GCa is often asymptomatic in the early stages. Common signs and symptomsin advanced disease include dysphagia, asthenia, indigestion, vomiting, weight loss, early satiety and/or iron deficiency anaemia.¹

Tumour staging is essential to ensure patients are appropriately selected for treatment interventions. ESMO recommends the American Joint Committee on Cancer/Union for International Cancer Control tumour-node-metastasis 8th edition staging system.¹

Treatment recommendations for advanced or metastatic disease

Overall, about 60% of people with GCa are not eligible for curative treatment owing to late presentation or comorbidities, according to ESMO. The 2022 ESMO guideline for the diagnosis, treatment and follow-up in GCa recommends the following treatment options for patients with advanced or metastatic disease:¹

First-line ChT, targeted therapy and immunotherapy

• First-line chemotherapy (ChT) with a platinum and fluoropyrimidine. Oxaliplatin is preferred, especially for older patients
• Due to higher levels of toxicity and uncertain survival benefit over recommended doublet regimens, first-line taxane-based triplet ChT is not recommended as a standard approach
• Irinotecan-5-fluorouracil can be considered an alternative option for patients who do not tolerate platinum compounds
• Trastuzumab is recommended in patients with human epidermal growth factor receptor 2-positive (HER2+) tumours.

Second- and later-line treatment

• Ramucirumab-paclitaxel is recommended for second-line treatment. Ramucirumab monotherapy is also an option
• If ramucirumab is not available, paclitaxel, docetaxel or irinotecan monotherapy are recommended
• Treatment with trastuzumab is not recommended after first-line therapy in HER2+advanced GCa.
• For patients previously treated with two lines of therapy, trifluridine-tipiracil is recommended
• Alternative treatments include a taxane or irinotecan.

Surgery for metastatic disease

• Gastrectomy is not recommended in metastatic GCa unless required for palliation of symptoms
• Resection of metastases cannot be recommended in general but might be considered as an individual approach in highly selected cases with oligometastatic disease and response to ChT.

Supportive care and nutrition

Care for patients should include an early palliative care referral and nutritional support.

REGARD and RAINBOW

Circulating vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis have been implicated in increased tumour aggressiveness and reduced survival. Trastuzumab and ramucirumab are the only globally approved targeted therapies in GCa. These therapies target HER-2 and VEGFR-2, respectively.^2,3,4

In the Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD) trial, Fuchs et al assessed whether ramucirumab, a VEGFR-2 agonist, prolonged overall (OS) in patients with advanced GCa.²

Patients (n=355) with advanced GCa or GOJ adenocarcinoma and disease progression after first-line platinum- or fluoropyrimidine-containing ChT were randomised in a 2:1 ratio to either best supportive care plus either ramucirumab (8mg/kg) or placebo, intravenously (IV) once every two weeks. The primary endpoint was OS.²

At the end of the study period (three years) the median OS rate was 5.2 months in patients in the ramucirumab group and 3.8 months in those in the placebo group. The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors. Rates of hypertension were higher in the ramucirumab group than in the placebo group (16% vs 8%), whereas rates of other adverse events were mostly similar between groups (94% vs 88%).²

Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced GCa or GOJ adenocarcinoma progressing after first-line ChT. Their findings validate VEGFR-2 signalling as an important therapeutic target in GCa, concluded the authors.²

In the Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW) trial, Wilke et al, patients (n=665) with advanced GCa or GOJ adenocarcinoma and disease progression on or within four months after first-line ChT (platinum plus fluoropyrimidine with or without an anthracycline) were randomised in a 1:1 ratio to ramucirumab (8mg/kg) or placebo IV on days one and 15, plus paclitaxel (80 mg/m²) IV on days one, eight, and 15 of a 28-day cycle. The primary endpoint was OS.³

At the end of the study period (three years), OS was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9.6 months vs 7.4 months (hazard ratio 0.87 [95% CI 0.678-0.962], p=0.017).³

Grade 3 or higher adverse events that occurred in >5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (41% vs 19%), leucopoenia (17% vs 7%), hypertension (14% vs eight 2%), fatigue (12% vs 5%), anaemia (9% vs 10%), and abdominal pain (6% vs 3%). The incidence of grade 3 or higher febrile neutropenia was low in both groups (3% vs 2%).³

The authors concluded that the combination of ramucirumab with paclitaxel significantly increases OS compared with placebo plus paclitaxel and could be regarded as a new standard second-line treatment for patients with advanced GCa.³

Approved indications for ramucirumab in South Africa

In South Africa, ramucirumab is approved in combination with paclitaxel for the treatment of adult patients with advanced GCa or GOJ adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy.⁴

It is also approved as monotherapy for the treatment of adult patients with advanced GCa or GOJ adenocarcinoma with disease progression after prior platinum or fluoropyrimidine ChT, for whom treatment in combination with paclitaxel is not appropriate.⁴

REFERENCES