Approach

Multidisciplinary evaluation is strongly encouraged before therapy is started.[26][27] The goal of treatment is to cure patients with localized disease, to improve quality of life in patients with metastatic disease, and to palliate symptoms.

Localized disease

Surgery is the primary treatment option for patients with localized (T1b-T2, N0) gastric cancer, with a goal of complete resection with negative margins.[26][27]​ Patients with carcinoma in situ (Tis) or T1a tumors may be candidates for endoscopic therapies.[26]

For more advanced disease (T2 or higher, and any N), perioperative or adjuvant chemotherapy in addition to gastrectomy is recommended.[26][27]

Surgery

The aim is complete resection of the primary tumor with negative margins. The type of resection (i.e., subtotal or total gastrectomy) and the extent of lymph node dissection is the subject of debate.[26]

Subtotal gastrectomy is the preferred approach for distal gastric cancer.[26] Patients undergoing total gastrectomy for distal gastric cancers have no survival benefit compared with those undergoing subtotal gastrectomy.[34][35]

Proximal gastrectomy or total gastrectomy is usually recommended for patients with proximal tumors.[26]

The American Society for Gastrointestinal Endoscopy (ASGE) suggests surgery over endoscopic approaches for 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.[36]

Patients with superficial early gastric cancer (Tis or T1a) can be treated with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).[26] 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.[37][38][39]

The factors to consider while choosing between ESD and EMR as per ASGE include differentiation (well or moderate vs. poor), morphology (ulcerated vs. nonulcerated), type of cancer (intestinal vs. diffuse), and size.[36]​ Either ESD or EMR can be used in early-stage, well- or moderately differentiated, nonulcerated, 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.[36]

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, celiac, and splenic arteries).[26] 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.[40][41][42] [ Cochrane Clinical Answers logo ]

Laparoscopic resection

Short-term outcomes from randomized 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.[43][44][45] [ 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.[46]

Chemoradiation therapy

Postoperative chemoradiation therapy is recommended for patients who have undergone gastrectomy with limited (D0 or D1) lymph node dissection. Postoperative chemoradiation therapy is associated with a significantly lower local recurrence rate in this group of patients, compared with surgery alone.[47][48][49]​ The preferred regimen is radiation therapy and fluorouracil or capecitabine.[26]

Postoperative chemoradiation therapy 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.[26][47][50]

Patients with localized disease who are not surgical candidates should be offered chemoradiation therapy. The preferred regimens consist of radiation therapy and fluorouracil plus oxaliplatin or cisplatin.[26] Other recommended regimens include a fluoropyrimidine (fluorouracil or capecitabine) plus paclitaxel. Overall survival is higher in patients with locally advanced gastric cancer treated with chemoradiation therapy, compared with patients treated with radiation therapy 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, leucovorin, oxaliplatin, docetaxel).[26] Fluorouracil plus cisplatin is an alternative regimen.[26] FLOT is associated with better outcomes in patients with resectable gastric and gastroesophageal 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.[26]

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 tumor biomarker expression.[26] First-line treatment differs based on tumor 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.[26]

First-line treatment: HER2 overexpression negative adenocarcinoma

Treatment with immune checkpoint inhibitors, combined with fluoropyrimidine- and platinum-based chemotherapy, is specifically preferred for HER2-negative tumors expressing PD-L1 having a combined positive score of 1+.[26]​ First-line options include:[26]

  • A fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin plus nivolumab

  • A fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin plus pembrolizumab

  • A fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin plus tislelizumab

The American Society of Clinical Oncology recommends nivolumab for tumors expressing PD-L1 having a combined positive score of 5+ and pembrolizumab for tumors expressing PD-L1 having a combined positive score of 10+, in combination with platinum- and fluoropyrimidine-based chemotherapy in patients with HER2-negative esophageal or gastroesophageal junction adenocarcinoma.[64]

Alternatively, a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin (without an immune checkpoint inhibitor) is recommended.[26]

A fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin plus zolbetuximab (an anti-CLDN18.2 monoclonal antibody) is recommended for first-line treatment of CLDN18.2 positive, unresectable locally advanced or metastatic gastric cancer.[26]​

Studies have demonstrated that fluorouracil can be replaced by capecitabine, and cisplatin by oxaliplatin (except in regimens including irinotecan).[26][65][66]​​ Oxaliplatin is preferred over cisplatin owing to its lower toxicity.[26][65][67]​​ Leucovorin is indicated with certain fluorouracil-based regimens. Depending on availability, the regimens may be used with or without leucovorin.[26]

First-line treatment: HER2 overexpression positive adenocarcinoma

In tumors with HER2 overexpression, trastuzumab (a humanized monoclonal antibody that acts on the HER2 receptor) should be added to chemotherapy.[26] 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 tumors expressing PD-L1 having a combined positive score of 1+.[26] Oxaliplatin is preferred over cisplatin owing to its lower toxicity.[26]

First-line treatment: microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) tumors

Targeted therapies may be indicated for patients with high microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) tumors. Pembrolizumab and dostarlimab are anti-PD-1 monoclonal antibodies that may be considered for patients with high MSI-H/dMMR tumors.[26]​ Other options for MSI-H/dMMR tumors include nivolumab plus ipilimumab, or a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin plus nivolumab or pembrolizumab.

First-line treatment: alternative regimens

The following alternative regimens may be used in patients with HER2 overexpression negative adenocarcinoma, HER2 overexpression positive adenocarcinoma, or MSI-H/dMMR tumors:[26]

  • Fluorouracil plus irinotecan

  • Docetaxel with or without cisplatin

  • Paclitaxel with or without carboplatin or cisplatin

  • Fluoropyrimidine (fluorouracil or capecitabine) monotherapy

  • Docetaxel plus cisplatin or oxaliplatin plus fluorouracil.

First-line treatment: neurotrophic tropomyosin-related kinase (NTRK) gene fusion positive tumors

The tropomyosin receptor kinase inhibitors entrectinib, larotrectinib, or repotrectinib may be considered for patients with NTRK gene fusion positive tumors.[26]

Peritoneal carcinoma as the only disease

In patients with peritoneal carcinoma as the only disease, intraperitoneal chemotherapy/hyperthermic intraperitoneal chemotherapy may be considered.[26]

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 tumor HER2 overexpression status (except for fam-trastuzumab deruxtecan, an antibody-drug conjugate composed of trastuzumab covalently linked to a topoisomerase I inhibitor).

Ramucirumab (a vascular endothelial growth factor inhibitor) plus paclitaxel is considered a second-line therapy for patients with locally advanced, recurrent, or metastatic disease.[26] 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.[68]

Ramucirumab monotherapy has been shown to improve median overall survival in patients with advanced gastric or gastroesophageal junction adenocarcinoma who have disease progression after first-line platinum- or fluoropyrimidine-containing chemotherapy.[69]

Fam-trastuzumab deruxtecan is recommended as second- or third-line treatment for patients with HER2 overexpression positive adenocarcinoma who have received prior trastuzumab-based therapy.[26] Compared with standard therapies, fam-trastuzumab deruxtecan significantly improved response rate and overall survival in one open-label, randomized phase 2 trial of patients with treatment-refractory HER2-positive gastric or gastroesophageal junction adenocarcinoma.[70] Myelosuppression and interstitial lung disease were reported in patients receiving the drug.

Other recommended second-line therapies include: monotherapy with docetaxel, paclitaxel, or irinotecan; fluorouracil plus irinotecan; irinotecan plus cisplatin; fluorouracil plus irinotecan plus ramucirumab; irinotecan plus ramucirumab; or docetaxel plus irinotecan.[26] A taxane or irinotecan, as a single agent or in combination, provides a modest improvement in overall survival compared with best supportive care.[71][72]

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.[26]

Endoscopic treatment, interventional radiology, gastrectomy, and chemotherapy may relieve symptoms such as pain, bleeding, nausea and vomiting, and obstruction.[26]

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