Therapy structure

Multidisciplinary planning is required for any initial treatment recommendation. It should be developed in a qualified multidisciplinary tumor board.

Core members of the multidisciplinary board include the following disciplines: Visceral Surgery, Medical Oncology, Radiation Oncology, Gastroenterology, Radiology and Pathology. Whenever possible, patients should be treated in clinical trials.

Therapy is stage adapted. A treatment algorithm for the stage-adapted management of gastric cancer is shown in Fig. 1.

Fig. 1

Algorithm for stage-adapted management of gastric cancer

Stage IA—T1a

Since the probability of lymph node metastasis in mucosal gastric cancer (T1a) is very low, endoscopic resection (ER) may be sufficient [10]. If histopathologic workup after endoscopic resection reveals that tumor infiltration extends into the submucosa (T1b), surgical resection with systematic lymphadenectomy should be performed, as lymph node metastases may already be present in up to 30% of cases.

Gastric cancers classified as pT1a cN0 cM0 should be treated with endoscopic resection, considering the adapted Japanese criteria [1, 11]. A (limited) surgical approach is an alternative.

Perioperative or adjuvant chemotherapy is not indicated for stage IA (T1a) patients.

Stage IA—T1b

For stage IA gastric cancer with infiltration of the submucosa, the risk of lymph node metastases is 25–28%. The 5-year survival rate is 70.8% for all stage IA in the SEER database [12], and the cancer-specific survival rate at 10 years is 93% in the Italian IRGGC analysis. Therapy of choice in stage I (T1b category) is radical surgical resection (subtotal, total, or transhiatal extended gastrectomy). Limited resection can be recommended only in exceptional cases due to the imprecise accuracy of pre-therapeutic staging.

A benefit from perioperative or adjuvant chemotherapy has not been established for stage IA (T1b) patients.

Stage IB—III

In stage IB—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 tumor-free margins of 5 and 8 cm for intestinal and diffuse tumor growth types, respectively, are no longer accepted. The scientific evidence for definitive recommendations is low. A negative oral margin in the intraoperative frozen section is crucial.

Perioperative chemotherapy with a platinum derivative, a fluoropyrimidine, and an anthracycline significantly prolonged overall survival in patients with resectable gastric cancer in the MAGIC trial [13]. In the French FNCLCC/FFCD multicenter study, perioperative chemotherapy with a platinum derivative and a fluoropyrimidine without anthracycline showed a comparable effect size on improving survival [14]. Currently, neither chemotherapy regimen is the first choice.

Treatment according to the FLOT regimen (5-fluorouracil/folinic acid/oxaliplatin/docetaxel) further improved progression-free survival (hazard ratio, HR 0.75) and overall survival (HR 0.77) in patients with stage ≥ cT2 and/or cN + compared with therapy analogous to MAGIC. The relatively higher efficacy of FLOT was shown to be consistent across relevant subgroup analyses such as age, histology, and tumor location. The rate of perioperative complications was comparable [15].

For patients with gastric cancer ≥ stage IB who received resection without prior chemotherapy (e.g., due to misdiagnosed tumor stage prior to surgery), adjuvant chemotherapy may be recommended.

In HER2-positive tumors, a benefit from combining perioperative chemotherapy with a HER2 antibody in the perioperative setting in terms of overall survival has not been proven, and therefore cannot be recommended outside of clinical trials. The AIO-PETRARCA phase 2 study showed a higher histopathologic remission rate when FLOT chemotherapy was combined with trastuzumab + pertuzumab and a trend in favor of better progression-free and overall survival [16]. These data require validation in larger and independent cohorts.

In microsatellite instability (MSI-H) localized gastric carcinoma, the efficacy of perioperative chemotherapy, based on retrospective data analyses [17], has been controversially discussed. However, more recent data from the DANTE trial show that complete and subtotal tumor remissions can be achieved with FLOT chemotherapy even in MSI-H subtype gastric carcinomas [18]. Thus, according to the current status, perioperative chemotherapy with the FLOT regimen remains indicated for MSI-H gastric cancers if tumor response is pursued. The FFCD-NEONIPIGA phase 2 study showed a high histopathologic remission rate after 12 weeks of therapy with nivolumab + ipilimumab without chemotherapy in resectable MSI-H cancers [19]. Data require validation in larger and independent patient cohorts.

After R1 resection, adjuvant radiochemotherapy may be considered.

Stage IV

The aim of therapy is usually non-curative. The first priority is systemic drug therapy, supplemented in individual cases by local therapeutic measures. Active symptom control and supportive measures such as nutritional counseling, psychosocial support, and palliative care are an integral part of treatment. The prognosis of patients with locally advanced and irresectable or metastatic (pooled here as "advanced") gastric cancer is unfavorable. Studies evaluating the benefit from chemotherapy have shown a median survival of less than 1 year [20]. However, there is evidence that chemotherapy can prolong the survival of patients with advanced gastric cancer compared to best supportive therapy alone and maintain quality of life longer [21].

Systemic tumor therapy

The current recommended algorithms for drug therapy of patients with advanced gastric cancer are shown in Figs. 2, 3, and 4.

Fig. 2

Algorithm for first-line therapy of advanced gastric cancer. 1Nivolumab is approved in Europe for PD-L1 CPS ≥ 5 according to Checkmate-649; pembrolizumab is approved in Europe for adenocarcinoma of the esophagus and esophago-gastric junction for PD-L1 CPS ≥ 10 according to Keynote-590. Positive phase III trial results in patients with PD-L1 CPS-positive gastric cancer were also reported from Keynote-859 and subgroup analyses from several first-line studies (Checkmate-649, Keynote-062, Keynote-859) show benefit for nivolumab or pembrolizumab in combination with chemotherapy in patients with MSI-H/dMMR tumors

Fig. 3

Algorithm for second-line therapy of advanced gastric cancer. 1Since many tumors lose HER2 overexpression after trastuzumab failure, reassessment of HER2 status using a fresh biopsy is recommended prior to second-line trastuzumab deruxtecan (T-DXd) therapy. 2Pembrolizumab in second line for MSI-high advanced gastric cancer is not recommended when immunotherapy was administered in first-line treatment

Fig. 4

Algorithm for third-line therapy of advanced gastric cancer. 1According to the Destiny Gastric 01 study, re-testing of HER2 status is not mandatory for third-line T-DXd therapy, 2 if not administered in second-line treatment

First-line chemotherapy, molecular targeted therapy, and immunotherapyChemotherapy

The standard of care for first-line chemotherapy of advanced gastric cancer is a platinum–fluoropyrimidine doublet. Oxaliplatin and cisplatin are comparably effective, with a more favorable side effect profile for oxaliplatin. This may contribute to a trend toward better efficacy, especially in patients > 65 years [6, 22]. Fluoropyrimidines can be administered as infusion (5-FU) or orally (capecitabine or S-1). Oral fluoropyrimidines are comparably effective to infused 5-FU [23,24,25,26]. Capecitabine is approved in combination with a platinum derivative and has been studied with both cis- and oxaliplatin in European patients. S-1 is established as a standard of care in Japan and approved in Europe for palliative first-line therapy in combination with cisplatin. Infused 5-FU should be preferred over oral medications in patients with dysphagia or other feeding problems. In elderly or frail patients, results of the phase III GO-2 trial support a dose-reduced application of oxaliplatin–fluoropyrimidine chemotherapy (to 80 or 60% of the standard dose from the beginning), resulting in fewer side effects with comparable efficacy [27].

The addition of docetaxel to a platinum–fluoropyrimidine combination (three-weekly DCF regimen) improved radiographic response rates and prolonged overall survival in a historical phase III trial, but also resulted in significantly increased side effects [28]. Other phase II trials examined modified docetaxel–platinum–fluoropyrimidine triplets and showed reduced toxicity compared with DCF in some cases [29,30,31,32]. However, the higher response rate of a triplet (37% vs. 25% [28] does not translate into prolonged survival in recent trials, which included effective second-line regimens. In the phase III JCOG1013 trial, patients with advanced gastric cancer received either cisplatin plus S-1 or cisplatin plus S-1 and docetaxel. There were no differences in radiographic response, progression-free survival, or overall survival [33]. Therefore, with increased toxicity and uncertain impact on overall survival, no recommendation can be made for first-line docetaxel–platinum–fluoropyrimidine therapy, so that a platinum–fluoropyrimidine doublet remains the standard approach. In individual cases, e.g., when fast tumor regression is urgently required, first-line therapy with a platinum–fluoropyrimidine–docetaxel triplet may be indicated.

Irinotecan-5-FU has been compared with cisplatin-5-FU and with epirubicin–cisplatin–capecitabine in randomized phase III trials and showed comparable survival with controllable side effects [34, 35]. Irinotecan-5-FU can, therefore, be considered a treatment alternative to platinum–fluoropyrimidine doublets according to scientific evidence; however, irinotecan has no formal approval in Europe for gastric cancer.

HER2-positive gastric cancer

HER2 positivity is defined in gastric cancer as the presence of protein expression with immunohistochemistry score [IHC] of 3 + or IHC 2 + and concomitant gene amplification on in situ hybridization [ISH], HER2/CEP17 ratio ≥ 2.0. HER2 diagnosis should be quality controlled [36, 37]. Trastuzumab should be added to chemotherapy in patients with HER2-positive advanced gastric cancer [21, 38]. The recommendation is based on data from the phase III ToGA trial, showing a higher response rate and prolonged survival for trastuzumab–cisplatin–fluoropyrimidine chemotherapy vs. chemotherapy alone using the above selection criteria; the additional trastuzumab side effects are minor and controllable [38]. Combinations of trastuzumab and oxaliplatin plus fluoropyrimidine show comparable results to the historical cisplatin-containing ToGA regimen [39,40,41]. Based on data from the not yet fully reported results of the Keynote-811 study, the Commission for Human Medical Products (CHMP) of the European Medicines Agency (EMA) published a positive opinion for pembrolizumab plus trastuzumab and chemotherapy as first-line treatment for HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma expressing PD-L1 (CPS ≥ 1) on 20th of July 2023 (https://www.ema.europa.eu/en/medicines/human/summaries-opinion/keytruda-10). If available, this combination should be preferred over trastuzumab plus chemotherapy in the respective patient population (Fig. 2).

Immunotherapy

The phase III CheckMate 649 trial evaluated the addition of nivolumab to chemotherapy (capecitabine-oxaliplatin or 5-FU/folinic acid-oxaliplatin) in patients with previously untreated gastric, esophago-gastric junction, or esophageal adenocarcinoma [42]. The study included patients regardless of tumor PD-L1 status; the dual primary endpoints were overall survival and progression-free survival. Approximately 60% of the study population had tumors with a PD-L1 CPS ≥ 5. Nivolumab plus chemotherapy yielded a significant improvement over chemotherapy alone in overall survival (14.4 vs. 11.1 months, HR 0.71 [98.4% CI 0.59–0.86]; p < 0.0001) and progression-free survival (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. Overall survival benefit was enriched in patients with MSI-H tumors with nivolumab plus chemotherapy vs. chemotherapy (unstratified hazard ratio 0.38; 95% confidence interval 0.17, 0.84).

The Asian phase II/III ATTRACTION-04 trial also showed a significant improvement in progression-free survival with nivolumab and first-line chemotherapy, but with no significant improvement in overall survival compared to first-line chemotherapy alone. The most likely reason for the lack of survival benefit (> 17 months in both arms) is that many patients received post-progression therapies including immunotherapy after first-line therapy [43].

The multinational randomized phase III Keynote-859 trial included 1589 patients with advanced incurable gastric cancer. Patients received either platinum–fluoropyrimidine plus pembrolizumab or the same chemotherapy plus placebo every 3 weeks. Overall survival was prolonged in the pembrolizumab group (HR 0.78 [95% CI 0.70–0.87], p < 0.0001). The effect was more pronounced in the subgroup with a PD-L1 CPS ≥ 10 (HR 0.64), whereas efficacy was lower for CPS < 10 (HR 0.86). Overall survival benefit was enriched in patients with MSI-H tumors with pembrolizumab plus chemotherapy vs. chemotherapy (hazard ratio 0.34; 95% confidence interval 0.176, 0.663) [44]. The results, thus, complement the positive trial 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 esophago-gastric junction [45].

Positive phase III trial data were also presented on two immune checkpoint (PD-1) inhibitors not currently approved in Europe. Sintilimab in combination with oxaliplatin and capecitabine improved overall survival in the phase III ORIENT-16 trial [46]. In the phase III Rationale-305 study, tislelizumab prolonged overall survival in combination with platinum–fluoropyrimidine or platinum-investigator-choice chemotherapy in patients with a positive PD-L1 score. PD-L1 was evaluated according to a scoring system not yet established internationally (the so-called Tumor Area Proportion score, TAP) [47]. ORIENT-16 and Rationale-305 have not been fully published to date, but support the overall assessment that PD-1 immune checkpoint inhibitors can improve the efficacy of chemotherapy (depending on PD-L1 expression).

Claudin 18.2

Data from the multinational phase III Spotlight trial were recently published. These show that in patients with advanced irresectable gastric cancer and tumor claudin 18.2 expression in ≥ 75% of tumor cells, zolbetuximab, a chimeric monoclonal IgG1 antibody directed against claudin 18.2, in combination with FOLFOX chemotherapy prolongs overall survival (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 applications [48]. The results of the phase III Spotlight trial are largely confirmed by the multinational phase III GLOW trial, in which the chemotherapy doublet was used as a control therapy or combination partner for zolbetuximab [49]. It remains to be seen whether the European Medicines Agency will grant approval to zolbetuximab in patients with claudin 18.2-positive metastatic and previously untreated gastric cancer.

Second-line and third-line therapy chemotherapy and anti-angiogenic therapy

Figures 3 and 4 show the algorithm for second- and third-line therapy for patients with advanced gastric cancer. The evidence-based chemotherapy options in this setting are paclitaxel, docetaxel, and irinotecan, which have comparable efficacy with different specific toxicities [21, 50,51,52]. Irinotecan may be preferred in patients with preexisting neuropathy; however, there is no EU approval. 5-FU/folinic acid plus irinotecan (FOLFIRI) is also occasionally used, but the scientific evidence for its use in second- and third-line treatment is limited [53]. Ramucirumab plus paclitaxel is the recommended standard for second-line therapy and is approved in the EU. The addition of the anti-vascular endothelial growth factor receptor-2 (VEGFR-2) antibody ramucirumab to paclitaxel increases tumor response rates and prolongs progression-free and overall survival according to the results of the phase III RAINBOW trial [54]. Already in the phase III REGARD trial, ramucirumab monotherapy showed prolonged survival compared to placebo, albeit with a low radiological response rate [55].

Immunotherapy in second- and third-line therapy

In the phase III KEYNOTE-061 trial, pembrolizumab monotherapy did not show prolonged overall survival compared with chemotherapy [56]. However, an exploratory subgroup analysis recognized a clear benefit for anti-PD-1 immunotherapy in patients with MSI-H gastric cancer [57]. Therefore, PD-1 inhibition is recommended in advanced MSI-H carcinomas at the latest in second-line treatment. Pembrolizumab has European approval for this indication based on the Keynote-061 and Keynote-158 trials [58]. Of note, pembrolizumab in second line for MSI-High advanced gastric cancer is not recommended when immunotherapy was administered in first-line treatment. Other biomarkers, particularly EBV and tumor mutation burden, are also discussed as predictive factors for PD-1 immune checkpoint inhibitor efficacy [59,60,61]. However, the evidence to date is insufficient to support a positive recommendation for immunotherapy based upon the presence of these biomarkers.

HER2-targeted therapy

Studies evaluating trastuzumab, lapatinib, and trastuzumab emtansine for second-line treatment in patients with HER2-positive carcinomas were negative [62,63,64,65]. Therefore, these drugs should not be used in gastric cancer outside of clinical trials. A randomized phase II trial showed an improvement in tumor response rate and overall survival for the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) compared with standard chemotherapy in patients with pretreated HER2-positive advanced gastric cancer [66]. Destiny-GC-04 is an ongoing study, assessing the efficacy and safety of T-DXd compared with ramucirumab and paclitaxel in participants with HER2-positive (defined as immunohistochemistry [IHC] 3 + or IHC 2 + /in situ hybridization [ISH] +) gastric or esophago-gastric junction adenocarcinoma who have progressed on or after a trastuzumab-containing regimen and have not received any additional systemic therapy (https://classic.clinicaltrials.gov/ct2/show/NCT04704934).

Prerequisites for inclusion in the Destiny-GC-01 study were at least two prior lines of therapy, prior treatment with a platinum derivative, a fluoropyrimidine, and trastuzumab, and previously confirmed HER2 positivity. The study was recruited exclusively in East Asia. The results of Destiny-GC-01 were largely confirmed in the single-arm phase II Destiny-GC-02 trial, which included non-Asian patients in second-line therapy. Mandatory was platinum–fluoropyrimidine–trastuzumab pretreatment and confirmed HER2 positivity of the tumor in a recent re-biopsy before initiating T-DXd therapy [67].

The EU approval includes the following indication of T-DXd: monotherapy for the treatment of adult patients with advanced HER2-positive adenocarcinoma of the stomach or esophago-gastric junction who have received a prior trastuzumab-based regimen.

We recommend, according to the classically established HER2 diagnostic criteria, to check the HER2 status prior to therapy with T-DXd, especially if use in second-line therapy is planned, where a valid alternative with paclitaxel–ramucirumab is available. This recommendation is based on the inclusion criteria of the Destiny-GC-02 trial and the knowledge that loss of HER2 status occurs in approximately 30% of gastric cancers after first-line therapy with trastuzumab [