Trimodality treatment in gastric and gastroesophageal junction cancers: Current approach and future perspectives

Table 1 Postoperative chemoradiation clinical trials

Study name/phase	Size/stage/primary tumor location/histology	Intervention	Primary endpoint
INT-0116/phase III[37]	556 patients, IB-IVM0/stomach/adenocarcinoma	Gastrectomy D0-2 (both arms) AND E: 5-FU/LV + 45Gy radiation OR C: No post-surgical treatment	mOS: 27 m control vs 36 m experimental, HR: 1.35 (95% CI: 1.09-1.66, P = 0.005)
McNamara et al[87]/phase II	60 patients/T3-4/N1/M1a/esophagus/22% GEJ 78%/adenocarcinoma	Induction epirubicin, oxaliplatin, 5-FU → gastrectomy → E: adjuvant concurrent cisplatin, 5-FU + 50 to 55 Gy radiation	Surgical resection: 90% underwent surgical resection
Adelstein et al[39]/phase II	50 patients/T3/N1/M1a/esophagus/ 28% GEJ 72% adenocarcinoma 86% SCC 14%	Gastrectomy → E: cisplatin, 5-FU + 50.4-59.4 Gy radiation	OS rate: 51% 4-yr OS rate
Xie et al[42]/phase III	144 patients/T3-4/N1-3/stomach/adenocarcinoma	Gastrectomy D2 (both arms) AND E: capecitabine, oxaliplatin, 45 Gy radiation OR C: capecitabine, oxaliplatin	DFS rate: 72.8% experimental vs 76.3% control 3-yr DFS rate (P = 0.868)
ARTIST/phase III[43]	458 patients, IB-IV/stomach/adenocarcinoma (39% intestinal, 57% diffuse)	Gastrectomy D2 (both arms) AND E: capecitabine, cisplatin + 45 Gy radiation OR C: capecitabine, cisplatin	DFS rate: 78% experimental vs 74% control 3-yr DFS rate P = 0.0862
CRITICS/phase III[44]	788 patients/IΒ-IVA/stomach/ 83% GEJ 17% adenocarcinoma (32% intestinal 30% diffuse)	Preoperative epirubicin, cisplatin or oxaliplatin, capecitabine → Gastrectomy D1 (both arms) AND E: epirubicin, cisplatin or oxaliplatin, capecitabine or 5-FU + 45 Gy radiation OR C: epirubicin, cisplatin or oxaliplatin, capecitabine or 5-FU	mOS: 43 m control vs 37m experimental HR 1.01 (95%CI: 0.84-1.22; P = 0.90)
ARTIST 2/phase III[46]	538 patients/II/III N+/stomach/adenocarcinoma	Gastrectomy D2 (both arms) AND E1: S-1, oxaliplatin, + 45 Gy radiation OR E2: S-1, oxaliplatin ΟR C: S-1	DFS rate: 65% control, 78% experimental 2, 73% experimental 1 3-yr DFS rate experimental 2 vs experimental 1 HR 0.910, (P = 0.667)

mOS: Median overall survival; mDFS: Median disease-free survival; mPFS: Median progression-free survival; E: Experimental; C: Control; HR: Hazard ratio; 5-FU: 5-fluorouracil; LV: Leucovorin; Gy: Gray; S-1: Tegafur/gimeracil/oteracil; pCR: Pathologic complete response; GEJ: Gastroesophageal junction; CRT: Chemoradiation; AEG: Adenocarcinomas of the esophagogastric junction.

Table 2 Preoperative chemoradiation clinical trials

Study name/phase	Size/stage/primary tumor location/histology	Intervention	Primary endpoint
Rivera et al[47]/phase II	23 patients/II-IV, M0/stomach/57% GEJ 43% adenocarcinoma	Irinotecan, cisplatin + 45 Gy radiation → surgery	pCR: 2/23 (9%) achieved pCR after CRT
RTOG 9904/phase II[48]	43 patients/IB-III/stomach/adenocarcinoma	Cisplatin, 5-FU/LV + 45 Gy radiation → gastrectomy	pCR: 26% achieved pCR
S0356/phase II[49]	93 patients/II-III/esophagus/60% GEJ 40% adenocarcinoma	Oxaliplatin, 5-FU + 45 Gy radiation → surgery	pCR: 28% achieved pCR
Ilson et al[50]/phase II	55 patients/uT1N1M0-uT2-4NanyM0/esophagus 67% GEJ 33%/adenocarcinoma 75% SCC 22%	Cisplatin, irinotecan + 50.4 Gy radiation → surgery	pCR: 16% achieved pCR
Ajani et al[51]/phase II	126 patients/II-III/esophagus 3.2% GEJ 96.8% (AEG1 64.3%, AEG2 32.5%)/adenocarcinoma 96.8% SCC 3.2%	E: induction oxaliplatin, 5-FU OR C: no induction chemotherapy AND oxaliplatin, 5-FU + 50.4 Gy radiation → surgery (both arms)	pCR: 13% control vs 26% experimental (P = 0.094)
NeoRes/phase II[54]	181 patients/T1-3, Nany (except T1N0)/esophagus 82% GEJ 18%/adenocarcinoma 72% SCC 28%	E: cisplatin, 5-FU + 40 Gy radiation OR C: cisplatin, 5-FUAND surgery (both arms)	pCR: 28% experimental vs 9% control
CALGB 9781/phase III[56]	56 patients/T1-3Nany/esophagus/ GEJ adenocarcinoma 75% SCC 25%	E: cisplatin, 5-FU + 50.4 Gy radiation OR C: no preoperative treatment AND surgery (both arms)	mOS: 4.48 y experimental vs 1.79 y control (P = 0.002)
POET/phase III[52]	119 patients/T3-4/GEJ/adenocarcinoma	E: induction cisplatin, 5-FU/LV → cisplatin, etoposide + 30 Gy radiation OR C: cisplatin, 5-FU/LV AND surgery	OS rate: 46.7% experimental vs 26.1% control 3-yr OS HR 0.65, (95%CI: 0.42-1.01, P = 0.055)
CROSS/phase III[57]	366 patients/T1N1, T2-3N0-1/esophagus 73.2% GEJ 24%/adenocarcinoma 75% SCC 23%	E: carboplatin, paclitaxel + 41.4 Gy radiation OR C: no chemoradiation AND surgery (both arms)	mOS: 49.4 m experimental vs 24 m control HR 0.657, (95%CI: 0.495-0.871, P = 0.003)
Neo-AEGIS/phase III[60]	377/cT2-3N0-3M0/esophagus GEJ/adenocarcinoma	E: carboplatin, paclitaxel + 41.4 Gy radiation OR C: epirubicin, cisplatin/oxaliplatin, 5-FU/capecitabine or docetaxel, oxaliplatin, leucovorin, 5-FU ANDsurgery (all arms)	OS rate: 56% experimental vs 57% 3-yr OS HR 1.02, (95%CI: 0.74-1.42)

mOS: Median overall survival; mDFS: Median disease-free survival; mPFS: Median progression-free survival; E: Experimental; C: Control; HR: Hazard ratio; 5-FU: 5-fluorouracil; LV: Leucovorin; Gy: Gray; S-1: Tegafur/gimeracil/oteracil; pCR: Pathologic complete response; GEJ: Gastroesophageal junction; CRT: Chemoradiation; AEG: Adenocarcinomas of the esophagogastric junction.

Table 3 Chemoradiation and targeted therapies clinical trials

Study name/phase	Size/stage/primary tumor location/histology	Intervention	Primary endpoint
Ku et al[72]/phase II	33 patients/uT2-3N0-1/esophagus 33% GEJ 66%/adenocarcinoma	E: cisplatin, irinotecan + bevacizumab + 50.4 Gy radiation → surgery	Tolerability: 59% grade 3/4 hematologic toxicity 42% grade 3/4 non-hematologic toxicity (including deep vein thrombosis)
TOXAG/phase II[70]	34 patients/76% > IIIA/stomach GEJ/adenocarcinoma HER2 positive	E: gastrectomy D2 → oxaliplatin, capecitabine + 45 Gy radiation + trastuzumab	Tolerability: 90.3% completed 3 cycles of treatment
SAKK 75/08/phase III[71]	300 patients/T2N1-3, T3Nany, T4aNany/esophagus 50% GEJ 50%/adenocarcinoma 64% SCC 36%	E: docetaxel, cisplatin + 45 Gy radiation + cetuximab → surgery → cetuximab OR C: docetaxel, cisplatin + 45 Gy radiation AND surgery (both arms)	mPFS: 2.9 y experimental vs 2 y control HR 0.79; (95%CI: 0.58 to 1.07, P = 0.13)
RTOG 1010/phase III[69]	203 patients/T1N1-2, T2-3N0-2/esophagus GEJ/adenocarcinoma HER2 positive	E: carboplatin, paclitaxel + 50.4 Gy radiation + trastuzumab → surgery → trastuzumab ORC: carboplatin, paclitaxel + 50.4Gy radiation → Surgery	mDFS: 19.6 m experimental vs 14.2 control HR 0.97 (95%CI: 0.69-1.36)
CheckMate 577/phase III[66]	794 patients/II-III, ≥ ypT1 or ≥ ypN1/esophagus 60% GEJ 40%/adenocarcinoma 71% SCC 29%	Neoadjuvant chemoradiation → surgery (both arms) AND E: nivolumab OR C: placebo	mDFS: 22.4 m experimental vs 11 m control HR 0.69 (95%CI: 0.56-0.86, P = 0.0003)

mOS: Median overall survival; mDFS: Median disease-free survival; mPFS: Median progression-free survival; E: Experimental; C: Control; HR: Hazard ratio; 5-FU: 5-fluorouracil; LV: Leucovorin; Gy: Gray; S-1: Tegafur/gimeracil/oteracil; pCR: Pathologic complete response; GEJ: Gastroesophageal junction; CRT: Chemoradiation; AEG: Adenocarcinomas of the esophagogastric junction.

Table 4 Clinical trials comparing chemotherapy regimens

Study name/phase	Size/stage/primary tumor location/histology	Intervention	Primary endpoint
ECOG E7296/phase II[74]	38 patients/T2N1-2, T3-4Nany/stomach 45% GEJ 55%/adenocarcinoma 95% SCC 5%	E: neoadjuvant cisplatin, paclitaxel → surgery → 5-FU/LV + 45 Gy radiation	Tolerability: 66% grade 3/4 toxicities during neoadjuvant treatment 7.9% completed per protocol treatment
CALGB 80803/ Phase II[76]	241 patients/T1N1-3M0, T2-4NanyM0 (resectable)/esophagus GEJ adenocarcinoma	E1: induction oxaliplatin, 5-FU/LV OR E2: induction carboplatin, paclitaxelAND PET scan → non-responders change chemotherapy arm, responders continue → chemotherapy + 50,4 Gy radiation → surgery (both arms)	pCR: 18% [95%CI (7.5-33.5)] experimental 1; and 20% [95%CI (10, 33.7)] experimental 2 of PET non-responders who switched chemotherapy arm achieved pCR
E1201/phase II[77]	81 patients/II-Iva/esophagus GEJ/adenocarcinoma	E1: preoperative cisplatin, irinotecan + 45 Gy radiation → surgery → cisplatin, irinotecan OR E2: preoperative cisplatin, paclitaxel + 45 Gy radiation → surgery → cisplatin, paclitaxel	pCR: 15.4%, exact, unadjusted 90% binomial CI: 6.9%-28.1% experimental 1 and 16.7%, exact, unadjusted 90% binomial CI: 8.1%-29.0% experimental 2 achieved pCR
RTOG-0114/phase II[78]	73 patients/IB-IIIB/stomach/adenocarcinoma	Gastrectomy (both arms) AND E1: cisplatin, paclitaxel, 5-FU + 45 Gy radiation OR E2: cisplatin, paclitaxel + 45 Gy radiation	DFS rate: E1 closed early due to toxicity (14.6 m DFS) 52% (95%CI: 36%-68%) experimental 2 2-yr DFS
NCCTG N0849/phase II[79]	42 patients/T3-4N0, TanyN+/III-IVA/esophagus/55% GEJ 40% cardia 3.6% adenocarcinoma	E: induction docetaxel, oxaliplatin, capecitabine OR C: no induction AND oxaliplatin, 5-FU + 50.4 Gy radiation → surgery (both arms)	pCR: 33% experimental and 48% control achieved pCR
CALGB 80101/phase III[80]	546 patients/IB-IV (M0)/stomach 78% (4% proximal gastric, 41% distal gastric, 15% stomach NOS, 17% multicentric) GEJ 22%/adenocarcinoma	Surgery (both arms) AND E: epirubicin, cisplatin, 5-FU → 5-FU + 45 Gy radiation → chemotherapy OR C: 5-FU/LV → 5-FU + 45 Gy radiation → chemotherapy	OS rate: 44% control vs 44% experimental multivariate HR 0.98 (95%CI: 0.78-1.24, P = 0.69) 5-yr OS
PRODIGE5/ACCORD17 phase II/III[81]	259 patients/I-IVA/esophagus/adenocarcinoma 14% SCC 86%	E: oxaliplatin, 5-FU/LV + 50 Gy radiation OR C: cisplatin, 5-FU + 50 Gy radiation	mPFS: 9.7 m experimental vs 9.4 m control HR 0.93 (95%CI: 0.70-1.24, P = 0.64)

mOS: Median overall survival; mDFS: Median disease-free survival; mPFS: Median progression-free survival; E: Experimental; C: Control; HR: Hazard ratio; 5-FU: 5-fluorouracil; LV: Leucovorin; Gy: Gray; S-1: Tegafur/gimeracil/oteracil; pCR: Pathologic complete response; PET: Positron emission tomography; GEJ: Gastroesophageal junction; CRT: Chemoradiation; AEG: Adenocarcinomas of the esophagogastric junction.

Table 5 Ongoing clinical trials

Study name/phase	Size/stage/primary tumor location/histology	Intervention	Primary endpoint
NCT02730546/Phase Ib/II suspended	68 patients/IB-IIIB/GEJ cardia/adenocarcinoma	E: carboplatin, paclitaxel + radiation or 5-FU, oxaliplatin, leucovorin + pembrolizumab → surgery	pCR and 1-yr PFS rate
PROCEED/phase II/NCT03064490recruiting	38 patients/locally advanced stomach GEJ esophagus/adenocarcinoma	E: carboplatin, paclitaxel + 45 Gy radiation + pembrolizumab → surgery → pembrolizumab	pCR
NCT03257163/phase II recruiting	40 patients/IB-IIIC/gastric adenocarcinoma MSI or EBV positive	E: pembrolizumab → surgery → pembrolizumab + capecitabine + radiation	3-yr RFS rate
NCT03776487/phase I/II recruiting	30 patients/0-IVA/stomach GEJ/adenocarcinoma	E: oxaliplatin, 5-FU + nivolumab, ipilimumab + radiation → surgery → nivolumab	Tolerability
NCT00857246/phase II/completed	30 patients/T3N0, T4, TanyN1-3, M0/stomach GEJ	E: induction cisplatin, irinotecan + cetuximab → surgery → cetuximab + 5-FU/LV + 37.5 Gy radiation	RR
NCT01183559/phase I/completed	9 patients/potentially resectable/esophagus GEJ stomach	E: vandetanib + carboplatin, paclitaxel + 5-FU + 45 Gy radiation → surgery	Maximum tolerated dose: 200 mg vandetanib
NCT04162665/recruiting	36 patients/T1-T2N1, T3Nany/stomach AEG3/adenocarcinoma	E: MRI guided 25 Gy radiation + oxaliplatin, capecitabine	pCR
NCT04308837/phase II recruiting	29 patients/uT3-4NanyM0/stomach	E: laparoscopic hyperthermic intraperitoneal chemotherapy → carboplatin, paclitaxel + IM radiation T>6M → gastrectomy D2 → oxaliplatin, 5-FU/LV	pCR
CRITICS-II/phase II/NCT02931890/recruiting[83]	207 patients/IB-IIIC/resectable/stomach GEJ/adenocarcinoma	E1: docetaxel, oxaliplatin, capecitabine OR E2: induction docetaxel, oxaliplatin, capecitabine → carboplatin, paclitaxel + 45 Gy radiation OR E3: carboplatin, paclitaxel + 45 Gy radiation AND gastrectomy (all arms)	1-yr EFS rate
Neo-CRAG/phase III	620 patients/cT3N2/N3M0, cT4aN + M0, cT4bNanyM0/gastric adenocarcinoma	E: oxaliplatin, capecitabine + 45 Gy radiation OR C: oxaliplatin, capecitabine AND gastrectomy D2 → oxaliplatin, capecitabine (both arms)	3-yr DFS rate
PREACT/phase III	682 patients/IIB (T3N1 only)-IIIC (excluding T2N3)/stomach GEJ (excluding AEG1)/adenocarcinoma	E: S-1, oxaliplatin + 45 Gy radiation OR C: S-1, oxaliplatin AND gastrectomy D2 → S-1, oxaliplatin (both arms)	3-yr DFS rate
ITACA S-2/phase III/NCT01989858/ terminated	1180 patients/T3-4N0M0, TanyN + M0/stomach/adenocarcinoma	E1: epirubicin, oxaliplatin, capecitabine (EOX) or epirubicin, cisplatin, 5-FU (ECF) → gastrectomy → EOX or ECF OR C1: gastrectomy → EOX or ECF E2: EOX or ECF → gastrectomy → EOX or ECF → capecitabine or 5-FU + 45 Gy radiation OR C2: gastrectomy → EOX or ECF → capecitabine or 5-FU + 45 Gy	5-yr OS rate
Enriched-CRT 2017/phase III/NCT03680261/not yet recruiting	556 patients/pT2-4aN1-3M0 LVI+/stomach GEJ/adenocarcinoma	Gastrectomy D1/D2 (both arms) AND E: oxaliplatin, capecitabine or S-1 + 45 Gy radiation OR C: oxaliplatin, capecitabine or S-1	3-yr OS rate
TOPGEAR/phase III[61]	620 patients/IB (T1N1 only)-IIIC/resectable stomach GEJ/adenocarcinoma	E: induction EOX or ECF or epirubicin, cisplatin, capecitabine (ECX) or docetaxel, oxaliplatin, 5-FU/LV (FLOT) → 5-FU or capecitabine + 45 Gy radiation OR C: induction EOX or ECF or ECX or FLOT AND gastrectomy D1+ → EOX or ECF or ECX or FLOT (all arms)	5-yr OS rate

mOS: Median overall survival; mDFS: Median disease-free survival; mPFS: Median progression-free survival; E: Experimental; C: Control; HR: Hazard ratio; 5-FU: 5-fluorouracil; LV: Leucovorin; Gy: Gray; S-1: Tegafur/gimeracil/oteracil; pCR: Pathologic complete response; GEJ: Gastroesophageal junction; CRT: Chemoradiation; AEG: Adenocarcinomas of the esophagogastric junction; EOX: Epirubicin, oxaliplatin, capecitabine; ECF: Epirubicin, cisplatin, 5-fluorouracil; ECX: Epirubicin, cisplatin, capecitabine; FLOT: Docetaxel, oxaliplatin, 5-fluorouracil/leucovorin.