📋 Key Information Summary
- Gastric adenocarcinoma is the fifth most common cancer in Australia, with ~2,500 new cases diagnosed annually and a 5-year survival rate of approximately 30%.
- Risk factors include Helicobacter pylori infection, tobacco smoking, high-salt diet, family history, gastric atrophy, and intestinal metaplasia.
- Lauren classification (intestinal vs diffuse) and WHO histological classification remain the primary pathological frameworks guiding prognosis and treatment.
- Early-stage disease is often asymptomatic; alarm features (dysphagia, unintentional weight loss, iron-deficiency anaemia, persistent vomiting) warrant urgent upper GI endoscopy.
- CT staging (chest/abdomen/pelvis), endoscopic ultrasound (EUS), and PET-CT form the staging triad; laparoscopy with peritoneal lavage is recommended for stage II–III disease to detect occult peritoneal metastasis.
- Perioperative chemotherapy (FLOT regimen: 5-fluorouracil, leucovorin, oxaliplatin, docetaxel) is the standard of care for resectable locally advanced (cT2 or N+) gastric adenocarcinoma in fit patients.
- D2 lymphadenectomy is the recommended surgical standard in Australian centres; R0 resection is the primary surgical goal.
- Adjuvant capecitabine plus oxaliplatin (CAPOX) or S-1 is used post-operatively when pre-operative chemotherapy was not given; HER2-directed therapy (trastuzumab) is first-line for HER2-positive metastatic disease.
- Nivolumab plus chemotherapy is approved first-line for advanced/metastatic gastric cancer regardless of PD-L1 status in Australia (PBS-listed).
- Molecular profiling (HER2, microsatellite instability [MSI], PD-L1, Claudin 18.2) is now essential for all advanced-stage cases to guide targeted and immunotherapy.
- Aboriginal and Torres Strait Islander peoples experience higher rates of H. pylori infection and later-stage presentation; culturally safe, community-based screening programmes are critical.
- Multidisciplinary team (MDT) discussion at a designated cancer centre is mandatory for all cases, ideally prior to any treatment decisions.
Introduction & Australian Epidemiology
Gastric carcinoma is a malignant epithelial neoplasm of the stomach, with adenocarcinoma accounting for over 90% of all gastric malignancies. Despite declining global incidence, gastric cancer remains a significant cause of cancer-related mortality in Australia due to late-stage presentation and the aggressive biology of certain subtypes.
In Australia, approximately 2,500 new cases of gastric cancer are diagnosed each year, with an age-standardised incidence of approximately 7.9 per 100,000 population. The median age at diagnosis is 70 years, and males are affected approximately twice as frequently as females. The 5-year overall survival remains poor at approximately 30%, reflecting the fact that the majority of patients present with locally advanced or metastatic disease.
Geographic and ethnic variation in incidence is notable. Higher rates are observed in East Asian countries, and within Australia, individuals of East Asian, Eastern European, and South American descent carry elevated risk. The incidence in Aboriginal and Torres Strait Islander peoples is comparable to or slightly higher than the non-Indigenous population, but outcomes are significantly worse owing to later diagnosis, comorbidity burden, and barriers to timely healthcare access.
The anatomical distribution of gastric adenocarcinoma has shifted over recent decades, with an increase in proximal (cardia and gastro-oesophageal junction) tumours in Western countries, including Australia, contrasting with the traditionally more common distal (antral/pyloric) predominance seen in high-incidence regions and in association with H. pylori infection.
Epidemiology & Risk Factors
Key Risk Factors
| Risk Factor | Relative Risk | Mechanism / Notes |
|---|---|---|
| Helicobacter pylori infection | 2–6× | Chronic gastritis → atrophy → intestinal metaplasia → dysplasia → carcinoma (Correa cascade). CagA-positive strains carry highest risk. |
| Chronic atrophic gastritis / intestinal metaplasia | 6–10× | Surveillance endoscopy every 3 years recommended for extensive metaplasia (MAPS II guidelines). |
| Tobacco smoking | 1.5–2× | Dose-dependent risk; cessation reduces risk over 10–15 years. |
| Family history (first-degree relative) | 2–3× | Higher if relative diagnosed <50 years. Consider hereditary diffuse gastric cancer (CDH1 mutation). |
| Hereditary diffuse gastric cancer (HDGC) | Very high | CDH1 pathogenic variant; prophylactic gastrectomy recommended by age 20–30. |
| High-salt diet / processed meat / nitrosamines | 1.5–2× | Promotes mucosal inflammation and H. pylori colonisation. |
| Low fruit and vegetable intake | 1.5–2× | Reduced antioxidant defence and vitamin C intake. |
| Pernicious anaemia / autoimmune gastritis | 2–4× | Risk of type 1 gastric neuroendocrine tumour and adenocarcinoma. |
| Prior gastric surgery (>15 years) | 2–4× | Stump carcinoma following partial gastrectomy (Billroth II > Billroth I). |
| Epstein-Barr virus (EBV) | Variable | ~10% of gastric adenocarcinomas are EBV-positive; associated with PIK3CA mutations and favourable immunotherapy response. |
Protective Factors
- Diets rich in fresh fruit and vegetables
- Successful H. pylori eradication (reduces risk by ~34% in meta-analyses)
- Non-smoking status
- Regular aspirin / NSAID use (modest risk reduction; not recommended solely for this indication)
Pathology & Classification
Lauren Classification
| Type | Frequency | Features | Association |
|---|---|---|---|
| Intestinal | ~50–60% | Gland-forming, cohesive tumour cells; resembles intestinal epithelium | H. pylori, atrophic gastritis, environmental factors, older age, male predominance |
| Diffuse | ~30–40% | Non-cohesive, signet-ring cells; infiltrates submucosally; poor differentiation | Younger patients, CDH1 mutation, E-cadherin loss, worse prognosis |
| Mixed / Indeterminate | ~10% | Features of both types | Variable prognosis |
WHO Histological Classification
- Tubular adenocarcinoma
- Papillary adenocarcinoma
- Mucinous adenocarcinoma
- Poorly cohesive carcinoma (including signet-ring cell carcinoma)
- Mixed carcinoma
Molecular Subtypes (TCGA Classification)
The Cancer Genome Atlas (TCGA) project identified four molecular subtypes of gastric adenocarcinoma, increasingly used to guide therapy:
| Subtype | Frequency | Key Features | Therapeutic Implications |
|---|---|---|---|
| EBV-positive | ~10% | PIK3CA mutations, PD-L1/2 amplification, high CpG island methylation | Favourable response to immune checkpoint inhibitors (ICI) |
| Microsatellite instability–high (MSI-H) | ~20% | MLH1 promoter hypermethylation, high tumour mutational burden | Best ICI response; avoid 5-FU in some contexts; better prognosis |
| Genomically stable (GS) | ~20% | Diffuse histology, CDH1 and RHOA mutations | Potential targets: CLDN18.2 (zolbetuximab), FGFR2 |
| Chromosomal instability (CIN) | ~50% | TP53 mutations, RTK/RAS amplification (HER2, EGFR, MET) | HER2-targeted therapy (trastuzumab); anti-VEGFR (ramucirumab) |
Borrmann Macroscopic Classification
- Type I: Polypoid / fungating
- Type II: Ulcerated with raised margins
- Type III: Ulcerated with infiltrative margins (most common)
- Type IV: Diffusely infiltrative (linitis plastica) — worst prognosis
Clinical Features & Diagnosis
Presenting Features
Early gastric cancer is frequently asymptomatic or produces only non-specific dyspeptic symptoms, contributing to late diagnosis. The following alarm features should prompt urgent investigation in patients aged ≥50 years or those with risk factors:
Alarm features requiring urgent upper GI endoscopy (within 2 weeks): dysphagia, unintentional weight loss (>5% body weight in 6 months), persistent vomiting, iron-deficiency anaemia, palpable abdominal mass, positive faecal occult blood test (FOBT) without colonic cause, new-onset dyspepsia in patients aged ≥50 years, or family history of gastric cancer.
| Symptom | Frequency at Diagnosis | Clinical Note |
|---|---|---|
| Epigastric pain / discomfort | ~70% | Often initially responsive to PPI, causing diagnostic delay |
| Weight loss | ~60% | Strong predictor of advanced disease |
| Nausea / vomiting | ~50% | Suggests gastric outlet obstruction if proximal/distal tumour |
| Dysphagia | ~25% | Indicates proximal / cardia involvement |
| GI bleeding (melaena / haematemesis) | ~20% | May cause iron-deficiency anaemia |
| Early satiety | ~15% | Suggests reduced gastric compliance / linitis plastica |
Paraneoplastic Syndromes
- Dermatomyositis / acanthosis nigricans: may be presenting feature
- Virchow's node: left supraclavicular lymphadenopathy (Troisier sign)
- Sister Mary Joseph nodule: periumbilical metastatic deposit
- Krukenberg tumour: ovarian metastasis with signet-ring cells
- Irish node: left axillary lymphadenopathy
- Mikulicz syndrome: lacrimal and salivary gland enlargement (rare)
Diagnostic Pathway
1
Upper GI Endoscopy (OGD)
Gold standard for diagnosis. Obtain ≥6 biopsies from suspicious lesions (including ulcer edges); additionally sample non-involved mucosa for H. pylori and gastritis assessment. MBS Item 30473.
2
Histopathological Confirmation
Report should include: Lauren type, WHO grade, depth of invasion (if ESD specimen), HER2 status (immunohistochemistry ± FISH), MSI/dMMR status, PD-L1 combined positive score (CPS).
3
Cross-sectional Imaging
CT chest/abdomen/pelvis with IV contrast (MBS Item 57332); assess local extent, nodal disease, distant metastasis, and peritoneal disease.
4
Endoscopic Ultrasound (EUS)
T-staging accuracy 80–90%. Essential for early gastric cancer (T1 vs T2 distinction) and to guide neoadjuvant planning. MBS Item 30491.
5
PET-CT
Not universally recommended; useful to detect occult distant metastasis, particularly for mucinous/signet-ring histology (lower FDG avidity). MBS Item 61499 (on referral).
6
Staging Laparoscopy ± Peritoneal Lavage
Recommended for all stage II–III (cT3–4 or N+) cases to detect occult peritoneal carcinomatosis (upstaging ~15% of patients). Cytology positive = M1 disease.
7
Molecular Profiling
Essential for all advanced/metastatic cases: HER2, MSI/MMR, PD-L1 CPS, Claudin 18.2. Performed on biopsy or resection specimen. Tissue-based NGS panel recommended where available.
Investigations
Essential
Upper GI Endoscopy with Biopsy
≥6 targeted biopsies. Sensitivity ~95% for visible lesions. MBS Item 30473.
Essential
CT Chest/Abdomen/Pelvis (IV Contrast)
Staging workhorse. Detects liver, peritoneal, and nodal metastasis. MBS Item 57332.
Essential
Histopathology + Molecular Markers
HER2 IHC/FISH, MSI/dMMR testing, PD-L1 CPS. Available at all major pathology labs (Sonic, Douglass Hanly Moir).
Available
Endoscopic Ultrasound (EUS)
T-staging (accuracy 80–90%); FNA of suspicious nodes. MBS Item 30491. Available at tertiary centres.
Available
PET-CT
FDG-PET. Limited sensitivity for mucinous/signet-ring and peritoneal disease. MBS Item 61499.
Surgical referral
Staging Laparoscopy ± Peritoneal Lavage
Detects occult peritoneal disease in ~15% of CT-negative patients. Cytology = M1. Performed at surgical centres with upper GI subspecialty.
Available
Claudin 18.2 IHC
Emerging biomarker for zolbetuximab eligibility. Available through specialised pathology providers and clinical trials.
Available
FBC, LFTs, CEA, CA 19-9, Albumin
Baseline bloods. CA 19-9 may be elevated; not diagnostic but useful for monitoring. Nutritional assessment (albumin, prealbumin) critical for surgical fitness.
Staging & Management
AJCC / UICC TNM Staging (8th Edition)
| Stage | TNM | 5-Year Survival (Approx.) | Primary Management |
|---|---|---|---|
| I | T1N0M0 | ~90% | Endoscopic resection (EMR/ESD) if criteria met; or surgery (D1+ lymphadenectomy) |
| II | T1N1–2 / T2N0–1 / T3N0M0 | ~60–70% | Perioperative chemotherapy (FLOT) → D2 gastrectomy |
| III | T2N2 / T3N1–2 / T4a–bN0–2M0 | ~20–45% | Perioperative chemotherapy (FLOT) → D2 gastrectomy; adjuvant chemo if pre-op not given |
| IV | Any T, Any N, M1 | ~5–10% | Systemic palliative chemotherapy; molecular-guided targeted/immunotherapy |
Early Gastric Cancer — Endoscopic Resection Criteria
Expanded criteria for endoscopic submucosal dissection (ESD):
- Differentiated-type, mucosal cancer, no ulceration, any size
- Differentiated-type, mucosal cancer, ulceration, ≤30 mm
- Undifferentiated-type, mucosal cancer, no ulceration, ≤20 mm
- SM1 invasion (≤500 μm submucosal), differentiated-type, no lymphovascular invasion
ESD should be performed at experienced tertiary centres. If curative criteria not met, surgical gastrectomy with D1+ lymphadenectomy is recommended.
Perioperative Chemotherapy — Standard of Care
FLOT regimen is the recommended perioperative chemotherapy for resectable locally advanced (cT2 or N+) gastric and gastro-oesophageal junction (GOJ) adenocarcinoma. Based on the FLOT4 trial, FLOT demonstrated superior overall survival compared with ECF/ECX. This should be discussed at MDT for all stage II–III patients who are medically fit.
FLOT Regimen (Cycle)
5-Fluorouracil + Leucovorin + Oxaliplatin + Docetaxel · Perioperative
Regimen
Docetaxel 50 mg/m² IV + Oxaliplatin 85 mg/m² IV + Leucovorin 200 mg/m² IV + 5-FU 2,600 mg/m² IV (24h infusion), Day 1, q14d
Duration
4 cycles pre-op (8 weeks) + 4 cycles post-op (8 weeks)
Renal adjustment
5-FU: dose reduce if CrCl <30 mL/min; Oxaliplatin: avoid if CrCl <25 mL/min
Key toxicity
Neutropenia (grade 3/4 ~50%), diarrhoea, peripheral neuropathy, nausea
PBS status
✔ PBS General Benefit (5-FU, Oxaliplatin)
✔ PBS General Benefit (Docetaxel)
Adjuvant Chemotherapy (when pre-operative therapy not given)
Capecitabine + Oxaliplatin (CAPOX)
Xeloda® + generic oxaliplatin · Adjuvant
Adult dose
Capecitabine 1,000 mg/m² PO BD Days 1–14 + Oxaliplatin 130 mg/m² IV Day 1, q21d
Duration
8 cycles (6 months)
Renal adjustment
Capecitabine: reduce dose if CrCl 30–50 mL/min; contraindicated if <30 mL/min
PBS status
✔ PBS General Benefit
Surgery — D2 Lymphadenectomy
D2 gastrectomy (removal of level 1 and 2 lymph nodes) is the recommended surgical standard in Australia, performed at high-volume centres. Key principles include:
- Goal: R0 (microscopically negative) resection with ≥16 lymph nodes harvested
- Total gastrectomy: For proximal tumours, tumours crossing the incisura, or diffuse-type (signet-ring) cancers
- Distal subtotal gastrectomy: For distal tumours with adequate proximal margin (≥5 cm intestinal / ≥8 cm diffuse)
- Roux-en-Y reconstruction: Preferred after total gastrectomy to minimise reflux
- Minimally invasive approach: Laparoscopic gastrectomy equivalent outcomes at experienced centres; robotic surgery increasingly available
Metastatic Disease — First-Line Systemic Therapy
First-line treatment of metastatic gastric adenocarcinoma is guided by molecular profiling. All patients should have HER2, MSI/dMMR, and PD-L1 testing.
Nivolumab + Chemotherapy
Opdivo® · CheckMate-649 · First-line metastatic
Adult dose
Nivolumab 360 mg IV q21d (or 240 mg IV q14d) + CAPOX or FOLFOX
Indication
HER2-negative, unresectable or metastatic gastric/GOJ adenocarcinoma (CPS ≥5 preferred, all CPS per PBS)
Key toxicity
Immune-related adverse events (thyroiditis, hepatitis, pneumonitis, colitis); fatigue, nausea
PBS status
✔ PBS Authority Required
Trastuzumab + Chemotherapy
Herceptin® · HER2-positive first-line
Adult dose
Trastuzumab 8 mg/kg IV loading → 6 mg/kg IV q21d + CAPOX or FOLFOX
Indication
HER2-positive (IHC 3+ or IHC 2+/FISH+) metastatic gastric adenocarcinoma
Key toxicity
Cardiotoxicity (monitor LVEF), infusion reactions, diarrhoea
PBS status
✔ PBS Authority Required
Metastatic Disease — Subsequent Lines
Ramucirumab ± Paclitaxel
Cyramza® · RAINBOW / REGARD · Second-line
Adult dose
Ramucirumab 8 mg/kg IV Day 1 + 15, q28d ± Paclitaxel 80 mg/m² IV Days 1, 8, 15
PBS status
✔ PBS Authority Required
Trastuzumab Deruxtecan (T-DXd)
Enhertu® · DESTINY-Gastric01 · HER2+ 2nd-line+
Adult dose
6.4 mg/kg IV q21d
Key toxicity
Interstitial lung disease / pneumonitis (monitor closely); nausea, neutropenia
PBS status
✖ Not currently PBS-listed for gastric (access via SAS-B or clinical trials)
Zolbetuximab + Chemotherapy
Vyloy® · GLOW/SPOTLIGHT · CLDN18.2+ first-line
Adult dose
Zolbetuximab 800 mg/m² IV loading → 600 mg/m² IV q21d + mFOLFOX6 or CAPOX
Indication
HER2-negative, CLDN18.2-positive (≥75% cells with moderate-to-strong membrane staining), locally advanced or metastatic gastric adenocarcinoma
Key toxicity
Nausea, vomiting (pre-medicate aggressively), fatigue
PBS status
✖ Not currently PBS-listed (TGA-approved; PBS listing pending)
Monitoring & Follow-Up
Post-Surgical Surveillance (Resected Disease)
| Timepoint | Investigations | Purpose |
|---|---|---|
| Every 3–6 months × 2 years | Clinical review, FBC, LFTs, CEA, CA 19-9, CT CAP q6–12m | Early recurrence detection |
| Every 6–12 months, years 3–5 | Clinical review, tumour markers, CT if symptoms | Late recurrence surveillance |
| After 5 years | Annual clinical review; imaging if symptomatic | Long-term survivorship care |
| Post-gastrectomy (ongoing) | Vitamin B12, iron studies, calcium, vitamin D q6–12m | Nutritional deficiency monitoring (B12, iron, calcium) |
Nutritional Support Post-Gastrectomy
- Dumping syndrome: Small, frequent meals; avoid simple carbohydrates; complex carbohydrate–rich snacks
- Vitamin B12: Lifelong supplementation — cyanocobalamin 1,000 μg IM monthly (or 100 μg SC every 2–3 months) if total gastrectomy; monitor levels annually
- Iron: Ferrous fumarate 200 mg PO BD; IV iron (ferric carboxymaltose) if intolerant of oral
- Calcium + Vitamin D: Calcium carbonate 1.2 g PO daily + cholecalciferol 1,000 IU PO daily; DEXA scan at baseline and q2 years
- Dietitian referral: All patients post-gastrectomy should receive specialist dietitian input
Special Populations
Pregnancy
Gastric cancer in pregnancy is extremely rare. Diagnosis is often delayed due to symptom overlap with pregnancy-related nausea.
Management requires MDT with obstetric, surgical, and oncology input. Chemotherapy generally contraindicated in first trimester; platinum/5-FU may be considered in 2nd/3rd trimester with careful monitoring. Surgical resection can be performed in 2nd trimester if urgent.
Paediatric / Young Adult
Gastric adenocarcinoma in patients <40 years is uncommon but often presents as diffuse-type (signet-ring / linitis plastica) with worse prognosis.
Genetic testing for CDH1 (HDGC), MAP3K6, and other hereditary gastric cancer predisposition genes should be performed. Prophylactic gastrectomy discussed for CDH1 carriers. Fertility preservation prior to systemic therapy is essential.
Elderly (≥75 years)
Gastric cancer most commonly affects older adults. Surgical fitness must be individualised using comprehensive geriatric assessment (CGA).
FLOT may be too toxic for frail elderly — consider attenuated regimens (e.g., capecitabine monotherapy, reduced-dose CAPOX) or palliative intent. Post-operative morbidity higher; enhanced recovery after surgery (ERAS) protocols recommended.
Renal Impairment
5-FU: No standard renal dose adjustment, but caution if CrCl <30 mL/min. Oxaliplatin: Avoid if CrCl <25 mL/min or use reduced dose. Capecitabine: Dose reduce if CrCl 30–50; contraindicated <30. Docetaxel: Limited data; dose reduce by 25–50% in severe impairment.
Nephrologist co-management recommended for patients on dialysis. Nivolumab: no dose adjustment required for renal impairment.
Hepatic Impairment
Docetaxel: Contraindicated if bilirubin >1.5× ULN or transaminases >3.5× ULN with ALP >6× ULN. 5-FU / Capecitabine: Caution in severe impairment. Nivolumab: Caution in moderate-severe hepatic impairment (hepatotoxicity risk).
Hepatic metastases are common. Liver function should be optimised before commencing chemotherapy. Surgery with hepatic resection may be considered for oligometastatic disease at experienced centres.
Immunocompromised
Patients on immunosuppressive therapy (e.g., post-transplant) have higher H. pylori infection rates. ICI therapy (nivolumab) contraindicated in solid organ transplant recipients due to graft rejection risk.
HIV-positive patients: adjust for drug interactions (particularly with azoles, NNRTIs). Chemotherapy regimens generally similar but closer infection monitoring required.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
📚 References
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- 3. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40.
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