Approach

Multidisciplinary evaluation is strongly encouraged before therapy is started.[39][40] 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.

Treatment for early-onset gastric cancer generally follows the same principles as later-onset disease.[14]​ All patients with early-onset disease are suggested to undergo germline genetic testing to identify underlying hereditary syndromes and somatic genomic profiling to identify the genomic variants. Multidisciplinary care is essential for patients with early-onset gastric cancer and should include a dedicated focus on fertility counselling and preservation and comprehensive psychosocial support.[14]

Localised disease

Surgery is the primary treatment option for patients with localised (T1b or higher) gastric cancer, or actively bleeding cancer, or when post-operative chemotherapy is preferred.[39][40]​​ Patients with carcinoma in situ (Tis) or T1a tumours may be candidates for endoscopic therapies.[39]

For more advanced disease (T2 or higher, and any N), perioperative or adjuvant chemotherapy is the preferred option. Neoadjuvant or perioperative immunotherapy may be considered for microsatellite instability/mismatch repair deficiency [MSI-H/dMMR] tumours.[39]​​

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 the subject of debate.[39]

Subtotal gastrectomy is the preferred approach for distal gastric cancer.[39] Patients undergoing total gastrectomy for distal gastric cancers have no survival benefit compared with those undergoing subtotal gastrectomy.[47][48]

Proximal gastrectomy or total gastrectomy is usually recommended for patients with proximal tumours.[39]

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.[49]

Patients with superficial early-stage gastric cancer (Tis or T1a) can be treated with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).[39] Patients who are medically fit with early-stage gastric adenocarcinoma confined to the mucosa, <2 cm in diameter, low or moderate degree of differentiation, without evidence of ulcer, and with no lymphovascular involvement can be effectively treated with either EMR or ESD.[50][51][52]

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.[49]​ 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.[49]

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).[39] 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.[53][54][55] [ 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.[56][57][58] [ 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.[59]

Chemoradiotherapy

Post-operative chemoradiotherapy is recommended for patients who have undergone gastrectomy with limited (D0 or D1) lymph node dissection. Post-operative chemoradiotherapy is associated with a significantly lower local recurrence rate in this group of patients, compared with surgery alone.[60][61][62]​ The preferred regimen is radiotherapy and fluorouracil or capecitabine.[39]

Post-operative 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 post-operative chemotherapy with a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin instead.[39][60][63]

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.[39] 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.[64][65]

Chemotherapy ± immunotherapy

Perioperative chemotherapy has been shown to improve overall survival in patients with stage 2 or higher disease compared with surgery alone.[66][67]​​​ The preferred regimen for most patients with good-to-moderate performance status is FLOT (fluorouracil, folinic acid, oxaliplatin, docetaxel).[39] Other preferred regimens include FLOT plus durvalumab (for tumours with PD-L1 CPS ≥1 or tumour area positivity score ≥1%), or a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin.[39][68]

Fluorouracil plus cisplatin is an alternative regimen.[39] FLOT is associated with better outcomes in patients with resectable gastric and gastro-oesophageal junction cancer treatment compared with other regimens.[69]

Post-operative chemotherapy with a fluoropyrimidine plus oxaliplatin is indicated for patients who have undergone gastrectomy with primary D2 lymph node dissection.[39]

Neoadjuvant or perioperative immune checkpoint inhibitors may be considered for certain patients with MSI-H/dMMR tumours. Preferred options include nivolumab plus ipilimumab, pembrolizumab, and tremelimumab plus durvalumab.[39]

Advanced and metastatic disease

Chemotherapy improves quality of life and survival when compared with best supportive care in patients with metastatic gastric cancer.[70][71][72] [ Cochrane Clinical Answers logo ] ​​​​ Immunotherapy plus chemotherapy is associated with improved survival, compared with chemotherapy alone, in patients with metastatic gastric cancer.[73][74][75][76][77][78]​​​

Chemotherapy regimens should be chosen in the context of the patient's performance status (PS), medical comorbidities, toxicity profile, and tumour biomarker expression.[39] First-line treatment differs based on tumour HER2 expression.

First-line treatment: HER2 over-expression negative adenocarcinoma

Treatment with immune checkpoint inhibitors, combined with fluoropyrimidine- and platinum-based chemotherapy, is specifically preferred for HER2-negative tumours expressing PD-L1 having a combined positive score of 1+.[39]​ First-line options include:[39]

  • 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 (ASCO) 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.[79]​ The UK National Institute for Health and Care Excellence (NICE) recommends pembrolizumab combined with fluoropyrimidine- and platinum-based chemotherapy for HER2-negative tumours expressing PD-L1 having a combined positive score of 1+.[80]

Alternatively, a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin or cisplatin (without an immune checkpoint inhibitor) is recommended.[39]

Zolbetuximab, an anti-CLDN18.2 monoclonal antibody, combined with fluoropyrimidine- and platinum-based chemotherapy is recommended for first-line treatment of CLDN18.2 positive, unresectable locally advanced or metastatic gastric cancer.[39][81][82][83]​​​ However, NICE recommends against the use of zolbetuximab plus chemotherapy for this patient group due to a lack of comparative efficacy data with the well-established alternative treatments such as nivolumab plus chemotherapy or pembrolizumab plus chemotherapy and due to a possibility that zolbetuximab may be less effective in people who can have nivolumab or pembrolizumab.[84]​ Patients already undergoing treatment with zolbetuximab plus chemotherapy are unaffected by this recommendation and can continue their treatment as usual.​​​​

Studies have demonstrated that fluorouracil can be replaced by capecitabine, and cisplatin by oxaliplatin (except in regimens including irinotecan).[39][85][86]​​​​ Oxaliplatin is preferred over cisplatin owing to its lower toxicity.[39][85][87]​​​​ Folinic acid is indicated with certain fluorouracil-based regimens. Depending on availability, the regimens may be used with or without folinic acid.[39]

First-line treatment: HER2 over-expression positive adenocarcinoma

In tumours with HER2 over-expression, trastuzumab (a humanised monoclonal antibody that acts on the HER2 receptor) should be added to chemotherapy.[39] This combination has been shown to improve overall survival in patients with advanced gastric cancer.[73] Pembrolizumab, an immune checkpoint inhibitor, may be added to first-line fluoropyrimidine- and platinum-based chemotherapy and trastuzumab for patients with HER2-positive disease with tumours expressing PD-L1 having a combined positive score of 1+.[39] However, NICE recommends against the use of this combination for patients with untreated locally advanced unresectable or metastatic HER2‑positive gastric or gastroesophageal junction adenocarcinoma as the treatment is not cost-effective and long-term effects are very uncertain.[88]​ Patients already undergoing treatment with pembrolizumab plus trastuzumab plus chemotherapy are unaffected by this recommendation and can continue their treatment as usual.

Oxaliplatin is preferred over cisplatin owing to its lower toxicity.[39]

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

Targeted therapies may be indicated for patients with high microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) tumours. Pembrolizumab and dostarlimab are anti-PD-1 monoclonal antibodies that may be considered for patients with high MSI-H/dMMR tumours.[39]​ NICE in the UK recommends pembrolizumab as an option for treating tumours with MSI-H/dMMR in adults with unresectable or metastatic stomach cancer that has progressed during or after one therapy.[89]​ Other options for MSI-H/dMMR tumours 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 tumours:[39]

  • 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 tumours

The tropomyosin receptor kinase inhibitors entrectinib, larotrectinib, or repotrectinib may be considered for patients with NTRK gene fusion positive tumours.[39]

Second-line or subsequent therapy depends on prior therapy and performance status.[39]

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.[39][90]

Endoscopic treatment, interventional radiology, gastrectomy, and chemotherapy may relieve symptoms such as pain, bleeding, nausea and vomiting, and obstruction.[39]

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