Between evidence and new perspectives on the current state of the multimodal approach to gastric cancer: Is there still a role for radiation therapy?

Table 1 The main randomized trials in gastric cancer that evaluate the postoperative therapy

Trial	Year	Randomization scheme	OS	DFS, PFS	Limits
SWOG/INT-0116[6]	2001	S-alone vs S + CRT	3-yr: 50% vs 41% (P = 0.005)	3-yr: 48% vs 31% (P < 0.001)	Low rates of D2 node dissection, 2D RT technique
Update SWOG/INT-0116[7]	2012	S-alone vs S + CRT	HR = 1.32 (95%CI: 1.10-1.60; P = 0.0046)	HR = 1.51 (95%CI: 1.25-1.83; P < 0.001)	Low rates of D2 node dissection, 2D RT technique
ARTIST[11] CRITICS[16]	2012 2018	S + CT + CRT + CT vs S + CT CT + S + CT vs CT + S + CRT	NR Median OS 43 vs 37 mo (P = 0.09)	3-yr: 78% vs 74% (P = 0.086)	Planned events not reached, lower % of locally advanced tumors Poor postoperative patient compliance in both treatment arms
NCC, South Korea[17]	2012	S + CRT vs S + CT	NR	5-yr: 73.5% vs 54.6%, (P = 0.056)	Poor accrual Sometimes 2D RT technique
Chinese Study[18]	2012	S + CRT vs S + CT	5-yr: 48.4% vs 41.8% (P = 0.122)	5-yr: 45.2% vs 35.8% (P = NS)	Small series
ACTS-GC[19]	2007	S-alone vs S + CT	3-yr: 80.1% vs 70.1% (P = 0.003)	3-yr: 59.6% vs 72.2% (P < 0.001)	Closed earlier due to significant survival benefit in the CT-arm
CLASSIC[20]	2012	S-alone vs S + CT	NR	3-yr: 59% vs 74% (P < 0.0001)	Stopped after the interim efficacy analysis

OS: Overall survival; DFS: Disease-free survival; PFS: Progression-free survival; RT: Radiotherapy; S: Surgery; CT: Chemotherapy; CRT: Chemoradiation; NR: Not reported; HR: Hazard ratio; CI: Confidence interval; NS: Not significant.

Table 2 The main randomized trials in gastric cancer that evaluate the preoperative therapy

Trial	Year	Randomization scheme	OS	DFS, PFS	Limits
MAGIC[25]	2006	S-alone vs CT + S + CT	5-yr 23% vs 36% (P = 0.009)	3-yr 26% vs 38% (P < 0.001)	Low adherence to post-operative CT, inclusion of gastroesophageal junction or lower esophagus cancer
FNCLCC/ FFCD[26]	2011	S-alone vs CT + S + CT	5-yr 24% vs 38% (P = 0.02)	5-yr 19% vs 34% (P = 0.003)	Inclusion of gastroesophageal junction or lower esophagus cancer, small series
MAGIC-B[28]	2017	CT/Beva + S + CT/ Beva vs CT + S + CT	3-yr 48.1% vs 50.3% (P = 0.36)	NR	Inclusion of gastroesophageal junction or lower esophagus cancer
POET trial[29]	2009	CT + S vs CT + CRT + S	3-yr 27.7% vs 47.4% (P = NS)	NR	Gastroesophageal junction tumors, closed earlier

OS: Overall survival; DFS: Disease-free survival; PFS: Progression-free survival; RT: Radiotherapy; S: Surgery; CT: Chemotherapy; CRT: Chemoradiation; NR: Not reported; NS: Not significant; Beva: Bevacizumab.

Table 3 The main phase I/II trials in gastric cancer that evaluate the preoperative therapy

Trial	Year/type	N° of patients	Treatment schedule	Median FU	Severe toxicity	Clinical efficacy	Survival	Limits/characteristics
Matsuda[51]	2014/ Phase I	9	SP q15 + RT	NR	Diarrhea (11.1) Anorexia (11.1)	PR (78) SD (22)	NR	MTD: CDDP 25 mg/m2
Michel[37]	2014/ Phase II	42	FOLFIRIx4→CRT	38.1 mo	During FOLFIRI (26.2) During RT (19.1)	CR (8.6) Median PFS: 12.3 mo	Median OS: 26.4 mo	Reduced feasibility, 73.8% of patients completed the schedule
Trip[38]	2014/ Phase I/II	25	CBDCA-PTX + RT	NR	Nausea (4) Anorexia (4) Esophagitis (4) Leukopenia (12) Febrile neutropenia (4) Thrombosis (4) Fatigue (4)	CR (16) PR (52)	Median OS: 15 mo
Wydmanski[40]	2014/ Phase II	13	5FU + RT	30.1 mo	Nausea (7.7) Vomiting (7.7) Thrombocytopenia (92.3) Leukopenia (7.7)	NR	Median OS: 17.1 mo 3-yr OS: 48%	Inoperable patients. High rate of severe thrombocytopenia, with 5FU 325 mg/m2 d1-5 and 29-33
Liu[52]	2017/ Phase II	40	SOXx1→S-1 + RT → SOXx1 → surgery→SOXx4	26.5 mo	Leukopenia (10) Neutropenia (10) Thrombocytopenia (2.5)	CR (7.5) PR (30) SD (40) PD (12.5) 2-yr DFS: 47%	2-yr OS: 56%	Treatment compliance: 87.5%

CRT: Chemoradiotherapy; RT: Radiotherapy; CR: Complete response; OS: Overall survival; NR: Not reported; PR: Partial response; SD: Stable disease; MTD: Maximum tolerated dose; PD: Progressive disease; DFS: Disease-free survival; PFS: Progression-free survival.

Table 4 The main phase I/II trials in gastric cancer that evaluate the postoperative therapy

Trial	Year/type	N° of patients	Treatment schedule	Median FU	Severe toxicity	Clinical efficacy	Survival	Limits/characteristics
Michel[37]	2014/Phase I	21	FOLFIRIx4→RCT	26.6 mo	During FOLFIRI (23.8) During RT (9.5)	Median PFS: 22.8 mo	Median OS: 32.9 mo	Parallel study with a neoadjuvant schedule (see above). Study closed for futility (42.9% completed the schedule)
Wang[41]	2014/ Phase I	18	5FU + RT→FOLFOX4 (8) FOLFOX4→5FU+RT (7) 5FU + RT (3)	45 mo	Nausea (11.1) Vomiting (5.6) Esophagitis (5.6) Leukopenia (11.1) Neutropenia (5.6)	4-yr LRC: 93.8%	4-yr OS: 68.1%	MTD: 5FU 800 mg/m2 twice daily
Zhai[42]	2014/ Phase II	30	FOLFOX6x2→5FU + RT	21 mo	Nausea (33.3) Vomiting (33.3) Diarrhea (6.7) Hepatic (3.3) Cutaneous (3.3) Neutropenia (40) Sensory (23.3)	3-yr DFS: 65%	3-yr OS: 72.7%
Wang[43]	2014/ Phase II	110	FOLFOXx1→FOLFOXd1, 22 + RT→FOLFOXx5	43 mo	Nausea and vomiting (14.5) Diarrhea (0.9) Anorexia (11.8) Fatigue (6.4) Abdominal pain (2.7) Leuko-/neutropenia (9.1) Hemorrhage (0.9)	3-yr RFS: 67.8%	3-yr OS: 77.6%	Stage ≤ IIIA significant factor predicting more favorable OS
Qiu[48]	2015/ Phase I	21	SOXx1→S-1 + RT	26 mo	Nausea (19) Vomiting (19) Fatigue (4.7) Anorexia (14.2) Leukopenia (4.7)	2-yr DFS: 66.7%	2-yr OS: 90.4%	MTD: S-1 70 mg/m2·d
Shim[49]	2016/ Phase II	46	SPx1→S-1 + RT→SPx2	56.5 mo	Nausea (17.4) Vomiting (8.7) Diarrhea (4.3) Anorexia (15.2) Fatigue (6.5) Neutropenia (28.2) Anemia (6.5) Thrombocytopenia (4.3)	3-yr DFS: 65.2%	3-yr OS:76.1%	Treatment compliance: 73.9% Intestinal-type tumor showed better DFS and OS
Goody[46]	2016/ Phase I/II	55	5FU-CDDP + RT	36.4 mo	Hematological (36.3) Constitutional (9) Dermatologic (3.6) Gastrointestinal (18.1) Infection (5.4) Muscoloskeletal (1.8)	2-yr LRR: 16.8% 2-yr RFS: 74%	2-yr OS: 85%	MTD: CDDP 40 mg/m2 w1,3,5,7 Treatment compliance: 85.5%
Liu[44]	2017/ Phase II	55	mDCFx2→TXL + RT→ mDCFx2	61 mo	Nausea (63) Vomiting (49) Diarrhea (12) Anorexia (34) Fatigue (31) Neutropenia (60) Thrombocytopenia (51) Thrombocytopenia (15) Anemia (13) Febrile neutropenia (10)	3-yr PFS: 75% 5-yr PFS: 59%	3-yr OS: 72% 5-yr OS:61%	Treatment compliance 76%
Liu[45]	2017/ Phase II	36	mDCFx2→wTXL + RT→mDCFx2	35.6 mo	Nausea (63) Vomiting (48) Diarrhea (9) Anorexia (33) Stomatitis (44) Fatigue (27) Neutropenia (53) Thrombocytopenia (62) Thrombocytopenia (16) Anemia (13) Febrile neutropenia (9)	RR: 83% CR: 36% 3-yr PFS: 32%	3-yr OS: 42%	Inoperable patients. RT was delivered with IMRT technique
Wang[50]	2018/ Phase I/II	73	S-1 + RT Various adjuvant CT before or after RT	37.6 mo	Nausea (9.6) Vomiting (5.7) Anorexia (9.6) Esophagitis (3.8) Stomatitis (1.9) Fatigue (1.9) Leukopenia (11.5) Neutropenia (3.8)	3-yr LRFS: 92.2%	3-yr OS: 70%	MTD: S-1 80 mg/m2

CRT: Chemoradiotherapy; RT: Radiotherapy; CR: Complete response; OS: Overall survival; NR: Not reported; MTD: Maximum tolerated dose; PD Progressive disease; DFS: Disease-free survival; PFS: Progression-free survival; LRC: Loco-regional control; RFS: Relapse-free survival; RR: Response rate; LRFS: Local relapse-free survival.