Approach

Multidisciplinary evaluation is strongly encouraged before therapy is started.[25][26] The goal of treatment is to cure patients with localised disease, to improve quality of life in patients with metastatic disease, and to palliate symptoms.

Localised disease

Surgery is the primary treatment option for patients with localised (T1b-T2, N0) gastric cancer, with a goal of complete resection with negative margins.[25][26] Patients with carcinoma in situ (Tis) or T1a tumours may be candidates for endoscopic therapies.[25]

For more advanced disease (T2 or higher, and any N), perioperative or adjuvant chemotherapy in addition to gastrectomy is recommended.[25][26]

Surgery

The aim is complete resection of the primary tumour with negative margins. The type of resection (i.e., subtotal or total gastrectomy) and the extent of lymph node dissection is an area of debate.[25]

Subtotal gastrectomy is the preferred approach for distal gastric cancer.[25] Patients undergoing total gastrectomy for distal gastric cancers have no survival benefit compared with those undergoing subtotal gastrectomy.[33][34]

Proximal gastrectomy or total gastrectomy is usually recommended for patients with proximal tumours.[25]

The American Society for Gastrointestinal Endoscopy (ASGE) suggests surgery over endoscopic approaches in lesions that are poorly differentiated and of any size; however, surgery is not recommended in early-stage lesions that are well- or moderately differentiated, intestinal type, and measure ≤3 cm.[35]

Patients with superficial early gastric cancer (Tis or T1a) can be treated with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).[25] Appropriate candidates for EMR are those with adenocarcinoma confined to the mucosa, <2 cm in diameter, low or moderate degree of differentiation, without evidence of ulcer, and with no lymphovascular involvement.[36][37][38]

The factors to consider while choosing between ESD and EMR as per ASGE include differentiation (well or moderate vs. poor), morphology (ulcerated vs. non-ulcerated), type of cancer (intestinal vs. diffuse), and size.[35]​ Either ESD or EMR can be used in early-stage, well- or moderately differentiated, non-ulcerated, intestinal type gastric cancers measuring <20 mm, while ESD is preferred over EMR in well- or moderately differentiated lesions measuring 20-30 mm, with or without ulceration.[35]

Studies have failed to show survival benefit between D1 dissection (dissection of the perigastric nodes) and D2 dissection (dissection of perigastric nodes and nodes along the left gastric, hepatic, coeliac, and splenic arteries).[25] D2 dissection may be associated with lower rates of locoregional recurrence and gastric cancer-related death, but may also be associated with higher rates of morbidity and mortality. A modified (spleen-preserving) D2 dissection is recommended by, and considered a standard at, many institutions. The addition of para-aortic dissection to D2 dissection does not improve survival.[39][40][41] [ Cochrane Clinical Answers logo ]

Laparoscopic resection

Short-term outcomes from randomised controlled trials suggest that laparoscopic gastrectomy for clinical stage 1 gastric cancer is safe and has the benefit of lower occurrence of wound complication compared with conventional open gastrectomy, although evidence is low quality.[42][43][44] [ Cochrane Clinical Answers logo ]

Other studies show no difference in short-term mortality between laparoscopic and open gastrectomy and no evidence for any differences in short-term or long-term outcomes between laparoscopic and open gastrectomy, based on low-quality evidence.[45]

Chemoradiotherapy

Postoperative chemoradiotherapy is recommended for patients who have undergone gastrectomy with limited (D0 or D1) lymph node dissection. Postoperative chemoradiotherapy is associated with a significantly lower local recurrence rate in this group of patients, compared with surgery alone.[46][47][48] The preferred regimen is radiotherapy and fluorouracil or capecitabine.[25]

Postoperative chemoradiotherapy has not been shown to reduce local recurrence rates in patients who have undergone gastrectomy with D2 lymph node dissection; these patients should be offered postoperative chemotherapy with a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin instead.[25][46][49]

Preoperative chemoradiotherapy may be offered as it potentially downstages the cancer and increases resectability.[50] Recommended regimens include radiotherapy and:[25]

  • Paclitaxel plus carboplatin

  • Fluorouracil plus oxaliplatin

  • Fluorouracil plus cisplatin; or

  • Fluoropyrimidine monotherapy.

Patients with localised disease who are not surgical candidates should be offered chemoradiotherapy. The preferred regimens consist of radiotherapy and fluorouracil plus oxaliplatin or cisplatin.[25] Other recommended regimens include a fluoropyrimidine (fluorouracil or capecitabine) plus paclitaxel. Overall survival is higher in patients with locally advanced gastric cancer treated with chemoradiotherapy, compared with patients treated with radiotherapy alone.[51][52]

Chemotherapy

Perioperative chemotherapy has been shown to improve overall survival in patients with stage 2 or higher disease compared with surgery alone.[53][54]​ The preferred regimen for most patients with good-to-moderate performance status is FLOT (fluorouracil, folinic acid, oxaliplatin, docetaxel).[25] Fluorouracil plus cisplatin is an alternative regimen.[25] FLOT is associated with better outcomes in patients with resectable gastric and gastro-oesophageal junction cancer treatment compared with other regimens.[55]

Postoperative chemotherapy with a fluoropyrimidine plus oxaliplatin is indicated for patients who have undergone gastrectomy with primary D2 lymph node dissection.[25]

Advanced and metastatic disease

Chemotherapy improves quality of life and survival when compared with best supportive care in patients with metastatic gastric cancer.[56][57][58] [ Cochrane Clinical Answers logo ] ​ Immunotherapy plus chemotherapy is associated with improved survival, compared with chemotherapy alone, in patients with metastatic gastric cancer.[59][60][61][62][63]

Chemotherapy regimens should be chosen in the context of the patient's performance status (PS), medical comorbidities, toxicity profile, and tumour biomarker expression.[25] First-line treatment differs based on tumour HER2 expression.

Two-drug cytotoxic regimens are preferred for patients with advanced disease because of lower toxicity; three-drug regimens are reserved for medically fit patients with good PS and access to frequent toxicity evaluation.[25]

First-line treatment: HER2 over-expression negative adenocarcinoma

First-line treatment for HER2 over-expression negative metastatic disease includes a combination of a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin plus nivolumab.[25] Results from open-label and double-blind randomised controlled trials indicate that the addition of nivolumab to chemotherapy improves median survival, significantly prolongs disease-free survival, and improves progression and overall survival, compared with chemotherapy alone.[60][61][62][63]​​​​​​ Nivolumab is the first immunotherapy approved for first-line treatment of gastric cancer. The National Institute for Health and Care Excellence in the UK recommends nivolumab with platinum- and fluoropyrimidine-based chemotherapy (within its marketing authorisation) for treating HER2-negative advanced or metastatic gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma in patients with tumours expressing PD-L1 having a combined positive score of 5+.[64]​ The American Society of Clinical Oncology also recommends the same combination chemotherapy as the first-line therapy in patients with HER2-negative gastric adenocarcinoma with tumours expressing PD-L1 having a combined positive score of 5+.[65] Alternatively, a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin is recommended. Pembrolizumab may be added to this combination for tumours expressing PD-L1 having a combined positive score of 1+.[25][66]​​ The American Society of Clinical Oncology recommends nivolumab for tumours expressing PD-L1 having a combined positive score of 5+ and pembrolizumab for tumours expressing PD-L1 having a combined positive score of 10+, in combination with platinum- and fluoropyrimidine-based chemotherapy in patients with HER2-negative oesophageal or gastro-oesophageal junction adenocarcinoma.[65]

Studies have demonstrated that fluorouracil can be replaced by capecitabine, and cisplatin by oxaliplatin (except in regimens including irinotecan).[25][67][68]​ Oxaliplatin is preferred over cisplatin owing to its lower toxicity.[25][67][69]​ Folinic acid is indicated with certain fluorouracil-based regimens. Depending on availability, the regimens may be used with or without folinic acid.[25]

In patients with peritoneal carcinoma as the only disease, intraperitoneal chemotherapy/hyperthermic intraperitoneal chemotherapy may be considered.[25]

Alternative first-line regimens include:[25]

  • Fluorouracil plus irinotecan

  • Docetaxel with or without cisplatin

  • Fluoropyrimidine monotherapy (fluorouracil or capecitabine)

  • Docetaxel plus cisplatin or oxaliplatin plus fluorouracil.

First-line treatment: HER2 over-expression positive adenocarcinoma

In tumours with HER2 over-expression, scoring 3+ by immunohistochemistry (IHC) or 2+ by IHC and fluorescence in situ hybridisation (FISH) positive, trastuzumab (a humanised monoclonal antibody that acts on the HER2 receptor) should be added to chemotherapy.[25] This combination has been shown to improve overall survival in patients with advanced gastric cancer.[59] A fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin plus trastuzumab plus pembrolizumab is the recommended first line therapy for tumours expressing PD-L1 having a combined positive score of 1+.[25] Oxaliplatin is preferred over cisplatin owing to its lower toxicity.[25]

Second-line and subsequent therapy

Second-line and subsequent therapies depend on prior therapy and the patient's performance status.

Choice of therapy generally does not depend on tumour HER2 over-expression status (except for trastuzumab deruxtecan, an antibody-drug conjugate composed of trastuzumab covalently linked to a topoisomerase I inhibitor). Targeted therapies may be indicated for patients with high microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) tumours, patients with high tissue tumour mutation burden (tTMB-high) status, and patients with neurotrophic tropomyosin-related kinase (NTRK) gene fusion-positive tumours.[25]

Ramucirumab (a vascular endothelial growth factor inhibitor) plus paclitaxel is considered a second-line therapy for patients with metastatic disease.[25] In one trial of patients with metastatic gastric adenocarcinoma (RAINBOW trial), ramucirumab added to paclitaxel (as a second-line therapy) demonstrated a significant improvement in both progression-free survival and overall survival over paclitaxel alone.[70]

Ramucirumab monotherapy has been shown to improve median overall survival in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who have disease progression after first-line platinum- or fluoropyrimidine-containing chemotherapy.[71]

Trastuzumab deruxtecan is recommended as second- or third-line treatment for patients with HER2 over-expression positive adenocarcinoma who have received prior trastuzumab-based therapy.[25] Compared with standard therapies, trastuzumab deruxtecan significantly improved response rate and overall survival in an open-label, randomised phase 2 trial of patients with treatment-refractory HER2-positive gastric or gastro-oesophageal junction adenocarcinoma.[72] Myelosuppression and interstitial lung disease were reported in patients receiving the drug.

Other recommended second-line therapies include: monotherapy with docetaxel, paclitaxel, or irinotecan; or fluorouracil plus irinotecan.[25] A taxane or irinotecan, as a single agent or in combination, provides a modest improvement in overall survival compared with best supportive care.[73][74]

Trifluridine/tipiracil is considered a third-line therapy.[25] It is approved for patients with unresectable metastatic gastric adenocarcinoma, who have received at least two previous chemotherapy regimens and experienced radiological disease progression. Approval was based on the results of one double-blind, placebo-controlled phase 3 trial (TAGS trial). The trial reported significantly improved median overall survival among pre-treated patients with non-resectable metastatic gastric adenocarcinoma who were randomised to trifluridine/tipiracil (5.7 vs. 3.6 months in the placebo group; hazard ratio 0.69, 95% CI 0.56 to 0.85).[75] Trifluridine/tipiracil was also associated with improved progression-free survival. The most frequently reported grade 3 (severe but not life-threatening), or worse, adverse events in the trifluridine/tipiracil group were neutropenia (114 [34%]), anaemia (64 [19%]), and leukopenia (31 [9%]). The National Institute for Health and Care Excellence in the UK recommends trifluridine/tipiracil (within its marketing authorisation) for treating metastatic gastric cancer and gastro-oesophageal junction adenocarcinoma in adults who have had ≥2 treatment regimens.[76]

Pembrolizumab and dostarlimab are PD-1 blocking monoclonal antibodies that may be considered for patients with high microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) tumours.[25] Pembrolizumab may also be considered for patients with high tissue tumour mutation burden (tTMB-high) status.[25] In one phase 2 study, 29% of patients with tTMB-high solid tumours who received pembrolizumab as a second-line or subsequent treatment were more likely to respond to pembrolizumab, compared with 6% of patients with lower tTMB status.[77]

Dostarlimab has shown an objective response rate of 41.6% among patients with solid MSI-H/dMMR tumours in one phase 1 open-label study.[78]

Entrectinib or larotrectinib, both tropomyosin receptor kinase (TRK) inhibitors, may be considered for patients with neurotrophic tropomyosin-related kinase (NTRK) gene fusion positive tumours.[25]

Palliative care/best supportive care

The aim of best supportive care is to relieve the patients' symptoms, regardless of the stage of disease, to support the best quality of life for them and their families. For gastric cancer, interventions to relieve major symptoms may prolong life.[25]

Endoscopic treatment, interventional radiology, gastrectomy, and chemotherapy may relieve symptoms such as pain, bleeding, nausea and vomiting, and obstruction.[25]

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