Gastric Cancer

Definition — adenocarcinoma in a resectable population

Gastric cancer for the surgeon means resectable adenocarcinoma of the stomach or gastroesophageal junction: histologically proven disease at clinical stage cT2 or higher, or node-positive (cN+), or both, with no evidence of distant metastases — the entry population of every modern perioperative trial.^[1] Behaviour splits by Lauren type: in early-onset early-stage disease, intestinal type, T1b stage, and tumour size above 3 cm are the independent risk factors for lymph-node metastasis, and intestinal-type early disease carries poorer prognosis than diffuse-type.^[27] The infectious anchor is Helicobacter pylori, the most important risk factor in gastric carcinogenesis, whose eradication confers durable long-term protection.^[53]

Hereditary diffuse disease — CDH1, testing, gastrectomy versus surveillance

Hereditary diffuse gastric cancer is an autosomal dominant syndrome of diffuse gastric plus lobular breast cancer, largely caused by inactivating germline CDH1 mutations with CTNNA1 pathogenic variants in a minority of families.^[24] Test by the 2015 criteria: two or more gastric cancers with one confirmed diffuse case; diffuse cancer before age 40; diffuse plus lobular breast cancer with one diagnosis before 50 — with consideration for bilateral or familial lobular breast cancer before 50, diffuse cancer with cleft lip or palate, and signet-ring precursor lesions.^[25] Management is binary but no longer absolute: prophylactic total gastrectomy at a centre of expertise remains the recommended option for pathogenic CDH1 carriers, yet the 2020 IGCLC position accepts expert-centre endoscopic surveillance for patients who wish to postpone surgery or whose risk is undefined, under relaxed testing criteria with less restrictive age limits.^[24] Surveillance works only when done properly: signet-ring lesions are found in half of carriers under surveillance, targeted biopsies are positive in 11% against 0.9% for random biopsies, and over two-thirds of resection-positive cases had their lesions detected on biopsy — random sampling alone is inadequate.^[26] Women with CDH1 mutations need annual breast MRI from age 30.^[25]

Presentation and the resectability frame

Present resectability in trial language, not adjectives: cT2-or-higher or cN+ and M0 is potentially curable and belongs on a perioperative pathway; anything less staged belongs to palliation or the conversion frontier below.^[1][19] The cT2 data make the viva point: primary surgery versus neoadjuvant-then-surgery gives median overall survival of 51.0 against 114.0 months, with the benefit holding after propensity matching in cT2N0 disease — so every junctional or gastric cT2, node-negative included, is offered multimodal therapy.^[28] What this topic does not claim matters too: with the staging angle empty, no peritoneal-cytology numbers and no AJCC-8th specifics appear here — stage by resectable-versus-metastatic plus Siewert anatomy.^[37]

FLOT4 — the perioperative backbone

FLOT4 randomised 716 patients to perioperative FLOT against ECF/ECX and changed practice: overall-survival hazard ratio 0.77 with medians of 50 against 35 months — a 15-month median gain.^[1] The regimen to recite: four preoperative plus four postoperative 2-week cycles of docetaxel 50 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2600 mg/m² as 24-hour infusion, against three-plus-three 3-week ECF/ECX cycles.^[1] Toxicity is the reassuring half of the verdict: related serious adverse events 27% in both arms, toxic deaths two per arm, hospitalisation for toxicity 26% versus 25% — efficacy without excess severe toxicity.^[1] The pathologic down-payment came from the phase-2 part: complete regression (TRG1a) in 16% against 6%, with 93% versus 92% completing all planned preoperative cycles.^[2] Set the historical contrast for the examiner: the pre-FLOT neoadjuvant-versus-surgery meta-analysis (6 trials, 781 patients) showed overall-survival odds ratio 1.16 and R0 odds ratio 1.24, both non-significant — the negative equipoise that FLOT4 overturned.^[3]

Asian perioperative doctrine — PRODIGY, RESONANCE, PECORINO

Korea's PRODIGY proved perioperative therapy travels: neoadjuvant docetaxel-oxaliplatin-S-1 before D2 surgery and adjuvant S-1 improved progression-free survival with adjusted hazard ratio 0.70 — priced at two grade-5 neoadjuvant events, febrile neutropenia and dyspnea.^[9] China's RESONANCE showed the mechanism of perioperative gain: S-1 plus oxaliplatin before and after surgery versus surgery-then-chemotherapy gave 3-year disease-free survival of 61.7% against 53.8% with R0 resection of 94.9% against 83.7% — and identical surgical outcomes and complications, so the gain is oncologic, not technical.^[10] PECORINO is the regimen warning: in 69 randomised patients, curative surgery after neoadjuvant therapy was achieved in 94.3% with FLOT against 67.6% with XELOX, completion rates were identical, yet 2-year progression-free proportions were 45.7% against 18.8% — and the trial stopped early for XELOX preoperative inferiority through disease progression.^[13] The exam line: FLOT completion is achievable; XELOX fails before the operation, not after it.

Perioperative chemo-immunotherapy — four trials, one cautionary tale

MATTERHORN added durvalumab to FLOT in 948 patients: 2-year event-free survival 67.4% against 58.5% (hazard ratio 0.71, highly significant), pathological complete response 19.2% against 7.2% — but 2-year overall survival of 75.7% against 70.4% with a P-value of 0.03 against a threshold of 0.0001, which is not significant — and grade 3/4 adverse events identical near 71%.^[4] KEYNOTE-585 is the cautionary tale: pembrolizumab plus chemotherapy tripled pathological complete response (12.9% against 2.0%) yet event-free survival (hazard ratio 0.81, P = 0.0198 against threshold 0.0178) and overall survival (hazard ratio 0.90) both missed significance — and final analysis at nearly 5 years still showed survival hazard ratio 0.86 with confidence interval crossing unity.^[5][6] Pathologic response does not guarantee survival; quote the pair together. DANTE's phase-II signal points where the benefit concentrates: atezolizumab plus FLOT gave complete regression in 24% against 15% overall, 33% against 12% in PD-L1 CPS ≥10, and 63% against 27% in microsatellite-unstable tumours — with R0 near 96% in both arms and surgical morbidity indistinguishable.^[7] ASTRUM-006 confirms the CPS-stratified positive: serplulimab plus SOX in CPS ≥5 disease gave event-free survival not-reached against 42.0 months in CPS ≥10 (hazard ratio 0.65) and not-reached against 35.9 months overall (hazard ratio 0.73) — with grade ≥3 treatment-related events paradoxically lower at 47% against 59%.^[8] The phase-2 next wave agrees on direction: camrelizumab plus apatinib with chemotherapy raised major pathologic response (33.3% against 17.0%), objective response, and R0 (94.1% against 81.1%), while DRAGON IV's rivoceranib combination raised pathological complete response from 5.0% to 18.3% at the cost of more grade ≥3 neoadjuvant toxicity (34% against 17%) with surgical complications unchanged.^[11][12]

Chemoradiotherapy versus chemotherapy, and the junctional answer

Two meta-analyses favour neoadjuvant chemoradiotherapy on response: pathological complete response risk ratio 3.39 and odds ratio 4.39, R0 risk ratio 1.18 and odds ratio 2.21, 3-year survival hazard ratio 0.89 — but 5-year survival hazard ratio 1.03 is null, postoperative complications are identical, and gastrointestinal toxicity is higher.^[30][31] The Chinese phase III makes the same point prospectively: preoperative chemoradiotherapy against chemotherapy gave 3-year disease-free survival of 53.6% against 53.9% and overall survival of 62.8% against 60.5% — despite complete response of 12.0% against 2.1% and R0 of 81.0% against 74.5% — before premature termination.^[32] Same lesson as KEYNOTE-585: response without survival. For oesophageal and junctional adenocarcinoma, Neo-AEGIS (362 intention-to-treat) reports median survival of 48.0 against 49.2 months and 3-year survival of 55% against 57% (hazard ratio 1.03) — while complete response, major response, and R0 all favoured CROSS trimodality, neutropenia ran 27% against 6%, and operative mortality was 3% against 2% with quality of life identical.^[29] Response favours radiation; survival does not separate; equipoise continues.

D2 lymphadenectomy — cancer-specific wins, overall draws, age exceptions

The Dutch 15-year follow-up (711 treated with curative intent) is the doctrine's foundation: overall survival 21% against 29% is non-significant, but gastric-cancer death (48% against 37%), local recurrence (22% against 12%), and regional recurrence (19% against 13%) all favour D2 — priced at operative mortality of 10% against 4%, complications of 43% against 25%, and reoperations of 18% against 8%.^[14] Italy's 15-year data (267 patients) refine the indication: overall survival and disease-specific survival identical, but in pT>1N+ disease, disease-specific survival of 29.4% against 51.4% favours D2 — while patients over 70 and early-stage disease do better with D1.^[15] The 5-year Italian read agrees: overall survival 66.5% against 64.2% with equal morbidity and mortality, pT1 disease-specific survival of 98% with D1 against 83% with D2, and pT2–4 node-positive survival of 59% with D2 against 38% with D1.^[16] Price the history honestly: the MRC trial's D2 mortality of 13% against 6.5% with morbidity of 46% against 28% was driven by routine distal pancreaticosplenectomy and splenectomy — the obsolete manoeuvre behind the old D2 penalty.^[17] The six-trial meta-analysis (1,876 patients) still favours D1 on stay (−6.37 days), complications (odds ratio 0.42), anastomotic breakdown (0.40), and reoperation (0.33) — which is why the modern answer is conditional: spleen-preserving D2 in high-volume centres for resectable curable disease, D1 preferred beyond age 70 and in early disease.^[18][14][15]

Minimally invasive gastrectomy — LOGICA and the meta-analytic settlement

LOGICA randomised 227 Dutch patients (two-thirds-plus preop chemotherapy) to laparoscopic or open gastrectomy and refused the expected answer: median stay 7 days in both arms — laparoscopy did not shorten hospitalisation — with blood loss of 150 against 300 mL, operating time of 216 against 182 minutes, complications of 44% against 42%, R0 of 95% in both, nodal yield of 29 against 29, and 1-year survival of 76% against 78%.^[19] The advanced-disease meta-analysis (9 trials, 3,827 patients) settles the pattern: longer operations (+49 minutes), less blood (−51 mL), shorter stay (−0.83 days), more pancreatic fistula (risk ratio 2.44), equivalent nodes and mortality — and 3- and 5-year overall and relapse-free survival both at risk ratio 0.99.^[20] Distal gastrectomy data agree across 22 trials — less blood, longer operations, faster bowel recovery, fewer complications, equal nodes and margins — with the Cochrane count of 13 trials and 2,794 patients as the methods anchor.^[22][21] For the reconstruction question, intracorporeal against extracorporeal oesophagojejunostomy (17 studies, 2,960 patients) gives less stricture, bleeding, and surgical-site infection with identical leak rates and identical nodes, stay, and mortality.^[23]

Siewert junction strategy — retrospective conflict, no randomised verdict

Two meta-analyses disagree in direction, which is the exam answer. Transhiatal against transthoracic (11 studies, 2,331 patients) favours the transhiatal route — less blood, shorter stay, fewer pulmonary complications, longer 3-year survival — especially with esophageal invasion at or below 4 cm.^[33] Transabdominal against transthoracic (12 studies, 2,011 patients) finds everything comparable: operative time, nodes, complications, leak, death, recurrence, and 3- and 5-year survival all non-significant.^[34] The high-volume counterweight favours thoracic access: transthoracic esophagectomy against transhiatal gastrectomy in 800 neoadjuvantly treated type-II patients gives median survival of 78.0 against 40.0 months with the benefit surviving matching, plus higher nodal yield and R0 — and the registry analysis (999 esophagectomies against 8,595 gastrectomies, matched) gives median 51 against 68 months with hazard ratio 1.22 favouring esophagectomy.^[35][36] A smaller retrospective series agrees on short-term harm from thoracoabdominal access (Clavien-Dindo ≥III 4.4% against 30%) but carries no randomised weight.^[38] State the position plainly: retrospective conflict in opposite directions means no randomised verdict — CARDIA (262 planned patients, transthoracic esophagectomy against transhiatal extended gastrectomy for type-II tumours defined by midpoint ≤1 cm above to ≤2 cm below the folds, primary endpoint survival) is the awaited answer.^[37] And even junctional cT2N0 gets multimodal therapy given the understaging arithmetic above.^[28]

Early gastric cancer — keep the stomach, price the surveillance

Endoscopic submucosal dissection against gastrectomy trades equivalent survival for retained stomach plus surveillance: 5-year overall survival 96% against 96%, disease-specific 99.4% against 99.2%, disease-free non-significant — but recurrence-free 92.4% against 98.3%, recurrence risk ratio 2.5, synchronous-cancer risk ratio 5.7, metachronous-cancer risk ratio 10.1.^[39] The expanded-indication analysis (522 matched pairs across four criteria, including undifferentiated ≤2 cm and sm1 ≤3 cm) keeps overall and disease-specific survival non-significant in every subgroup — with recurrence-free survival shorter after ESD.^[42] Population data concur (matched cancer-specific hazard ratio 0.87, non-significant), and undifferentiated-type series show R0 of 86% against 98% with stays of 6.8 against 17.6 days and 5-year survival of 93% against 90%.^[41][43] The salvage rule is absolute: after non-curative ESD (17 cohorts, 5,880 patients), additional gastrectomy beats non-gastrectomy treatment — 5-year survival odds ratio 3.63, disease-specific 3.22, disease-free 4.39, hazard ratio 0.40 — including in the elderly (hazard ratio 0.54).^[40]

H. pylori eradication — the prevention arithmetic

The community proof comes from Linqu County: 180,284 participants over 11.8 years, intention-to-treat hazard ratio 0.86, strengthening to 0.81 with successful eradication.^[51] Duration strengthens the case: 26.5-year follow-up gives hazard ratio 0.57 overall, 0.37 without premalignant lesions at baseline, and 0.46 with successful eradication — with mortality endpoints non-significant.^[53] Two special populations sharpen the indication: after endoscopic resection, eradication halves metachronous cancer (7.2% against 13.4%, hazard ratio 0.50) while improving corpus atrophy (48.4% against 15.0%); in first-degree relatives, cancer falls from 2.7% to 1.2% (hazard ratio 0.45), and eradicated-against-persistent infection gives hazard ratio 0.27.^[54][55] Synthesis: healthy-individual risk ratio 0.54 (number needed to treat 72) with mortality risk ratio 0.61 (NNT 135), post-neoplasia risk ratio 0.49 (NNT 21) — updated in 2025 to 0.64 in healthy and 0.52 after endoscopic resection with mortality risk ratio 0.78 — against Cochrane's moderate-certainty verdict explicitly limited to Asian populations.^[52][57][56] And the screening caveat: Taiwan's 240,000-person invitation trial found incidence (0.032% against 0.037%) and mortality both non-significant on intention-to-screen — benefit appeared only after participation-adjusted analysis (0.79) — because invitation is not treatment.^[50]

Complications — duodenal stump leak, rescue, and drains

Stump-leak rates form a case-mix ladder: 0.93% across 16,475 Japanese multicentre patients, 2.6% across 2,422 European high-volume patients, 7.7% in a single-centre mixed elective-emergency cohort — volume and case-mix explain the spread.^[44][47][45] Prevention is reinforcement: 0.72% against 1.19% with seromuscular sutures or reinforced staplers, unreinforced stump an independent multinational risk, and purse-string reinforcement with zero cases against 0.6% for interrupted sutures.^[44][47][46] Memorise the independent risks: male sex, age ≥75, node-positive disease, BMI ≥25, laparoscopic approach, duodenal invasion or ulcer, contamination, low haemoglobin, duodenostomy, preoperative weight loss, Billroth II reconstruction, and postoperative transfusion.^{[44][46][47][45]} Price the rescue: stump-leak mortality runs 7.8% to 17.2% at 90 days; interventional radiology succeeds in 75%, reoperation in 74.4%; endoscopic clipping-or-stent closes 80% overall — but stump sites only 60% against 86–94% elsewhere, with stump location (adjusted odds ratio 4.51) and abscess (4.92) predicting failure — so drain adequately, feed, give antibiotics, and escalate by severity.^{[44][47][49][45]} Routine prophylactic drains, meanwhile, fail their audit: no-drain patients have fewer total complications (odds ratio 0.68), earlier soft diet, and shorter stay, with leak, abscess, reoperation, and mortality all identical — routine drainage is unnecessary and possibly harmful.^[48]

Frontier — conversion surgery is investigational

For initially unresectable stage-IV disease with remarkable chemotherapy response, JCOG2301 randomises conversion surgery against chemotherapy alone for overall survival — 126 planned patients across 63 Japanese institutions — with no results to quote.^[58] Name it as the frontier, never as doctrine.

Revision summary

Resectable gastric cancer is cT2-or-higher or node-positive M0 disease with Lauren-stratified nodal risk and H. pylori causation.^[1][27][53] CDH1 carriers choose expert gastrectomy or expert surveillance with targeted biopsies, plus breast MRI from 30.^[24][26][25] Even cT2N0 gets multimodal therapy for the understaging trap.^[28] FLOT (hazard ratio 0.77, medians 50 against 35 months) is the backbone; PRODIGY and RESONANCE extend it to Asia; XELOX fails preoperatively.^{[1][9][10][13]} Immunotherapy adds event-free and pathologic gains concentrated in CPS-high and MSI disease — but KEYNOTE-585 proves response need not mean survival.^[4][5][7][8] Radiation improves response, not survival; Neo-AEGIS keeps junctional equipoise.^[30][32][29] D2 is cancer-specific, not overall, except advanced node-positive disease — spleen-preserving, high-volume, with D1 beyond 70 and in early cancer.^[14][15][17] Laparoscopy matches open oncology without shortening Western stay; Siewert-II awaits CARDIA.^[19][37] ESD equals surgery on survival at the price of metachronous surveillance — and non-curative ESD mandates gastrectomy.^[39][40] Eradication halves individual risk within Asian-evidence limits.^[52][56] Reinforce every stump; drain by indication, not routine.^[44][48]

SRCC found in 50% of carriers under surveillance; targeted biopsies positive in 11% vs 0.9% random; 69% of SRCC-positive resections had lesions detected on biopsy — random sampling alone is inadequate (PMID 32408363).^[17][26] curative surgery after neoadjuvant therapy 94.3% vs 67.6%; completion 54.3% vs 50% NS; 2-yr PFS 45.7% vs 18.8%; early termination for XELOX inferiority — FLOT completion is achievable, XELOX preop progression is the examinable failure (PMID 40672074).^[13]

References58ShowHide

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