Neo-adjuvant chemo(radio)therapy in gastric cancer: Current status and future perspectives

Table 1 Pre-operative chemotherapy in non-resectable gastric cancer

Ref.	Regimen	No. patients	Stage	R0 resection (%)	Median survival (mo)
Wilkie et al[8]	EAP	34	NR	44	24
Plukker et al[9]	5-FU + MTX	20	NR	40	22
Rougier et al[10]	5-FU, P	30	NR	60	16
Kelsen et al[11]	FAMTX, IP 5FU-P	56	NR	61	15
Melcher et al[12]	ECF	27	R-NR	58 (R pts) 10 (NR pts)	10
Gallardo-Rincón et al[13]	P-ELF	60	NR	8,7	10
Cascinu et al[14]	EAFPLG	82	NR	45	17

NR: Non-resectable; EAP: Etoposide, doxorubicin, cisplatin; IP: Intraperitoneal; ECF: Epirubicin, cisplatin, 5-FU; R: Resectable; P-ELF: Cisplatin, etoposide, leucovorin, 5FU; EAPFLG: Epi-doxorubicin, 5-FU, cisplatin, leucovorin, glutathione; 5-FU: 5-fluorouracil.

Table 2 Peri-operative chemotherapy in resectable gastric cancer

Ref.	Phase	Selection criteria	Study arms	No. of patients	R0 resection (%)	Pathologic CR (%)	Median survival(mo)
Ajani et al[15]	II	M0 Resectable + EGJ	EFP × 2 + surgery + EFP × 3	25	72	0	15
Leichman et al[16]	II	M0 resectable	PFL × 2 + surgery (IP FUDR + IP cisplatin × 2)	8	88	8	> 17
Kang et al[17]	III RCT	M0 Loc. advanced	EFP × 3 + surgery + EFP × 3-6 vs surgery + EFP × 3-6	107 (53 + 54)	79 vs 61	8	43 vs 30
Ajani et al[18]	II	M0 resectable	EAP × 3 + surgery + EAP × 2	48	90	0	16
Rougier et al[19]	II	M0 Loc. advanced + EGJ	FP × 6 + surgery	30	78	0	16
Kelsen et al[11]	II	M0 Loc. advanced	FAMTX × 3 + surgery + IP FP + F	56	77	NS	15
Crookes et al[20]	II	M0 resectable + EGJ	PFL × 2 + surgery (IP FUDR +IP cisplatin × 2)	59	71	9	52
Songun et al[21]	II RCT	T2-T4; M0	FAMTX × 3 + surgery vs surgery alone	56 (27 + 29)	75 vs 75	NS	18 vs 30
Schuhmacher et al[22]	II	III-IV; M0 + EGJ	EAP + surgery	42	86	0	19
D’Ugo et al[23]	II	T3-4 any N; T ≤ 2 N+; M0	EEP × 3 or ECF × 3 + surgery + EEP × 3 or ECF × 3	34	82	3	> 28
Cunningham et al[6] (MAGIC trial)	III RCT	Resectable GC (II-IV); M0 + adenocarcinomas EGJ	ECF × 3 + surgery + ECF × 3 s vs surgery alone	503 (250 + 253)	74 vs 68	NS	18 vs 30
Ychou et al[24] (ACCORD trial)	III RCT	Resectable GC + adenocarcinomas EGJ	FP × 2-3 + surgery + FP × 3-4 vs surgery alone	224 (113 + 111)	84 vs 73	NS	NS
Schuhmacher et al[25] (EORTC trial)	III RCT	Loc. advanced GC T3-T4N × M0	PFL × 2 vs surgery alone	144 (72 + 72)	81.9 vs 66.7	NS	> 36
Kinoshita et al[26]	II	Schirrous resectable	S-1 × 2 + surgery	55	80.8	0	NS
Biffi et al[27]	III RCT	T3-4 any N or any T N1-3 M0 + EGJ	TCF × 4 + surgery vs surgery alone	69 (34 + 35)	85	11.7	NS
Yoshikawa et al[30],	II RCT	T2–3/N+ or T4aN0 + EGJ	SC × 2 + surgery vs SC × 4 + surgery vs PC × 2 + surgery vs PC × 4 + surgery	83 (21 + 20 + 21 + 21)	NS	10 10	NS

EL: Exploratory laparotomies; R0: Curative (R0) resections; CR: Complete response; EFP: Etoposide, fluorouracil, and cisplatin; GC: Gastric cancer; IP: Intraperitoneal; FUDR: 5-fluoro-2’-deoxyuridine; RCT: Randomized controlled trial; EAP: Etoposide, doxorubicin, cisplatin; FP: Fluorouracil, cisplatin; F: Fluorouracil; NS: Not stated; EEP: Etoposide, epirubicin, cisplatin; TCF: Docetaxel, cisplatin, fluorouracil; SC: S1, cisplatin; PC: S, cisplatin.

Table 3 Pre-operative chemo-radiotherapy in gastric and esophagogastric junction cancer

Ref.	Phase	Selection criteria	Study arms	No. of patients	R0 resection (%)	Pathologic CR (%)	Median survival (mo)
Zhang et al[36]	RCT	EGJ	40 Gy EBRT + surgery vs surgery alone	370 (171 + 199)	89.5	0	5-yr OS 30% vs 20%
Shchepotin et al[37]	RCT	M0 resectable and unresectable	Surgery alone vs 20 Gy EBRT vs 20 Gy EBRT + Hy	293 (98 + 100 + 95)	NS	NS	5-yr OS 21.3%
Skoropad et al[38]	RCT	M0 resectable + EGJ	20 Gy EBRT + Hy + 20 Gy IORT vs surgery alone	122 (59 + 53)	66	0	16
Safran et al[39]	Phase I	Unresectable M0	45 Gy EBRT+ Paclitaxel	27	NS	11	2-yr OS 35%
Lowy et al[40]	Phase I	T > 2, Any N, M0	45 Gy EBRT, 5-FU	24	75	11	NS
Ajani et al[41]	Phase II	T > 2, Any N	5FU, LV, P + 45 Gy EBRT, 5FU	33	70	30	34
Ajani et al[42]	Phase II	M0 resectable + EGJ	FP, paclitaxel + 45 Gy EBRT, 5FU	41	78	20	> 36
Allal et al[43]	Phase I	T3-T4, N+	FP, Leucovorin + 31.2–45.6 Gy EBRT	19	NS	5	5-yr OS 35%
Ajani et al[44]	Phase II	M0 resectable	FP, LV, P + 45 Gy EBRT, 5FU, cis	49	63	26	23
Stahl et al[45] POET trial	Phase III RCT	EGJ	PFL × 3 + 30 Gy + cisplatin/etoposide + surgery vs PFL × 2, 5 + surgery	126 (62+64)	72 vs 69	15.6 vs 2.0	33.1 vs 21.1
Van Hagen et al[48] CROSS trial	Phase III RCT	Esophageal or EGJ cancer	Carboplatin + paclitaxel + 41.1Gy + surgery vs surgery alone	366 (178 + 188)	92 vs 69	29 (CRT + surgery)	49.9 vs 24

R0: Curative (R0) resections; CR: Complete response; GEJ: Gastro-esophageal junction; RCT: Randomized controlled trial; EBRT: External beam radiotherapy; IORT: Intraoperative radiotherapy; Hy: Hypertermia; FP: Fluorouracil and cisplatin; LV: Leucovorin; NS: Not stated; OS: Overall survival.

Table 4 Currently recruiting trials for pre and peri-operative chemo(radio)therapy

Country	Title	Phase	Study arms	Trial registration
United Kingdom[51]	Chemotherapy with or without bevacizumab or lapatinib to Treat Operable Oesophagogastric Cancer (ST03)	II/III	ECX + bevacizumab vs ECX vs ECX + lapatinib	NCT00450203
United Kingdom[52]	A study of bevacizumab in combination with capecitabine and cisplatin as first-line therapy in Patients With Advanced Gastric Cancer (AVAGAST)	III	Bevacizumab + ECX vs ECX	NCT00548548
Multicenter study (24 countries)[53]	ToGA study - A study of herceptin (trastuzumab) in combination with chemotherapy compared with chemotherapy alone in patients with HER2-positive Advanced Gastric Cancer	III	Trastuzumab + fluorouracil/capecitabine + cisplatin vs fluorouracil/capecitabine + cisplatin	NCT01041404
Australia and New Zealand	Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma (TOPGEAR)	II/III	Epirubicin + cisplatin + 5-fluorouracil + 45 Gy vs Epirubicin + cisplatin + 5-fluorouracil	NCT01924819
Netherlands[54]	Randomized phase III trial of adjuvant chemotherapy or Chemoradiotherapy in Resectable Gastric Cancer (CRITICS)	III	ECC + surgery + ECC vs ECC + surgery + 45 Gy + capecitabine + cisplatin	NCT00407186
China	Peri-operative chemotherapy with ECX or XP in the treatment of advanced gastric cancer	III	Epirubicin + cisplatin + capecitabine vs capecitabine + cisplatin	NCT01558947
Korea	DOS regimen as neoadjuvant chemotherapy in advanced gastric cancer (PRODIGY)	III	Docetaxel + oxaliplatin + tegafur vs surgery only	NCT01515748
China	Peri-operative chemotherapy with ECX (epirubicin + cisplatin + capecitabine) or XP (capecitabine + cisplatin) in the treatment of advanced gastric cancer: A randomized, multicenter, parallel controlle	III	Epirubicin + cisplatin + capecitabine vs capecitabine + cisplatin	ChiCTR-TRC-11001319
Ireland	MAGIC vs CROSS Upper GI. ICORG 10-14	III	MAGIC regimen vs CROSS protocol	NCT01726452

AVAGAST: The Avastin in gastric cancer; ECX: Epirubicin, cisplatin and xeloda; TOPGEAR: Trial of preoperative therapy for gastric and esophagogastric junction adenoca rcinoma; CRITICS: Chemoradiotherapy after induction. chemotherapy in cancer of the stomach; XP: Xeloda and cisplatin; DOS: Docetaxel, oxaliplastin and S1; MAGIC: Medical research council adjuvant gastric infusional chemotherapy; CROSS: Chemoradiotherapy for oesophageal cancer followed by surgery study; ICORG: Ireland cooperative oncology research group.