al. Is preoperative chemotherapy followed by surgery the appropriate treatment for signet ring cell containing adenocarcinomas of the esophagogastric junction and stomach? Ann Surg Oncol 21:1739-1748, 2014. DOI:10.1245/s10434-013-3462-z
Messager M, Lefevre JH, Pichot-Delahaye V et al. FREGAT working group - FRENCH. The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study. Ann Surg 254:684-693, 2011. DOI:10.1097/SLA.0b013e3182352647
Piessen G, Messager M, Le Malicot K et al. Phase II/III multicenter randomized controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus perioperative chemotherapy for resectable gastric signet ring cell adenocarcinomas - PRODIGE 19 - FFCD1103 - ADCI002. BMC Cancer 13:281, 2013. DOI:10.1186/1471-2407-13-281
Eveno C, Adenis A, Bouche O et al. Adjuvant chemotherapy versus perioperative chemotherapy for resectable gastric signet ring cell gastric cancer: a multicenter, randomized phase II study (PRODIGE 19). J Clin Oncol 37,15_suppl, 2019. DOI:10.1200/JCO.2019.37.15_suppl.4019
Hofheinz RD, Merx K, Haag GM et al. FLOT versus FLOT/trastuzumab/pertuzumab perioperative therapy of human epidermal growth factor receptor 2-positive resectable esophagogastric adenocarcinoma: a randomized phase II trial of the AIO EGA study group. J Clin Oncol 40:3750-3761, 2022. DOI:10.1200/JCO.22.00380
André T, Tougeron D, Piessen G et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study. J Clin Oncol 41:255-265, 2023. DOI:10.1200/JCO.22.00686
Rha SY, Oh DY, Yañez P et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicenter, randomized, double-blind, phase 3 trial. Lancet Oncol 24:1181-1195, 2023. DOI:10.1016/S1470-2045(23)00515-6
Sun JM, Shen L, Shah MA et al; KEYNOTE-590 Investigators. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced esophageal cancer (KEYNOTE-590): a randomized, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021. DOI:10.1016/S0140-6736(21)01234-4
Leone AG, Mai AS, Fong KY et al. Immune checkpoint inhibitors in advanced gastroesophageal adenocarcinoma: a series of patient-level meta-analyses in different programmed death-ligand 1 subgroups. ESMO Open 9:103962, 2024. DOI:10.1016/j.esmoop.2024.103962
Qiu MZ, Oh DY, 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. BMJ 385:e078876, 2024. DOI:10.1136/bmj-2023-078876
Shitara K, Lordick F, Bang YJ 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. Lancet 401:1655-1668, 2023. DOI:10.1016/S0140-6736(23)00620-7
Shitara K, Shah MA, Lordick F et al. Zolbetuximab in gastric or gastroesophageal junction adenocarcinoma. N Engl J Med 391:1159-1162, 2024. DOI:10.1056/NEJMc2409512
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. Lancet Oncol 24:744-756, 2023. DOI:10.1016/S1470-2045(23)00215-2
Yamaguchi K, Bang YJ, Iwasa S et al. Trastuzumab deruxtecan in anti-human epidermal growth factor receptor 2 treatment-naive patients with human epidermal growth factor receptor 2-low gastric or gastroesophageal junction adenocarcinoma: exploratory cohort results in a phase II trial. J Clin Oncol 41:816-825, 2023. DOI:10.1200/JCO.22.00575
Asif B, Sarvestani AL, Gamble LA et al. Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study. Lancet Oncol 24:383-391, 2023. DOI:10.1016/S1470-2045(23)00057-8
Baretton GB, Lordick F, Gaiser T et al; Interdisciplinary Expert Group. Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. J Cancer Res Clin Oncol 149:16231-16238, 2023. DOI:10.1007/s00432-023-05180-5
Hess T, Maj C, Gehlen J et al. Dissecting the genetic heterogeneity of gastric cancer. EBioMedicine 92:104616, 2023. DOI:10.1016/j.ebiom.2023.104616
European Medicines Agency. Keytruda. https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda
Janjigian Y, Ajani J, Moehler M et al. First-line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III CheckMate 649 trial. J Clin Oncol 42:2012-2020, 2024. DOI:10.1200/JCO.23.01601
Janjigian YY, Al-Batran SE, Wainberg ZA et al; MATTERHORN Investigators. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med 393:217-230, 2025. DOI:10.1056/NEJMoa2503701
Janjigian YY, Kawazoe A, Bai Y et al. Pembrolizumab in HER2-positive gastric cancer. N Engl J Med 391:1360-1362, 2024. DOI:10.1056/NEJMc2408121
Kolbe K, Haffner I, Schierle K et al. Deviating HER2 test results in gastric cancer: analysis from the prospective multicenter VARIANZ study. J Cancer Res Clin Oncol 149:1319-1329, 2023. DOI:10.1007/s00432-022-04208-6
Li D, Jiang SF, Lei NY et al. Effect of Helicobacter pylori eradication therapy on the incidence of noncardia gastric adenocarcinoma in a large diverse population in the United States. Gastroenterology 165:391-401, 2023. DOI:10.1053/j.gastro.2023.04.026
Shitara K, Rha SY, Wyrwicz L et al. Pembrolizumab plus chemotherapy versus chemotherapy as perioperative therapy in locally advanced gastric and gastroesophageal junction cancer: final analysis of the randomized, phase III KEYNOTE-585 study. J Clin Oncol 2025 Aug 19:JCO2500486. DOI:10.1200/JCO-25-00486
Usui Y, Taniyama Y, Endo M et al. Helicobacter pylori, homologous-recombination genes, and gastric cancer. N Engl J Med 388:1181-1190, 2023. DOI:10.1056/NEJMoa2211807
Uzunparmak B, Haymaker C, Raso G et al. HER2-low expression in patients with advanced or metastatic solid tumors. Ann Oncol 34:1035-1046, 2023. DOI:10.1016/j.annonc.2023.08.005
van Velzen MJM, Braemer M, Nieuwenhuijzen GAP et al. Incidence, stage, treatment, and survival of noncardia gastric cancer. JAMA Netw Open 6:e2330018, 2023. DOI:10.1001/jamanetworkopen.2023.30018
Wagner AD, Grabsch HI, Mauer ME et al EORTC-1203 GITC "INNOVATION": Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy of HER-2 positive stomach cancer: overall survival results. J Clin Oncol 43(4_suppl), 2025. DOI:10.1200/JCO.2025.43.4_suppl.LBA331
Zaanan A, Bouché O, de la Fouchardière C et al. TFOX versus FOLFOX in first-line treatment of patients with advanced HER2-negative gastric or gastro-oesophageal junction adenocarcinoma (PRODIGE 51- FFCD-GASTFOX): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 26:732-744, 2025. DOI:10.1016/S1470-2045(25)00130-5
Raimondi A, Lonardi S, Murgioni S et al. Tremelimumab and durvalumab as neoadjuvant or non-operative management strategy of patients with microsatellite instability-high resectable gastric or gastroesophageal junction adenocarcinoma: the INFINITY study by GONO. Ann Oncol 36:285-296, 2025. DOI:10.1016/j.annonc.2024.11.016
Lordick F, Mauer ME, Stocker G et al. Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIGE study. Ann Oncol 36:197-207, 2025. DOI:10.1016/j.annonc.2024.10.829
Kang YK, Terashima M, Kim YW et al. Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 9:705-717, 2024. DOI:10.1016/S2468-1253(24)00156-0
Hoeppner J, Brunner T, Schmoor C et al. Perioperative chemotherapy or preoperative chemoradiotherapy in esophageal cancer. N Engl J Med 392:323-335, 2025. DOI:10.1056/NEJMoa2409408
Leong T, Smithers BM, Michael M et al. Preoperative chemoradiotherapy for resectable gastric cancer. N Engl J Med 391:1810-1821, 2024. DOI:10.1056/NEJMoa2405195
Al-Batran SE, Lorenzen S, Riera J et al. Effect of chemotherapy/targeted therapy alone vs. chemotherapy/targeted therapy followed by radical surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction: The IKF-575/RENAISSANCE phase III trial. J Clin Oncol 42(17_suppl), 2024 DOI:10.1200/JCO.2024.42.17_suppl.LBA4001
Onkopedia guideline on antiemesis in systemic tumor therapy (2021). https://www.onkopedia.com/s/OSE8TN
AWMF S3 guideline on complementary medicine in the treatment of oncology patients (2.0, 2024). https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/downloads/leitlinien/komplementär/version_2/ll_komplementärmedizin_langversion_2.0
Li J, Woods SL, Healey S et al. Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant. Am J Hum Genet 2016 98:830-842, 2016. DOI:10.1016/j.ajhg.2016.03.001
Gallanis AF, Bowden C, Lopez R et al. Adolescents and young adults with germline CDH1 variants and the risk of overtreatment. J Natl Cancer Inst 117:1027-1035, 2025. DOI:10.1093/jnci/djaf002
Garcia-Pelaez J, Barbosa-Matos R, Lobo S et al. Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes. Lancet Oncol 24:91-106, 2023. DOI:10.1016/S1470-2045(22)00643-X
Lee CYC, Olivier A, Honing J et al. Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study. Lancet Oncol 24:107-116, 2023. DOI:10.1016/S1470-2045(22)00700-8
van der Sluis L, van Dieren JM, van der Post RS, Bisseling TM. Current advances and challenges in managing hereditary diffuse gastric cancer (HDGC): a narrative review. Hered Cancer Clin Pract 22:21, 2024. DOI:10.1186/s13053-024-00293-5
Smyth EC, Kim KM, Rha SY et al. FGFR2b protein overexpression: An emerging biomarker in gastric and gastroesophageal junction adenocarcinoma. Cancer Treat Rev 139:102971, 2025. DOI:10.1016/j.ctrv.2025.102971
Sędłak K, Kobiałka S, Pelc Z et al. Staging laparoscopy in gastric cancer patients treated with curative intent: a European GASTRODATA cohort study. Ann Surg Oncol. 2025 Jul 26. DOI:10.1245/s10434-025-17905-6
Shitara K, Van Cutsem E, Gümüş M et al; DESTINY-Gastric04 Trial Investigators. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med 393:336-348, 2025. DOI:10.1056/NEJMoa2503119
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