Esophageal and gastric cancer

Overview and classification

• Epidemiology: ~52,000 gastroesophageal cases/yr in the US; gastric ca is ~5th most common ca worldwide. (US 2025 estimates: esophageal ~22,000 cases/~16,000 deaths; gastric ~30,000 cases/~11,000 deaths.)
• Old grouping: esophageal AC (Siewert type I) and GEJ AC (type II) were often grouped with esophageal SCC, while proximal gastric cardia AC was grouped with distal gastric AC.
• New classification:
  • Esophageal SCC → incidence ↓ (upper/middle third; risk: tobacco, alcohol, hot beverages).
  • GEJ AC = distal esophagus AC (Siewert I) + GEJ AC (II) + gastric proximal cardia AC (III) → incidence ↑↑.
  • Gastric AC = distal gastric AC → incidence ↓↓.
• GEA: GEJ AC + gastric AC are grouped together as gastroesophageal adenocarcinoma when considering treatment.
• Siewert classification of GEJ (relative to the GEJ): I = 1 to 5 cm above (treat as esophageal); II = 1 cm above to 2 cm below (true cardia); III = 2 to 5 cm below (treat as gastric).

Risk factors

• Esophageal SCC: African American, achalasia, caustic injury, tylosis (Howel-Evans syndrome, rare autosomal dominant palmoplantar hyperkeratosis), Plummer-Vinson syndrome, smoking, alcohol; HPV in the upper esophagus.
• GEJ AC: Barrett esophagus and GERD, White/Hispanic ↑, M>F, ↑ age, smoking, obesity/DM, Western diet. ASPECT trial (Barrett ≥ 1 cm without HGD or AC): high-dose PPI + ASA 300 mg/d had the best effect on the composite endpoint (all-cause mortality, esophageal AC, or HGD) vs low-dose PPI and no aspirin (separate reduction of esophageal AC alone was not shown).
• Gastric AC: M>F 2:1, African American men ↑, diet high in salt/nitrate and low in vitamins A and C, smoked/cured foods, lack of refrigeration, poor drinking water, rubber and coal exposure, smoking, EBV, radiation, prior gastric surgery for benign ulcer. H. pylori is a carcinogen; eradication reduces gastric AC incidence.
  • Genetic associations: blood type A, pernicious anemia, family history, HNPCC, Li-Fraumeni, FAP, polyposis syndromes, BRCA.
  • Hereditary diffuse gastric ca (HDGC): germline CDH1 (E-cadherin, calcium-dependent cell adhesion protein) mutation; CTNNA1 may also contribute. Suspect with family history of gastric AC, diffuse-type histology, early onset <40 y/o. Women have ↑ risk of lobular breast ca (screen with annual breast MRI starting age 30 (add mammography from 40; mammography alone inadequate); discuss risk-reducing mastectomy). If germline CDH1: risk-reducing prophylactic gastrectomy at age 20 to 30, or EGD q6 to 12 mo if declining surgery.
  • HER2 is more common in intestinal than diffuse type (26.7% vs 7.1%).

Presentation and staging

• Proximal tumors can invade the tracheobronchial tree → laryngeal nerve paralysis, cough, pneumonia.
• Carcinomatosis is common: ~30% of gastric AC and 10 to 15% of GEJ AC (especially diffuse/mixed and signet-ring), causing ascites, abdominal pain, anorexia, and bowel obstruction.
• EGD: diffuse-type gastric AC may have no obvious mass and initial workup can be negative → repeat EGD with random biopsies.
• CT chest/abdomen/pelvis with attention to liver metastases and celiac adenopathy; PET and EUS for better staging and occult sites (diffuse-type gastric AC can be PET-negative).
• Exam: assess supraclavicular nodes. MRI brain not needed if asymptomatic (rarely spreads to brain).
• Two primaries: given shared risk factors, consider separate lung and esophageal SCC primaries when a solitary lung lesion is seen at staging.
• Diagnostic laparoscopy identifies 20 to 30% of occult peritoneal metastases in GEA (especially distal gastric AC); ≥ T3 or LN+ on EUS have high risk of occult peritoneal disease even with negative CT/PET. Per NCCN, T1b and above should undergo staging laparoscopy (category 2B). If T3N0 but positive cytology on washings, this is stage IV.

Biomarkers

• Test all newly diagnosed metastatic/recurrent esophageal and gastric cancers for dMMR/MSI, PD-L1, and NGS; add HER2 and CLDN18.2 only in adenocarcinoma (not SCC) (also EBV in gastric; NTRK rare).
• HER2 testing combines IHC and FISH: IHC membranous reactivity in ≥10% of cells (surgical specimen; strong complete/basolateral staining = 3+) or a cluster of ≥5 cells (biopsy); FISH HER2-to-CEP17 ratio ≥2. IHC 0 = negative, 1+ = HER2-low, 2+ reflexes to FISH, 3+ = positive. ~10 to 15% of gastric AC and ~15 to 25% of GE AC overexpress/amplify HER2.

General approach for resectable disease

• SCC → neoadjuvant chemoRT then esophagectomy → add nivolumab × 1 yr if residual disease, or observe if pCR. Chemo with RT is usually carbo/paclitaxel or FOLFOX.
• Gastric AC → neoadjuvant chemo then gastrectomy with D2 resection then adjuvant chemo. Perioperative chemo usually FLOT, FOLFOX, or CAPOX × 3 to 4 cycles.

Localized disease: general approach by depth

• LGD → Barrett: endoscopic eradication therapy or surveillance (6 mo, 12 mo, then annual) + PPI; gastric: expert reassessment, resect visible lesions, H. pylori eradication.
• Tis/HGD (5-yr ca risk ~60% vs 4% for LGD) → Barrett: endoscopic resection of visible lesions + RFA of residual Barrett; gastric/squamous HGD: endoscopic resection (ESD), not routine RFA.
• T1aN0 (mucosa: invasion into lamina propria or muscularis mucosae; HGD without invasion = Tis, not T1a) → endoscopic resection.
• T1bN0 (submucosa) → surgery with LN dissection (15 to 40% occult LN+).
• T2N0 (muscularis propria, N0) → neoadjuvant CRT/chemo then surgery vs surgery alone (small to no benefit of neoadjuvant tx if adequate surgery).
• ≥ T3 (transmural/adventitia) and/or LN+, or T4a → neoadjuvant CRT then surgery then adjuvant nivolumab × 1 yr if residual disease (observe if pCR); gastric AC → perioperative chemo (FLOT).
• T4: T4a resectable. Esophageal T4b generally unresectable; selected nonmetastatic gastric T4b resectable via en bloc multivisceral resection if R0 feasible.
  • Esophageal cT4a: pleura, pericardium, azygos vein, diaphragm, peritoneum.
  • Gastric T4a: invades serosa (visceral peritoneum).
  • Esophageal cT4b (heart, great vessels, trachea, or adjacent organs such as liver, pancreas, lung, spleen): unresectable → definitive chemoRT or chemo alone.
  • Gastric T4b: invades adjacent organs (spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal, kidney, small intestine, retroperitoneum).
• Cervical esophageal ca <5 cm from the cricopharyngeus should receive definitive chemoRT only (no surgery).

Surgery and lymph node dissection

• Distal esophagus: transhiatal (better for lower esophageal tumors) vs transthoracic esophagectomy (Ivor-Lewis = thoracotomy + laparotomy; better for mid-esophageal tumors). Same survival, but transthoracic gives better LN sampling.
• Gastric: D1/D2 nodes, examine at least 16 LN (AJCC 8th); esophageal lymphadenectomy (not D-level terminology) cites at least 15 examined LN.
  • D1: perigastric LN only (greater/lesser curvature, stations 1 to 7). In Japan D1+ adds stations 8a, 9, 11p.
  • D2: D1 plus nodes along the named arteries. Total gastrectomy D2 = D1 + 8a, 9, 11p, 11d, 12a (routine splenic-hilum/station 10 dissection no longer standard); distal gastrectomy D2 has a different station set.
  • D3: superextended (D2 plus porta hepatis and periaortic, stations 1 to 16); not recommended by AJCC/UICC.
• Dutch D1 vs D2 trial: D2 reduced locoregional recurrence (12% vs 22%) and gastric-ca death (37% vs 48%) but increased postoperative morbidity (43% vs 25%) and mortality (10% vs 4%).
• MRC trial: same 5-yr OS (D2 33% vs D1 35%) with much higher D2 morbidity (46% vs 28%) and mortality (13% vs 6%).

Localized multimodality: esophageal/GEJ

• Indications for CRT then surgery: T3N0, T4aN0, or N+; and cT2N0 with high-risk features (LVI, ≥3 cm, poorly differentiated).
• CROSS: neoadjuvant carboplatin AUC 2 / paclitaxel 50 weekly × 5 + RT (41.4 Gy) then surgery vs surgery alone. Included esophagus 74% and GEJ 22% (no stomach); 23% SCC, 75% AC, 2% other. pCR SCC 49%, AC 23% (29% overall). mOS 48.6 vs 24.0 mo (5-yr OS 47% vs 33%); highest benefit for SCC (HR 0.48), smaller but significant OS benefit in AC (HR 0.73, p=0.038; mOS 43.2 vs 27.1 mo). CROSS replaced the more toxic cis/5-FU backbone.
• PRODIGE5/ACCORD17: definitive (not neoadjuvant) chemoRT, FOLFOX/RT vs 5-FU/cis/RT at 50 Gy in nonsurgical pts, same PFS (~9.5 mo) with better tolerance for FOLFOX.
• Definitive chemoRT (50 to 50.4 Gy + cis/5-FU or cis/cape) if not a surgical candidate: proximal tumors, ↑ age, comorbidities, poor PS, need for laryngectomy, T4b (aorta/vertebra/trachea), tracheoesophageal fistula, or cervical SCC. Patients with a clinical response may defer resection and pursue salvage esophagectomy at recurrence (similar survival but ↑ surgical morbidity: anastomotic leak 25% vs 3%).
• Surgery alone for low-risk lesions: <3 cm, well differentiated, T1b.

• CRT then surgery: carbo/paclitaxel weekly × 5 + RT or FOLFOX + RT (treated like SCC).
• FLOT × 4 / surgery / FLOT × 4 (5-FU, leucovorin, oxaliplatin, docetaxel); FOLFOX or CAPOX can substitute. FLOT4-AIO: mOS 50 vs 35 mo (FLOT vs ECF); included GEJ 56% and gastric 44%. ECF (MAGIC regimen) is too toxic, do not use.
• AC has ↑ risk of distant recurrence, so systemic therapy to address micrometastatic disease is important.

• Neo-AEGIS (CROSS vs perioperative chemo, ~85% MAGIC/ECF and only ~15% FLOT, in esophageal/GEJ AC): same 3-yr OS ~57%, but ↑ R0 with CRT (95% vs 82%) and ↑ pCR (16% vs 5%) and ypN0 (60% vs 45%). CROSS uses only 5 weekly chemo doses vs 4 months of FLOT chemo.
• ESOPEC (Hoeppner, NEJM 2025): FLOT/surgery/FLOT vs CRT/surgery (esophageal AC): 3-yr OS 57.4% vs 50.7% favoring FLOT (HR 0.70, p=0.01); 3-yr PFS 51.6% vs 35.0%. Perioperative FLOT is now favored over CROSS for resectable esophageal/GEJ AC.
• Other studies: DANTE (perioperative FLOT ± atezolizumab in GEA: 8.5% MSI, 50% PD-L1+; downsizing pT0 23% vs 15%, pN0 68% vs 54%).
• No role for trastuzumab perioperatively: NRG Oncology/RTOG 1010 (trastuzumab added to carboplatin/paclitaxel CRT 50.4 Gy then surgery vs CRT alone in HER2+ esophageal AC) was negative.

Localized multimodality: gastric AC (distal/noncardia)

• FLOT × 4 / surgery / FLOT × 4 (FLOT4): mOS 50 vs 35 mo vs ECF. MAGIC established chemo/surgery/chemo with ECF, now replaced by FLOT due to superior OS (50 vs 35 mo, HR 0.77); serious AEs similar (~27% each) with different profiles. ECF → nausea/vomiting; FLOT → diarrhea, neutropenia, infection. Use FOLFOX instead of FLOT if poor PS.
• Upfront surgery with D2 resection:
  • Adjuvant chemo alone: CAPOX q3wk × 8 (CLASSIC) or FOLFOX × 6 mo (or S1-OX in Japan).
  • After adequate R0 D2 resection: adjuvant chemo alone (CAPOX ×8 CLASSIC or FOLFOX). Postop chemo/CRT/chemo (INT-0116) reserved for D0/D1 or R1, not routine by T stage.
  • INT-0116/Macdonald: adjuvant chemoRT (5-FU + RT) for patients who went straight to surgery (e.g., D0/D1); largely replaced by perioperative chemo.
• Upfront surgery is not preferred in locally advanced gastric ca → do perioperative treatment. If D2 was not performed, consider adjuvant chemo/CRT/chemo. R1 or R2 resection → postoperative CRT.
• Preoperative CRT and total neoadjuvant therapy (TNT) for GEA: TOPGEAR (added preop CRT to perioperative chemo [ECF/ECX or FLOT]; both arms had postop chemo, not TNT): higher pCR (17% vs 8%) but no OS benefit (46 vs 49 mo, HR 1.05); CRITICS-II (3 arms: DOC ×4, or DOC ×2 then CRT, or CRT alone, each then surgery).
• CALGB 80803 (PET-directed): switching from carbo/taxol to FOLFOX (or vice versa) during chemoRT (50.4 Gy) in interim-PET nonresponders (esophageal/GEJ AC) improved pCR to ~20% vs historical 5%. (Note: routine PET/PET-CT surveillance in asymptomatic patients after curative treatment does not improve outcomes.)
• MATTERHORN (Janjigian, ASCO 2025 plenary; NEJM 2025): perioperative durvalumab + FLOT (durva × 2 pre + × 2 post + × 10 durva monotherapy) vs placebo + FLOT in resectable stage II to IVA gastric/GEJ AC (all-comers, n=948): mEFS not reached vs 32.8 mo (HR 0.71, p=0.001); pCR 19% vs 7%. OS HR 0.78 (p=0.021). New perioperative standard option for resectable gastric/GEJ AC; FDA approved Nov 25, 2025.
• KEYNOTE-585 (Shitara, Lancet Oncol 2024; final analysis JCO 2025, PMID 40829093, OS HR 0.86 NS): perioperative pembrolizumab + chemo (cis+cape or FLOT) vs chemo did NOT meet the EFS endpoint (44 vs 25 mo, HR 0.81, p=0.0198 vs prespecified 0.0178), though pCR improved (13% vs 2%). Contrast with positive MATTERHORN.

Metastatic esophagogastric ca

• No or limited role of surgery; mOS ~10 to 12 mo with chemo alone (14 to 16 mo in HER2+ with trastuzumab; ~20 mo or more with current HER2+ regimens, KEYNOTE-811, HERIZON-GEA-01).
• Chemo backbones: single-agent ORR 10 to 20%; doublet ORR 40 to 50% with ↑ OS. Standard doublets: FOLFOX (replaced ECF per CALGB 80403) or FOLFIRI. Triplets (FLOT, FOLFOXIRI, FOLFIRINOX) have similar ORR but ↑ toxicity and are discouraged. Oxaliplatin preferred over cisplatin; epirubicin is abandoned.
• Irinotecan when: quick recurrence (<6 mo from surgery or adjuvant tx, after adjuvant FLOT or CRT with carbo/paclitaxel), or contraindications to platinum/taxane (e.g., severe baseline neuropathy).

• CPS ≥ 10 → pembrolizumab + chemo (FOLFOX preferred, or CAPOX or 5-FU/cis). KEYNOTE-590 included SCC and AC; OS benefit per NCCN in CPS ≥ 10 for both. (KEYNOTE-590 overall mOS 12.4 vs 9.8 mo; FDA Mar 22, 2021; label now restricted to CPS ≥ 1.)
• CPS ≥ 5 (AC) or tumor-cell PD-L1 ≥ 1% (SCC) → nivolumab + chemo (FOLFOX/CAPOX or 5-FU/cis). CheckMate 649 (AC): mOS 14.4 vs 11.1 mo in CPS ≥ 5 (HR 0.71); no benefit in CPS <5 (12.4 vs 12.3 mo). FDA Apr 2021 (label now CPS ≥ 1). CheckMate 648 (SCC): OS benefit in tumor-cell PD-L1 ≥ 1% (HR 0.54) and all patients (HR 0.74).
• MSI-H/dMMR (any PD-L1) → pembrolizumab or dostarlimab.
• CPS < 5 (low): SCC → chemo/ICI has benefit per meta-analysis (low threshold to stop ICI if AEs); AC → chemo alone (FOLFOX/CAPOX or 5-FU/cis). Ipi/nivo only for SCC.
• Tislelizumab + chemo (RATIONALE-305): FDA-approved 1L for HER2-negative gastric/GEJ AC with PD-L1 ≥ 1.
• Pembrolizumab + chemo (KEYNOTE-859): mOS 12.9 vs 11.5 mo (HR 0.78). FDA Nov 2023 (label now restricted to PD-L1 CPS ≥ 1).

• Pembrolizumab + trastuzumab + chemo (FOLFOX/CAPOX or 5-FU/cis). KEYNOTE-811 (gastric and GE AC): ORR 74% vs 52%, mPFS 10.0 vs 8.1 mo (HR 0.73), mOS 20.0 vs 16.8 mo, HR 0.80 (final analysis; CPS ≥ 1 20.1 vs 15.7 mo, HR 0.79; FDA full approval Mar 19, 2025). FDA May 5, 2021 (accelerated); Nov 7, 2023 label restricted to PD-L1 CPS ≥ 1 (no benefit in CPS < 1).
• Trastuzumab + FOLFOX if not an immunotherapy candidate (originally 5-FU/cis in ToGA). ToGA: mOS 13.8 vs 11.1 mo in the overall (all HER2+) population and 16.0 vs 11.8 mo in the high-expression subgroup (IHC 3+ or IHC 2+/FISH+); asymptomatic EF decline 4.6% vs 1.1%. FOLFOX without 5-FU bolus preferred for tolerance.
• HERIZON-GEA-01 (Shitara, NEJM 2026): 1L HER2+ advanced GEA, zanidatamab (HER2 bispecific) + chemo ± tislelizumab vs trastuzumab + chemo: mPFS 12.4 mo in both zanidatamab arms vs 8.1 mo (HR 0.63 with tislelizumab, 0.65 without); mOS 26.4 vs 19.2 mo with zanidatamab + tislelizumab + chemo (HR 0.72); zanidatamab + chemo OS not significant at interim (HR 0.80). Diarrhea is the main toxicity. FDA Aug 25, 2026: zanidatamab + tislelizumab + chemo 1L for HER2+ (IHC 3+ or 2+/ISH+) gastric, GEJ, or esophageal AC; zanidatamab + chemo for IHC 3+.
• Other first-line HER2 strategies not approved: high-dose trastuzumab (no benefit, HELOISE), lapatinib + CAPOX (LOGiC/TRIO-013, no trastuzumab), and pertuzumab + trastuzumab (JACOB) all failed.

• Zolbetuximab (Vyloy), anti-claudin 18.2 (expressed in 70 to 80% of gastric ca), + FOLFOX/CAPOX for HER2-negative, CLDN18.2+ (≥75% moderate-to-strong membranous staining). SPOTLIGHT (FOLFOX): mOS 18.2 vs 15.5 mo (HR 0.75); GLOW (CAPOX): mOS 14.4 vs 12.2 mo (HR 0.77). FDA Oct 18, 2024. Toxicity: severe nausea/vomiting (premedicate aggressively).
• Claudins are tight-junction proteins overexpressed in GEA. CLDN18 amplification in ~3% of gastric AC; CLDN18-ARHGAP26 fusions reduce cell-to-matrix adhesion and promote migration. The earlier FAST study of claudiximab + EOX showed PFS/OS benefit, most pronounced with >70% expression.

• 1L pembrolizumab + chemo (KEYNOTE-590, Sun Lancet 2021): mOS 12.4 vs 9.8 mo. FDA Mar 22, 2021.
• Nivolumab + ipilimumab OR nivo + chemo (CheckMate 648, Doki NEJM 2022): mOS 13.2 mo (nivo+chemo) and 12.7 mo (ipi+nivo) vs 10.7 mo. FDA May 27, 2022 (label now restricted to tumor PD-L1 ≥ 1).
• Tislelizumab (Tevimbra) + chemo (RATIONALE-306): 1L PD-L1+ ESCC mOS 16.8 vs 9.6 mo (HR 0.66). FDA Mar 4, 2025 (PD-L1 ≥ 1).

Second-line and later therapy

• Pembrolizumab if CPS ≥ 10 or MSI-H or TMB ≥ 10 mut/Mb (KEYNOTE-181, vs investigator choice of paclitaxel, docetaxel, or irinotecan): SCC with CPS ≥ 10 mOS 10.3 vs 6.7 mo; no benefit in CPS < 10 or in AC.
• Nivolumab (any CPS): ATTRACTION-3 (vs taxane) SCC mOS 10.9 vs 8.4 mo.
• Tislelizumab monotherapy 2L (RATIONALE-302): mOS 8.6 vs 6.3 mo (HR 0.70). FDA Mar 14, 2024 for ESCC after prior systemic chemotherapy not containing a PD-(L)1 inhibitor.
• Good PS → FOLFOX/FOLFIRI, taxane-based, or cis/5-FU. Borderline PS → single-agent irinotecan, 5-FU, docetaxel (75 q3wk; COUGAR-02 improved OS vs active symptom control, but enrolled adenocarcinoma, not SCC), paclitaxel, or weekly nab-paclitaxel.

• Ramucirumab + paclitaxel (RAINBOW), after progression on platinum/fluoropyrimidine: mOS 9.6 vs 7.4 mo, ORR 28% vs 16%, mPFS 4.4 vs 2.9 mo. Note: anti-VEGF/VEGFR failed in 1L (RAINFALL ramucirumab and AVAGAST bevacizumab negative for OS).
• Ramucirumab + FOLFIRI (RAMIRIS) if not a RAINBOW candidate (quick recurrence <6 mo after FLOT/CRT, or neurotoxicity).
• Chemo: single-agent irinotecan or FOLFIRI doublet (after platinum + taxane), taxane (after platinum + irinotecan), docetaxel, or TAS-102 (trifluridine-tipiracil, TAGS: mOS 5.7 vs 3.6 mo in 3L).
• Ramucirumab monotherapy (REGARD, after 1L fluoropyrimidine/platinum): mOS 5.2 vs 3.8 mo (↑↑ HTN).
• Not approved: 3L pembrolizumab CPS ≥ 1 (KEYNOTE-059 approval withdrawn for lack of OS benefit; ORR 57% vs 9% for MSI-H vs MSS), 3L nivolumab (ATTRACTION-02, Asia only, mOS 5.3 vs 4.14 mo), 3L avelumab (JAVELIN-300 worse OS).

• Trastuzumab deruxtecan (T-DXd) (DESTINY-Gastric01), after ≥2 lines including trastuzumab: ORR 51% vs 14%, mOS 12.5 vs 8.4 mo (HR 0.59), mPFS 5.6 vs 3.5 mo. AEs: myelosuppression and ILD/pneumonitis ~10%. Studied in 3L, FDA-approved in 2L (Jan 2021); HER2 not reconfirmed in the trial.
• DESTINY-Gastric02 (Van Cutsem, Lancet Oncol 2023, PMID 37329891): Western HER2+ gastric/GEJ after a trastuzumab-containing regimen; T-DXd 6.4 mg/kg: confirmed ORR 42%, mPFS 5.6 mo, mOS 12.1 mo (confirms Western activity).
• Ramucirumab + paclitaxel or + FOLFIRI, or ramucirumab monotherapy; chemo monotherapy (irinotecan, weekly paclitaxel, TAS-102); apatinib (oral VEGFR2 TKI, not chemo) is 3L+ in China, not FDA-approved.
• Other HER2 drugs failed in 2L: continued trastuzumab after progression (T-ACT); lapatinib + paclitaxel (TyTAN, 2L HER2-amplified Asian, only ~6% prior trastuzumab, so not a dedicated post-trastuzumab trial), ado-trastuzumab emtansine (GATSBY). HER2 status was often not reconfirmed and loss of HER2 was documented in 16 to 69%.

Other targeted therapy

• BRAF V600E: dabrafenib + trametinib.
• NTRK fusion: entrectinib or larotrectinib.
• RET fusion: selpercatinib.
• Margetuximab (anti-HER2 with optimized Fc for CD16A on NK cells) + pembrolizumab: phase II ORR 18% in 2L, 50% in PD-L1+/HER2 3+ (data from phase Ib/II; MAHOGANY (margetuximab + retifanlimab or tebotelimab) was discontinued, not a pending phase III).
• Zanidatamab: dual-epitope HER2, ORR ~75% with chemo.
• Failed strategies: anti-EGFR + chemo (EXPAND cetuximab, REAL-3 panitumumab), MET inhibitors (RILOMET-1 rilotumumab, METGastric onartuzumab), mTOR, PARP, matrix metalloproteinase, and STAT3 inhibition.

Summary: metastatic systemic therapy

Palliative care in advanced GEC

• Options for tumor-related esophageal or gastric outlet obstruction: RT, esophageal stents, laser, endoscopic dilation, and gastric/jejunal feeding tubes. Over 80% of patients benefit from systemic palliative chemo, so chemo is often given first, with RT or stenting for refractory symptoms.
• For refractory bleeding: endoscopic cautery, IR embolization, or RT.
• Thromboembolism is common; DOACs carry higher bleeding risk than enoxaparin when the primary tumor is in place.
• Carcinomatosis and ascites (especially gastric AC): venting gastrostomy, peritoneal drains, and somatostatin analogs can palliate refractory bowel obstruction. Oxaliplatin neuropathy responds to duloxetine; the OPTIMOX strategy limits cumulative neuropathy.

High-yield esophageal/gastric pearls

• Test all metastatic/recurrent disease for PD-L1, MSI/MMR, and NGS; add HER2 and CLDN18.2 in AC.
• CROSS: neoadjuvant carbo/paclitaxel + 41.4 Gy then surgery for esophageal SCC (and AC if FLOT not feasible; perioperative FLOT favored for resectable esophageal/GEJ AC per ESOPEC).
• FLOT: perioperative SOC for gastric/GEJ AC (add durvalumab per MATTERHORN, FDA Nov 25, 2025).
• CheckMate 577: adjuvant nivolumab × 1 yr if residual disease after neoadjuvant chemoRT + surgery with R0 resection (esophageal/GEJ AC or SCC); median DFS SCC 29.7 vs 11.0 mo (HR 0.61), AC 19.4 vs 11.1 mo (HR 0.75). FDA May 2021.
• CheckMate 649: nivolumab + chemo 1L for HER2-negative gastric/GEJ (especially CPS ≥ 5).
• KEYNOTE-811: pembrolizumab + trastuzumab + chemo for HER2+ gastric (CPS ≥ 1).
• DESTINY-Gastric01: T-DXd for HER2+ (after trastuzumab + chemo).
• Zolbetuximab (Vyloy): CLDN18.2 ≥ 75% moderate-to-strong IHC, HER2-negative, 1L. FDA Oct 18, 2024.
• Tislelizumab (Tevimbra): ESCC 2L (Mar 14, 2024) and 1L PD-L1 ≥ 1 (Mar 4, 2025); gastric/GEJ AC 1L PD-L1 ≥ 1 (Dec 2024).
• Plummer-Vinson (triad: iron-deficiency anemia + dysphagia + upper-esophageal webs; glossitis common; increased risk of post-cricoid/hypopharyngeal and esophageal SCC).
• Linitis plastica (diffuse gastric ca, leather-bottle stomach): consider germline CDH1; treat established cancer therapeutically. Risk-reducing (prophylactic) gastrectomy is for unaffected carriers.
• Krukenberg tumor: bilateral ovarian mets from gastric (or other GI) signet-ring AC.
• Sister Mary Joseph node (umbilical), Virchow node (left supraclavicular), Blumer shelf (rectal shelf): classic gastric ca metastases.