Advancements and challenges in treating advanced gastric cancer in the West

Table 1 Surgery trials

Trial name	Country	Status	Years	Factors	Outcome
DGCT Trial	Netherlands	Complete	1989-1993	Randomization to D1 or D2 lymphadenectomy	Increased morbidity and mortality in D2 group
					Decreased gastric cancer-related deaths and locoregional recurrences after D2 resection
IGCSG-R01	Italy	Complete	1998-2006	Randomization to D1 or D2 lymphadenectomy	No difference in morbidity and mortality
					Improved 5-yr survival in subgroup analysis of patients with positive LN after D2 resection
KLASS-011	Korea	Complete	2006-2010	Randomization to open distal gastrectomy or laparoscopic distal gastrectomy	Decreased wound complication rate in laparoscopic group with no difference in morbidity or mortality
KLASS-022	Korea	Complete	2011-2015	Randomization to open or laparoscopic gastrectomy and D2 lymph node resection	Decreased complication rates and pain scores with shorter hospital stays in laparoscopic resections
JCOG 07031	Japan	Complete	2007-2008	Prospective study with patients undergoing laparoscopic distal gastrectomy with D1 lymph node resection	Laparoscopic surgery was safe with lower than expected rates of anastomotic leaks and pancreatic fistulas

¹Clinical stage I gastric cancers only;

²Locally advanced gastric cancers only. DGCT: Dutch Gastric Cancer Group Trial; IGCSG: Italian Gastric Cancer Study Group; LN: Lymph node; KLASS: Korean Laparoscopic Surgical Society; JCOG: Japan Clinical Oncology Group.

Table 2 Chemotherapy trials

Trial name	Country	Status	Years	Groups	Chemotherapy regimens	Outcome
MAGIC	UK	Complete	1994-2002	Surgery alone	-	Smaller tumors in chemo group (3 cm vs 5 cm)
				Surgery with perioperative chemo	Epirubicin, cisplatin, 5-FU (ECF)	Better PFS and OS in chemo group (5-yr OS 36% vs 23%)
ACCORD 07	France	Complete	1995-2003	Surgery alone	-	Improved curative resection rates with chemo (84% vs 73%)
				Surgery with perioperative chemo	Cisplatin and 5-FU	Better DFS and OS in chemo group (5-yr OS 38% vs 24%)
AIO-FLOT4 (Phase II)	Germany	Complete	2010-2012	Neoadjuvant ECF/ECX	Epirubicin and cisplatin with either 5-FU (ECF) or capecitabine (ECX)	Improved pathological complete regression in FLOT vs ECF/ECX
				Neoadjuvant FLOT	Docetaxel, oxaliplatin, 5-FU with leucovorin
AIO-FLOT4 (Phase III)	Germany	Complete	2010-2015	Neoadjuvant ECF/ECX	Epirubicin and cisplatin with either 5-FU (ECF) or capecitabine (ECX)	Improved OS in FLOT group with no increase in toxicities
				Neoadjuvant FLOT	Docetaxel, oxaliplatin, 5-FU with leucovorin

MAGIC: Medical Research Council Adjuvant Gastric Infusional Chemotherapy; UK: United Kingdom; 5-FU: 5-fluorouracil; PFS: Progression-free survival; OS: Overall survival; DFS: Disease-free survival; ECF: Epirubicin, cisplatin, and 5-fluorouracil; ECX: Epirubicin, cisplatin, and capecitabine; FLOT: 5-fluorouracil, leuocovorin, oxaliplatin, and docetaxel.

Table 3 Radiation trials

Trial name	Country	Status	Years	Trial group(s)	Regimens	Outcome
INT-0116	US	Complete	1991-1998	Surgery alone	-	Improved DSF and OS in radiation group (median survival 36 mo vs 27 mo)
				Surgery + adjuvant CRT	45 Gy with 5-FU and leucovorin
Ajani et al[60]	US	Complete	1999-2004	CRT	45 Gy with 5-FU, leucovorin, and cisplatin	77% R0 resection rate
						26% complete pathologic response rate
Martin-Romano et al[61]	Spain	Complete	2004-2014	Neoadjuvant chemotherapy	Variable	Improved pathologic response and nodal regression in CRT group
				Neoadjuvant CRT	Radiation: 45 Gy
					Chemo: Variable
CRITICS	Netherlands, Sweden, Denmark	Complete	2007-2015	Perioperative chemo	Epirubicin, cisplatin or oxaliplatin, capecitabine	No difference in OS or DFS
				Neoadjuvant chemo and adjuvant CRT	Chemo: Epirubicin, cisplatin or oxaliplatin, capecitabine
					CRT: 45 Gy with capecitabine
CRITICS-II (NCT02931890)	Netherlands, Sweden, Denmark	Ongoing	-	Neoadjuvant chemo	Docetaxel, oxaliplatin, capecitabine	-
				Neoadjuvant chemo and CRT	Chemo: Docetaxel, oxaliplatin, capecitabine
					CRT: 45 Gy with paclitaxel and carboplatin
				Neoadjuvant CRT	45 Gy with paclitaxel and carboplatin
ARTIST	Korea	Complete	2004-2008	Adjuvant chemo	Capecitabine and cisplatin	No difference in DFS overall
				Adjuvant chemo and CRT	Chemo: Capecitabine and cisplatin	Superior DFS in radiation group on subgroup analysis of patients with positive LNs
					CRT: 45 Gy with capecitabine
ARTIST-II (NCT01761461)	Korea	Ongoing	-	Adjuvant chemo	S-1	-
				Adjuvant chemo	S-1 and oxaliplatin
				Adjuvant chemo and CRT	Chemo: S-1 and oxaliplatin
					CRT: 45Gy with S-1
TOPGEAR (ACTRN12609000035224)	Australia	Ongoing	-	Perioperative chemo	Epirubicin, cisplatin, 5-FU (ECF)	-
				Perioperative chemo with Neoadjuvant CRT	Chemo: Epirubicin, cisplatin, 5-FU (ECF)
					CRT: 45 Gy with 5-FU

INT: Intergroup; US: United States; CRT: Chemoradiation therapy; Gy: Gray; DFS: Disease-free survival; OS: Overall survival; 5-FU: 5-fluorouracil; CRITICS: Chemoradiotherapy after Induction chemotherapy In Cancer of the Stomach; chemo: Chemotherapy; LN: Lymph node; TOPGEAR: Trial Of Preoperative therapy for Gastric and Esophago-gastric junction Adenocarcinoma; ECF: Epirubicin, cisplatin, and 5-fluorouracil.

Table 4 Targeted treatment trials

Trial name	Country	Status	Years	Target	Groups	Chemotherapy regimens	Outcome
EXPAND	Multiple	Complete	2008-2010	EGFR	Standard chemo	Capecitabine, cisplatin	No difference in PFS
					Standard chemo with cetuximab	Capecitabine, cisplatin, cetuximab
REAL3	Multiple	Complete	2008-2011	EGFR	Standard chemo	Epirubicin, oxaliplatin, capecitabine	No difference in OS
					Standard chemo with panitumumab	Epirubicin, oxaliplatin, capecitabine, panitumumab
AVAGAST	Multiple	Complete	2007-2008	VEGFR	Standard chemo	Capecitabine, cisplatin	Improved PFS in the bevacizumab group (median survival 6.7 mo vs 5.3 mo)
					Standard chemo with	Capecitabine, cisplatin,
					bevacizumab	bevacizumab
REGARD	Multiple	Complete	2009-2012	VEGFR	Best supportive care	-	Improved OS in ramucirumab group (median survival 5.2 mo vs 3.8 mo)
					Best supportive care	Ramucirumab
					with ramucirumab
ToGA Trial	Multiple	Complete	2005-2008	HER2	Standard chemo	Cisplatin with capecitabine or 5-FU	Improved OS in the trastuzumab group (median survival 13.8 mo vs 11.1 mo)
					Standard chemo with trastuzumab	Cisplatin, capecitabine or 5-FU, trastuzumab
KEYNOTE-012	Multiple	Complete	2013-2014	PD-L1	Pembrolizumab	Pembrolizumab	Median OS of 11.4 mo
GASTRICHIP (NCT01882933)	Multiple	Ongoing	-	HIPEC	Curative gastrectomy with D1-D2 lymph node dissection	-	-
					Curative gastrectomy with D1-D2 lymph node dissection with HIPEC	IP Oxaliplatin with IV 5-FU and leucovorin

EGFR: Endothelial growth factor receptor; chemo: Chemotherapy; PFS: Progression-free survival; OS: Overall survival; AVAGAST: Avastin in Gastric Cancer; VEGFR: Vascular endothelial growth factor receptor; ToGA: Trastuzumab for Gastric Cancer; HER2: Human epidermal growth factor receptor 2; 5-FU: 5-fluorouracil; PD-L1: Programmed death-ligand 1; HIPEC: Hyperthermic intraperitoneal chemotherapy; IP: Intraperitoneal; IV: Intravascular.