Interpretation of the development of neoadjuvant therapy for gastric cancer based on the vicissitudes of the NCCN guidelines

Table 1 Important studies of neoadjuvant therapy for gastric cancer

Ref.	Number	Characteristics of patients	Arms and interventions	Outcomes and conclusions
FAMTX, Hartgrink et al[37], 2004	59	Nonmetastatic resectable cancer of the stomach	Preoperative FAMTX chemotherapy and surgery vs surgery alone	FAMTX could not bring benefits to resectability rates or survival
MAGIC, Cunningham et al[14], 2006	503	Operable and nonmetastatic cancer of the stomach or lower esophagus, ≥ stage II	Perioperative ECF chemotherapy and surgery vs surgery alone	Perioperative ECF decreased tumor sizes and stages and improved PFS and OS
REAL-2, Cunningham et al[39], 2008	1002	Inoperable or metastatic cancer of the esophagus, EGJ, or stomach	Randomly received ECF, ECX, EOF, and EOX chemotherapy	Capecitabine and oxaliplatin were as effective as fluorouracil and cisplatin, respectively
EORTC 40954, Schuhmacher et al[15], 2010	144	Stages III and IV (cM0) cancer of the EGJ or stomach	Preoperative chemotherapy (cisplatin, leucovorin, and fluorouracil) and surgery vs surgery alone	Increased R0 resection rate, failed to demonstrate a survival benefit
FNCLCC and FFCD 9703, Ychou et al[16], 2011	224	Resectable lower esophagus, EGJ, or stomach cancer	Perioperative FP chemotherapy and surgery vs surgery alone	Perioperative FP improved curative surgical rate, OS, and DFS
V325, van Cutsem et al[42], 2006	445	Gastric or EGJ cancer with measurable metastatic disease or locally recurrent disease of lymph nodes	DCF chemotherapy vs CF chemotherapy	DCF prolonged the time-to-progression and OS, but associated with more adverse events
FLOT AIO, Al-Batran et al[43], 2008	59	Measurable metastatic cancer of the EGJ or stomach	Single arm, biweekly FLOT chemotherapy	Biweekly FLOT was effective and well tolerated
FLOT65+, Al-Batran et al[44], 2013	143	Locally advanced or metastatic esophagogastric cancer, age ≥ 65	FLO chemotherapy vs FLOT chemotherapy	FLOT improved response rates and PFS, but increased adverse events
Kim et al[20], 2012	129	Metastatic or recurrent gastric cancer	SOX chemotherapy vs CAPOX chemotherapy	SOX and CAPOX were equally effective and well tolerated
FLOT4, AI-Batran et al[17,18], 2016, 2019	300 (phase II), 716 (phase III)	Resectable gastric or EGJ cancer, staged ≥ cT2 and/or cN+	Perioperative ECF/ECX chemotherapy vs perioperative FLOT chemotherapy	FLOT achieved more pCR and increased medial survival time and OS than ECF/ECX
CALGB 80403/E1206, Enzinger et al[19], 2016	245	Measurable metastatic cancer of the esophagus or EGJ	ECF-C chemotherapy vs IC-C chemotherapy vs FOLFOX-C chemotherapy	FOLFOX and ECF regimen had similar efficacy, and FOLFOX was better tolerated
ACTS-GC, Sakuramoto et al[114], 2011	1059	Nonmetastatic gastric cancer staged as II, IIIA, or IIIB	Surgery and postoperative S-1 chemotherapy vs surgery alone	S-1 could prolong the 5-year OS and 5-year RFS rate
FLAGS, Ajani et al[102], 2010	1053	Unresectable, locally advanced or metastatic gastric or EGJ cancer	Cisplatin/S-1 chemotherapy vs cisplatin/fluorouracil chemotherapy	Cisplatin/S-1 could not prolong the OS but could improve safety profile
INT-0116, Macdonald et al[24], 2001	556	Operable cancer of the EGJ or stomach	Surgery and postoperative chemoradiotherapy vs surgery alone	Postoperative chemoradiotherapy prolonged the OS and RFS time
RTOG 9904, Ajani et al[25], 2006	49	Localized cancer of the EGJ or stomach, staged as T2-3N0-1 or T1N1	Single arm, induction chemotherapy, chemoradiotherapy, and surgery	Achieved a pCR rate of 26% and a R0 resection rate of 77%
CROSS, van Hagen et al[27], 2012	368	Resectable cancer of the esophagus or EGJ, staged as T1N1M0 or T2-3N0-1M0	Preoperative chemoradiotherapy and surgery vs surgery alone	Preoperative chemoradiotherapy improved survival and was well tolerated
FFCD 9102, Bedenne et al[22], 2007	444	Operable T3N0-1M0 cancer of the thoracic esophagus	Additional surgery vs additional chemoradiotherapy	Additional surgery had no benefits among patients who responded to chemoradiotherapy
CALGB 9781, Tepper et al[26], 2008	56	Operable cancer of the thoracic esophagus or EGJ, staged as T1-3, N1	Preoperative induction chemotherapy, chemoradiotherapy, and surgery vs surgery alone	The trimodality therapy improved median survival and 5-year survival
POET, Stahl et al[28], 2017	119	Locally advanced cancer of the EGJ, staged as T3 and T4	Chemotherapy and surgery vs induction chemotherapy, chemoradiotherapy, and surgery	Induction chemotherapy and chemoradiotherapy could prolong PFS

FAMTX: Fluorouracil, doxorubicin, and methotrexate; ECF: Epirubicin, cisplatin, and fluorouracil; ECX: Epirubicin, cisplatin, and capecitabine; EOF: Epirubicin, oxaliplatin, and fluorouracil; EOX: Epirubicin, oxaliplatin, and capecitabine; DCF: Docetaxel, cisplatin, and fluorouracil; CF: Cisplatin and fluorouracil; FLO: Fluorouracil, leucovorin, and oxaliplatin; FLOT: Docetaxel, fluorouracil, leucovorin, and oxaliplatin; SOX: S-1 and oxaliplatin; CAPOX: Capecitabine and oxaliplatin; ECF-C: ECF and cetuximab; IC-C: Irinotecan, cisplatin, and cetuximab; FOLFOX-C: Oxaliplatin, fluorouracil, leucovorin, and cetuximab; EGJ: Esophagogastric junction; pCR: Pathological complete regression; PFS: Progression-free survival; OS: Overall survival; RFS: Relapse-free survival.

Table 2 The vicissitudes of the recommendation categories of different neoadjuvant chemotherapy regimens in the NCCN gastric cancer guidelines

	2007	2008	2009	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019.V1	2019. V2
ECF[14]	1	1	1	1	1	1	1	1	1	2B	2B
ECF modifications[39,40]		1	1	1	1	1	1	2A	2A	2B	2B
Fluorouracil and cisplatin[16]							1	1	1	1	1	1	1	1
aFluorouracil and oxaliplatin[19-21]											2A	2Ab	2Ab	2Ab
FLOT[17]												1b	1b	1b

References quoted in Table 2 for each regimen were based on NCCN guidelines from 2007 to 2019. 1, 2A, 2B: Categories of recommendations.

^b: Preferred intervention.

^a: This regimen was based on extrapolations from literature and clinical practice according to NCCN guidelines, and was revised to fluoropyrimidine and oxaliplatin in 2017 NCCN guidelines. ECF: Epirubicin, cisplatin, and fluorouracil; FLOT: Docetaxel, fluorouracil, leucovorin, and oxaliplatin.

Table 3 Short-term and long-term effects of different pre/perioperative chemotherapy regimens

Ref.	Region	Regimen	n	Median age	EGJ/gastric (%)	pT stage (%)					pN stage (%)				Short-term effect		Long-term effect(mo; yr)
						0	1	2	3	4	0	1	2	3	aSurgery/R0 (%)	Response
Mongan et al[60], 2015	EU	EOX	59	65	71/29	6	9	23	58	4	30	44	17	9	80/54	Mandard et al[115], TRG 1-3: 34%	Median OS: 22 mo; 4-yr survival: 47%; recurrence rate: 40%; median time to recurrence: 13 mo
Bichev et al[59], 2015	EU	ECF/mECF	77	62.1	61/40	0b		4	91	5	14	86			88/69	Becker et al[116], TRG 1 + 2: 44.2%	5-yr cumulative survival: 36.3%; median OS: 23.7 mo; 5-yr TSS: 42.2%; median TSS: 32.9 mo; recurrence rate: 32%
Mingol et al[58], 2015	EU	ECF/ECX	53	64	17/83	33			67		35	17	48		91/72	Becker et al[116], TRG 1a + 1b: 17%	5-yr OS: 18%; 5-yr DSS: 22%; recurrence rate: 61.9%
Achilli et al[46], 2017	EU	ECF/ECX	67	67	0/100	0	8	18	65	9	NA	NA	73		99/96	CR + PR: 37%; Becker TRG 1: 29%	Median OS: 36.6 mo; median DFS: 25.7 mo; recurrence rate: 54%
REECE-SMITH et al[45], 2012	EU	ECF/ECX	100	66	68/32	4	9	32	46	9	50	32	14	5	78/76	Histological regression > 50%: 45.8%	Median survival: 31.7 mo; 2-yr survival: 53%
Favi et al[48], 2017	EU	FLOT	40	61.5	100/0	12	15	17	43	10	40	17	28	15	97/85	Cologne Regression Scale 1-3: 52%	1-yr OS: 72%; 2-yr OS: 60%; 3-yr OS: 37%; median OS: 2.4 yr
Al-Batran et al[47], 2017	EU	FLOT	51	66	39/61	0b		18	69	8	26	75			96/78	NA	Median OS and PFS not achieved
Schulz et al[50], 2015	EU	FLOT	58	61	59/38	20	12	16	40	8	54	16	16	10	86/74	Becker et al[116], TRG 1a + 1b: 40%	1-yr survival: 79.3%; 1-yr PFS: 67.2%; median DFS: 32.9 mo
Lorenzen et al[49], 2013	EU	FLOT	21	69	62/38	10	48		5		29	38			71/67	CR + PR: 59.1%	1.5-yr OS: 78%; 2-yr OS: 78%; median PFS: 21.1 mo
		FLO	22	71.5	41/59	0	68		5		32	41			77/68	CR + PR: 18.2%	1.5-yr OS: 70%; 2-yr OS: 56%; median PFS: 12.0 mo
Yoshikawa et al[52], 2016	AS	SC-2	21	66	33/67	0			5	95	5	60	20	15	95/81	NA	3-yr OS: 67%
		SC-4	20	63	25/75	0			5	95	20	40	20	20	90/75	NA	3-yr OS: 55%
Tsuburaya et al[55], 2014	AS	SC	53	63	NA	4	14	47	33	2	16	10	43	31	94/82	CR + PR: 65%; JCGC[108] grade 1b-3: 51%	3-yr OS: 59%; 5-yr OS: 53%; 3-yr and 5-yr RFS: 50%
Kochi et al[54], 2017	AS	SC	50	64	0/100	NA	12	8	40	36	22	14	32	30	98/88	pCR: 2%; clinical response for LN: 75.5%, for primary tumor: 59.2%	3-yr OS: 48%; 3-yr RFS: 42%
Ott et al[53], 2003	EU	FLP	49	58	0/100	0	10	55	24	12	26	36	21	17	86/76	Major pathological tumor regression: 17%	Median survival: 25.4 mo (for ITT patients) and 32 mo (for R0 patients); recurrence rate: 62.5%; median recurrence: 19 mo
Li et al[51], 2012	AS	FOLFOX	33	65	0/100	12	6	12	61	9	36	33	27	3	100/91	CR + PR: 69.7%; JRSGC[117] grade 2-3: 39.4%	Mean survival: 74 mo; 4-yr OS: 78%; 4-yr DFS: 78%
Xue et al[61], 2018	AS	SOX	25	≥ 65: 48%	0/100	12	8	36	8	36	60	16	8	16	100/100	JCGC[108] grade 2-3: 40%	5-yr OS: 70%
		CAPOX	25	≥ 65: 24%	0/100	4	8	32	20	36	44	20	16	20	100/100	JCGC[108] grade 2-3: 36%
Yu et al[57], 2019	AS	XELOX	54	65	30/70	13	13	17	33	25	31	15	31	23	91/83	CR + PR: 50%; JCGC[108] grade 1b-3: 41.6%	Median OS: 30.77 mo; 3-yr OS: 47.2%; disease progression: 55.6%; median PFS: 20.1 mo; 3-yr PFS: 43.8%
Feng et al[56], 2015	AS	SOX	80	60	40/60	15	11	30	19	25	59	16	14	11	100/95	CR + PR: 68.8%; pCR: 12.5%	NA

^a: Some data were amended in order to increase comparability.

^b: T and N stages in this study were clinical stages. EU: Europe; AS: Asia; EOX: Epirubicin, oxaliplatin and capecitabine; ECF: epirubicin, cisplatin and fluorouracil; mECF: ECF modifications; ECX: Epirubicin, cisplatin and capecitabine; FLOT: Docetaxel, fluorouracil, leucovorin and oxaliplatin; FLO: Fluorouracil, leucovorin and oxaliplatin; SC: S-1 and cisplatin; SC-2/4: S-1 and cisplatin for 2 cycles/4 cycles; FLP: 5-FU, cisplatin and leucovorin; FOLFOX: Oxaliplatin, fluorouracil and leucovorin; SOX: S-1 and oxaliplatin; CAPOX: Capecitabine and oxaliplatin; XELOX: Capecitabine and oxaliplatin; EGJ: Esophagogastric junction; LN: Lymph node; TRG: Tumor regression grade; JRSGC: Japanese research society for gastric cancer; JCGC: Japanese classification of gastric cancer; CR: Complete regression; PR: Partial regression; pCR: Pathological complete regression; OS: Overall survival; TSS: Tumor specific survival; DSS: Disease specific survival; DFS: Disease free survival; PFS: Progression-free survival; RFS: Relapse-free survival; ITT: Intention to treat; NA: Not available.