Copyright ©The Author(s) 2020.
World J Gastrointest Oncol. Jan 15, 2020; 12(1): 37-53
Published online Jan 15, 2020. doi: 10.4251/wjgo.v12.i1.37
Table 1 Important studies of neoadjuvant therapy for gastric cancer
Ref.NumberCharacteristics of patientsArms and interventionsOutcomes and conclusions
FAMTX, Hartgrink et al[37], 200459Nonmetastatic resectable cancer of the stomachPreoperative FAMTX chemotherapy and surgery vs surgery aloneFAMTX could not bring benefits to resectability rates or survival
MAGIC, Cunningham et al[14], 2006503Operable and nonmetastatic cancer of the stomach or lower esophagus, ≥ stage IIPerioperative ECF chemotherapy and surgery vs surgery alonePerioperative ECF decreased tumor sizes and stages and improved PFS and OS
REAL-2, Cunningham et al[39], 20081002Inoperable or metastatic cancer of the esophagus, EGJ, or stomachRandomly received ECF, ECX, EOF, and EOX chemotherapyCapecitabine and oxaliplatin were as effective as fluorouracil and cisplatin, respectively
EORTC 40954, Schuhmacher et al[15], 2010144Stages III and IV (cM0) cancer of the EGJ or stomachPreoperative chemotherapy (cisplatin, leucovorin, and fluorouracil) and surgery vs surgery aloneIncreased R0 resection rate, failed to demonstrate a survival benefit
FNCLCC and FFCD 9703, Ychou et al[16], 2011224Resectable lower esophagus, EGJ, or stomach cancerPerioperative FP chemotherapy and surgery vs surgery alonePerioperative FP improved curative surgical rate, OS, and DFS
V325, van Cutsem et al[42], 2006445Gastric or EGJ cancer with measurable metastatic disease or locally recurrent disease of lymph nodesDCF chemotherapy vs CF chemotherapyDCF prolonged the time-to-progression and OS, but associated with more adverse events
FLOT AIO, Al-Batran et al[43], 200859Measurable metastatic cancer of the EGJ or stomachSingle arm, biweekly FLOT chemotherapyBiweekly FLOT was effective and well tolerated
FLOT65+, Al-Batran et al[44], 2013143Locally advanced or metastatic esophagogastric cancer, age ≥ 65FLO chemotherapy vs FLOT chemotherapyFLOT improved response rates and PFS, but increased adverse events
Kim et al[20], 2012129Metastatic or recurrent gastric cancerSOX chemotherapy vs CAPOX chemotherapySOX and CAPOX were equally effective and well tolerated
FLOT4, AI-Batran et al[17,18], 2016, 2019300 (phase II), 716 (phase III)Resectable gastric or EGJ cancer, staged ≥ cT2 and/or cN+Perioperative ECF/ECX chemotherapy vs perioperative FLOT chemotherapyFLOT achieved more pCR and increased medial survival time and OS than ECF/ECX
CALGB 80403/E1206, Enzinger et al[19], 2016245Measurable metastatic cancer of the esophagus or EGJECF-C chemotherapy vs IC-C chemotherapy vs FOLFOX-C chemotherapyFOLFOX and ECF regimen had similar efficacy, and FOLFOX was better tolerated
ACTS-GC, Sakuramoto et al[114], 20111059Nonmetastatic gastric cancer staged as II, IIIA, or IIIBSurgery and postoperative S-1 chemotherapy vs surgery aloneS-1 could prolong the 5-year OS and 5-year RFS rate
FLAGS, Ajani et al[102], 20101053Unresectable, locally advanced or metastatic gastric or EGJ cancerCisplatin/S-1 chemotherapy vs cisplatin/fluorouracil chemotherapyCisplatin/S-1 could not prolong the OS but could improve safety profile
INT-0116, Macdonald et al[24], 2001556Operable cancer of the EGJ or stomachSurgery and postoperative chemoradiotherapy vs surgery alonePostoperative chemoradiotherapy prolonged the OS and RFS time
RTOG 9904, Ajani et al[25], 200649Localized cancer of the EGJ or stomach, staged as T2-3N0-1 or T1N1Single arm, induction chemotherapy, chemoradiotherapy, and surgeryAchieved a pCR rate of 26% and a R0 resection rate of 77%
CROSS, van Hagen et al[27], 2012368Resectable cancer of the esophagus or EGJ, staged as T1N1M0 or T2-3N0-1M0Preoperative chemoradiotherapy and surgery vs surgery alonePreoperative chemoradiotherapy improved survival and was well tolerated
FFCD 9102, Bedenne et al[22], 2007444Operable T3N0-1M0 cancer of the thoracic esophagusAdditional surgery vs additional chemoradiotherapyAdditional surgery had no benefits among patients who responded to chemoradiotherapy
CALGB 9781, Tepper et al[26], 200856Operable cancer of the thoracic esophagus or EGJ, staged as T1-3, N1Preoperative induction chemotherapy, chemoradiotherapy, and surgery vs surgery aloneThe trimodality therapy improved median survival and 5-year survival
POET, Stahl et al[28], 2017119Locally advanced cancer of the EGJ, staged as T3 and T4Chemotherapy and surgery vs induction chemotherapy, chemoradiotherapy, and surgeryInduction chemotherapy and chemoradiotherapy could prolong PFS
Table 2 The vicissitudes of the recommendation categories of different neoadjuvant chemotherapy regimens in the NCCN gastric cancer guidelines
2007200820092010201120122013201420152016201720182019.V12019. V2
ECF modifications[39,40]1111112A2A2B2B
Fluorouracil and cisplatin[16]11111111
aFluorouracil and oxaliplatin[19-21]2A2Ab2Ab2Ab
Table 3 Short-term and long-term effects of different pre/perioperative chemotherapy regimens
Ref.RegionRegimennMedian ageEGJ/gastric (%)pT stage (%)
pN stage (%)
Short-term effect
Long-term effect(mo; yr)
012340123aSurgery/R0 (%)Response
Mongan et al[60], 2015EUEOX596571/296923584304417980/54Mandard 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], 2015EUECF/mECF7762.161/400b4915148688/69Becker 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], 2015EUECF/ECX536417/83336735174891/72Becker et al[116], TRG 1a + 1b: 17%5-yr OS: 18%; 5-yr DSS: 22%; recurrence rate: 61.9%
Achilli et al[46], 2017EUECF/ECX67670/1000818659NANA7399/96CR + PR: 37%; Becker TRG 1: 29%Median OS: 36.6 mo; median DFS: 25.7 mo; recurrence rate: 54%
REECE-SMITH et al[45], 2012EUECF/ECX1006668/324932469503214578/76Histological regression > 50%: 45.8%Median survival: 31.7 mo; 2-yr survival: 53%
Favi et al[48], 2017EUFLOT4061.5100/012151743104017281597/85Cologne 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], 2017EUFLOT516639/610b18698267596/78NAMedian OS and PFS not achieved
Schulz et al[50], 2015EUFLOT586159/382012164085416161086/74Becker 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], 2013EUFLOT216962/3810485293871/67CR + PR: 59.1%1.5-yr OS: 78%; 2-yr OS: 78%; median PFS: 21.1 mo
FLO2271.541/590685324177/68CR + PR: 18.2%1.5-yr OS: 70%; 2-yr OS: 56%; median PFS: 12.0 mo
Yoshikawa et al[52], 2016ASSC-2216633/670595560201595/81NA3-yr OS: 67%
SC-4206325/7505952040202090/75NA3-yr OS: 55%
Tsuburaya et al[55], 2014ASSC5363NA414473321610433194/82CR + 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], 2017ASSC50640/100NA12840362214323098/88pCR: 2%; clinical response for LN: 75.5%, for primary tumor: 59.2%3-yr OS: 48%; 3-yr RFS: 42%
Ott et al[53], 2003EUFLP49580/1000105524122636211786/76Major 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], 2012ASFOLFOX33650/100126126193633273100/91CR + 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], 2018ASSOX25≥ 65: 48%0/100128368366016816100/100JCGC[108] grade 2-3: 40%5-yr OS: 70%
CAPOX25≥ 65: 24%0/1004832203644201620100/100JCGC[108] grade 2-3: 36%
Yu et al[57], 2019ASXELOX546530/7013131733253115312391/83CR + 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], 2015ASSOX806040/60151130192559161411100/95CR + PR: 68.8%; pCR: 12.5%NA