Current trends in perioperative treatment of resectable gastric cancer

Table 1 Landmark trials of perioperative treatment in gastric cancer

Treatment	Study	Arms	n	R0	pCR	PFS	HR (P value)	OS	HR (P value)	Ref.
NAC	EORTC 40954	PF-S	72	82%			NA	2-yr: 73%	0.84 (0.47)	[18]
		S alone	72	67%				2-yr: 70%
	OEO2	PFx2-S	400	60%			NA	5-yr: 23%	0.84 (0.03)	[17]
		S alone	402	54%				5-yr: 17%
	OE05	PFx2-S	451	59%	3%			3-yr: 39%	0.90 (0.19)	[19]
		ECXx4-S	446	66%	11%			3-yr: 42%
NACRT	CROSS	RT + pacli-carbo, w-S	180	92%	29%	5-yr: 44%	0.61 (0.006)	5-yr: 47%	0.68 (0.003)	[21]
		S alone	188	69%		5-yr: 27%		5-yr: 33%
Perioperative CT (+/-targeted)	MAGIC Trial	ECFx3-S-ECFx3	250	74%	8%	NR	0.66 (< 0.001)	5-yr: 36%	0.75 (0.009)	[22]
		S alone	253	68%		NR		5-yr: 23%
	FNLCC/FCCD	PFx2-S-PFx4	113	84%	3%	5-yr: 34%	0.65 (0.003)	5-yr: 38%	0.69 (0.02)	[23]
		S alone	111	73%		5-yr: 19%		5-yr: 24%
	The FLOT-4	FLOTx4-S-FLOTx4	356	84.0%	15.6%			5-yr: 45%	0.77 (0.012)	[7]
		ECX/ECFx3-S-ECX/ECFx3	360	77%	5.8%			5-yr: 36%
	ST03	ECXx3-S-ECXx3	533	64%	8%			3-yr: 50.3%	1.08 (0.36)	[35]
		ECXx3 + BV-S-ECXx3 + BV	530	61%	11%			3-yr: 48.1%
	PETRARCA (abstract only, ESMO 2020)	FLOTx4-S-FLOTx4	41	90%	12%	26 mo	0.57 (0.114)			[32]
		FLOT + T + Px4-S-FLOT + T + Px4 + 9 (T + P)	40	93%	35%	NR
	RAMSES[36] (abstract only, ESMO 2020)	FLOTx4-S-FLOTx4	90	83%	30%
		FLOT + RAM x4-S-FLOT + RAM x4 + 16 RAM	90	97%	27%
NAC, adjuvant CT -/+ RT	CRITICS	ECXx3-S-ECXx3	393			5-yr: 39%	0.99 (0.9)	5-yr: 42%	1.01 (0.9)	[24]
		ECXx3-S-CRT	395			5-yr: 38%		5-yr: 40%
Perioperative CT vs adjuvant CT	RESOLVE	S-XELOXx8	345	NR		3-yr: 51.1%	0.86 (0.17) (SOX vs XELOX)			[28]
		S-SOXx8	337	NR		3-yr: 56.5%
		3SOX-S-3SOX	365	NR		3-yr: 59.4%	0.77 (0.03) (SOX vs XELOX)
NAC vs CRT	PRODIGY	DOSX3-S-S1x8	266	95%	10%	3-yr: 66.3%	0.70 (0.023)			[29]
		S-S-1x8	264	84%		3-yr: 60.3%
	POET	PFLX3-RT (30 Gy)/C-S	62	71%	15.6%	3-yr: 47.4%	0.67 (0.07)	5-yr: 39.5%	0.65 (0.055)	[66]
		PFL2-S	64	69%	2%	3-yr: 22.7%		5-yr: 24.4%
	NEORES	CF-RT (40 Gy)-S	91	87%	28%			3-yr: 47%	(0.77)	[64]
		CF-S	90	74%	9%			3-yr: 49%
Adjuvant CRT	INT-0116 trial	5FU/LVx1-CRT-5FU/LVx2	281			3-yr: 48%	0.66 (0.001)	3-yr: 50%	0.74 (0.005)	[14]
		S alone	275			3-yr: 31%		3-yr: 41%
	CALGB 80101 Trial	5FU/LVx1-CRT-5FU/LVx2	280			3-yr: 46%	1.00 (0.99)	3-yr: 50%	1.03 (0.80)	[71]
		ECFx1-CRT-ECFx2	266			3-yr: 47%		3-yr: 52%
	ARTIST trial	XPx2-XRT-XP2	230			3-yr: 78%	0.74 (0.09)	5-yr: 75%	1.13 (0.53)	[15]
		XPx6	228			3-yr: 74%		5-yr: 73%
	ARTIST trial-2	S-1 (x12 mo)	182			3-yr: 65%	0.69 (0.04) (S-1 vs SOX)	NR	NR	[16]
		SOX (x6 mo)	181			3-yr: 74%	0.72 (0.07) (S-1 vs SOXRT)	NR	NR
		SOXRT	183			3-yr: 73%	0.97 (0.88) (SOX vs SOXRT)	NR	NR
Adjuvant CT	ACTS-GC trial	S1 (12 mo)	529			5-yr: 65%	0.65	5-yr: 72%	0.67	[14]
		S alone	530			5-yr: 53%		5-yr: 61%
	CLASSIC trial	XELOXx8 (6 mo)	520			5-yr: 68%	0.58 (< 0.0001)	5-yr: 78%	0.66 (0.53)	[11]
		S alone	515			5-yr: 53%		5-yr: 69%

5FU: 5-fluorouracil; BV: Bevacizumab; CF: Cisplatin and 5-fluorouracil; CRT: Chemoradiotherapy; CT: Chemotherapy; DOS: Docetaxel, oxaliplatin, S-1; ECF: Epirubicin, cisplatin, fluorouracil; ECX: Cisplatin, epirubicin, and capecitabine; ESMO: European Society for Medical Oncology; FLOT: Fluorouracil, leucovorin, oxaliplatin, docetaxel; HR: Hazard ratio; LV: Leucovorin; NA: Not available; NAC: Neoadjuvant chemotherapy; NACRT: Neoadjuvant chemoradiation; NR: No response; OS: Overall survival; pacli-carbo: Paclitaxel and carboplatin; pCR: Pathological complete response; PF: Cisplatin and fluorouracil; PFL: Cisplatin, fluorouracil, leucovorin; PFS: Progression-free survival; RAM: Ramucirumab; RT: Radiotherapy; S: S-1; SOX: S-1 and Oxaliplatin; T + P: Trastuzumab + pertuzumab; w-S: Followed by surgery; XELOX: Capecitabine and oxaliplatin; XP: Capecitabine and cisplatin.

Table 2 Overview of ongoing trials of biological and immunological agents in the perioperative treatment for gastric cancer

NCT	Agent	Target structure	Trial	Phase	Study design	Primary endpoint	Ref.
NCT04592913	Durvalumab	PD-L1	Matterhorn	III	FLOT + durvalumab	EFS	[72]
					FLOT + placebo
NCT03221426	Pembrolizumab	PD-1	Keynote-585	III	CF/FLOT + pembrolizumab	pCR, OS, EFS	[73]
					FLOT + placebo
NCT03421288	Atezolizumab	PD-L1	Dante	II	FLOT + atezolizumab	DFS	[50]
					FLOT + placebo
NCT03399071	Avelumab	PD-L1	Iconic	II	FLOT + avelumab	pCR	[74]
NCT05504720	Pembrolizumab + trastuzumab	PD-1/HER2	PherFlot	II	FLOT + pembrolizumab + trastuzumab	DFS, pCR	[75]
NCT02205047	Trastuzumab +/- pertuzumab	HER2	Innovation	II	CT	pCR	[76]
					CT + trastuzumab
					CT + trastuzumab + pertzumab

CF: Cisplatin and 5-fluorouracil; CT: Chemotherapy; DFS: Disease free survival, EFS: Event free survival; FLOT: Fluorouracil, leucovorin, oxaliplatin, docetaxel; HER: Human epidermal growth factor; OS: Overall survival; pCR: Pathological complete response; PD: Programmed cell death; PDL: Programmed cell death ligand.