Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake?

Table 1 Quality assessment of all the 16 randomized controlled trials found in literature and included in this study

Ref.	Randomization	Allocation concealment	Blind	Withdrawal and dropout	Jadad score	ITT
Yonemura et al[29], 1993	Adequate	Inadequate	Adequate	Well reported	5	NR
Shchepotin et al[30], 1995	Unclear	Unclear	Inadequate	NR	1	NR
Kang et al[31], 1996	Unclear	Unclear	Inadequate	Well reported	3	NR
Lygidakis et al[32], 1999	Inadequate	Unclear	Inadequate	Well reported	2	NR
Takiguchi et al[33], 2000	Unclear	Inadequate	inadequate	Well reported	2	NR
Wang et al[22], 2000	Unclear	Unclear	Inadequate	Well reported	3	NR
Kobayashi et al[35], 2000	Adequate	Adequate	Inadequate	Well reported	5	NR
Hartgrink et al[4], 2004	Adequate	Adequate	Inadequate	Well reported	5	NR
Nio et al[36], 2004	Inadequate	Inadequate	Inadequate	Well reported	1	NR
Zhao et al[37], 2006	unclear	Unclear	Inadequate	Well reported	3	NR
Cunningham et al[17], 2006	Adequate	Adequate	Adequate	Well reported	7	YES
Schuhmacher et al[15], 2010	Unclear	Unclear	Unclear	Well reported	4	YES
Imano et al[38], 2010	unclear	unclear	Unclear	Well reported	4	NR
Biffi et al[39], 2010	Unclear	Unclear	Unclear	Well reported	4	YES
Qu et al[40], 2010	Adequate	Unclear	Unclear	NR	4	NR
Ychou et al[18], 2011	Adequate	Well reported	Unclear	Well reported	6	YES

NR: Not reported; ITT: Intention-to-treat analysis.

Table 2 Positive human epidermal growth factor receptor 2 status by immunohistochemistry and/or fluorescence in situ hybridization for the patients enrolled in the ToGA trial[10,11,27]

AuthorCountries	Year,Type of publication	N° patientsrandomization	SiteStage	Regimen	Response rate	Resectability rate	Survival rate (HR; p)	Node dissection (D1,D2, others)
Yonemura et al[29] Japan	1993 Abstract	55 Tot 29 NAC + S 26 S	GC IV	PMUE	Adv NAC + S	Adv NAC + S	Adv NAC+S Rates NR	NR
Shchepotin et al[30] Ukraine	1995 Abstract	146 Tot 50 S 49 IVCH + S 47 IACH + S	GC NR	NR	Adv IACH + S	Adv IACH + S	Adv IACH + S P < 0.001	NR
Kang et al[31] South Korea	1996 Abstract	107 Tot 54 S 53 NAC + S	GC III/IV	PEF	NR	Adv NAC + S	No difference P = 0.114	NR
Lygidakis et al[32] Greece	1999 Paper	59 Tot 19 S 20 NAC + S + IVCH 20 NAC + S	GC All stages	Mitomycin-C + 5-FU + FA + Farmorubicin	NR	NR	Adv NAC + S + IVCH	NR
Takiguchi et al[33] Japan	2000 Abstract	262 Tot 139 S 123 NAC + S	GC III/IV	5FU + CDDP	Adv NAC + S	Adv NAC+S	Adv NAC + S P = 0.0996	NR
Wang et al[22] China	2000 Paper	60 Tot 30 S 30 NAC + S	EGJ NR	5FU	Adv NAC + S	NR	Adv NAC + S P = 0.17	NR
Kobayashi et al[35] Japan	2000 Paper	171 Tot 80 S 91 NAC + S	AGC	FUDR	NR	NR	Adv S P = 0.010	NR
Hartgrink et al[4] The Netherlands	2004 Paper	59 Tot 30 S 29 NAC + S	Proper AGC (not EGC)	FAMTX	32% CR or PR	EQUAL	Adv S 34% S vs 21% NAC + S P = 0.017	At least 15 nodes
Nio et al[36] Japan	2004 Paper	295 Tot 193 S 102 NAC + S	GC All stages > 50% stage I	UFT	NR	NR	Overall No Adv. NAC + S P = 0.6878 stage II/III -pN + Adv. NAC + S P = 0.0486	D2 48% S 56% NAC + S
Zhao et al[37] China	2006 Paper	60 Tot 20 5’-DFUR 20 5FU + CF 20 S	GC All stages	5’-DFUR Or 5FU+CF	5’-DFUR and 5FU + CF increase AI and reduce PI	NR	NR	NR
Cunningham et al[17] United Kingdom	2006 Paper	503 Tot 250 S 253 NAC + S	GC, EGJ, LE All stages	Epirubicin Cisplatinum 5-FU	Diameter 5 cm vs 3 cm P < 0.001 T1 + T2 stages > NAC + S P = 0.002	NR	Adv NAC + S OS/DFS 23% S 36.3%/NAC+S HR 0.75/0.66 P = 0.009/0.001 more evident for EGJ	D2 40% S 42% NAC + S
Schumacher et al[15] Germany	2010 Paper	282/144 Tot 72 S 72 NAC + S	GC, EGJ (Siewert II, III) stages III, IV	Cisplatinum + FF	Adv in S Tumor length, thickness and width and P Stages more	R0 67% S 81.9% NAC + S P = 0.036 LN + 76.5% S 61.4% NAC + S P = 0.018	No Adv NAC + S 52 ms S 64 ms NAC + S HR = 0.84 P = 0.46	D2 94% 92.6% S 95.7% NAC + S
Imano et al[38] Japan	2010 Paper	63 Tot 16 S 15 CDDP 16 5-FU 16 5-FU + CDDP	GC NR	5FU or CDDP or 5F +CDDP	5-FU + CDDP Increases AI Reduces PI	NR	No differences in 4 arms	D2 in all arms
Biffi et al[39] Italy	2010 Paper	240/70 Tot 35 S 34 NAC + S	EGJ (Siewert II, III), AG	TCF	65% CR + PR	Adv NAC + S (P value NR)	not evaluated premature interruption for low accrual	D2 in almost all cases
Qu et al[40] China	2010 Paper	78 Tot 39 S 39 NAC + S	AGC	Paclitaxel and FOLFOX4	Adv NAC + S P = 0.001	Adv NAC + S P = 0.025	Adv NAC+S P = 0.006 at 2 yr	NR
Ychou et al[18] France	2011 Paper	224 Tot 111 S 113 NAC + S	LE,EGJ,GC All stages	CDDP + 5FU	Adv NAC + S P = 0.054	Adv NAC + S P = 0.04	OS (NAC + S/S) = 38/24 HR = 0.69 P = 0.02 DFS (NAC + S/S) = 34/19 HR= 0.65 P = 0.003 more evident for EGJ	D2 recommended No data on the effect of D2 vs other LN dissection

GC: Gastric cancer; NAC: Neoadjuvant chemotherapy; S: Surgery; EGC: Early gastric cancer; AGC: Advanced gastric cancer; EGJ: Esophagogastric junction; LE: Lower esophagus; OS: Overall survival; DFS: Disease free survival; LN: Lymph node; D2: D2 lymphadenectomy; FA: Folinic acid; CR: Complete response; PR: Partial response; 5-FU: 5-fluorouracil; PMUE: Cisplatin + mitomycin C + etoposide +1-(2-tetrahydrofuryl)- + uracil; IVCH: Intravenous (systemic) chemotherapy; IACH: Super selective intra-arterial chemotherapy; PEF: Low dose cisplatinum + epirubicin + 5-fluorouracil; CDDP: Low dose cisplatinum; 5'-DFUR: 5'-deoxy-5-fluorouridine; FAMTX: 5-fluorouracil + doxorubicin + methotrexate; UFT: Tegafur + 5-fluorouracil; FF: d-L-folinic acid+fluouracile; TCF: Docetaxel + cisplatin + fluorouracil; FOLFOX4: 5-fluorouracil + leucovorin + oxaliplatin; Adv: Advantage; NR: Not reported; Tot: Total; AI: Apoptosis index; PI: Cell proliferation index; HR: Hazard ratio.

Table 3 Characteristics and outcomes of randomized controlled trial describing the type of lymph node dissection and the site of primary tumor in both arms

Ref.	No. patients randomization	Site of primary tumor	Node dissection (D1, D2, others)	Survival rate (HR, p)	HR for site of primary tumor
Nio et al[36], 2004	295 Tot 193 S 102 NAC + S	Stomach	D2 in less than 50% overall 48% S 56% NAC + S	Overall No Adv NAC + S P = 0.6878 stage II/III -pN+ Adv NAC + S P = 0.0486	NR
Cunningham et al[17], 2006	503 Tot 250 S 253 NAC + S	Stomach 73.9% EGJ 11.5% LE 14.6%	D2 in less than 50% 40% S 42% NAC + S	Adv NAC + S OS/DFS 5 yr-SR 23%/NR S 36.3%/NR NAC + S HR = 0.75/0.66 P = 0.009/0.001	HR LE 0.7 EGJ: 0.5 Stomach: 0.8
Schumacher et al[15], 2010	282/144 Tot 72 S 72 NAC + S	Stomach 47.2% EGJ 52.8% (Siewert II, III)	Proper D2 in 94% overall 92.6% S 95.7% NAC+S	No adv NAC + S 52 ms S 64 ms NAC + S HR = 0.84 P = 0.46	NR
Imano et al[38], 2010	63 Tot 16 S 15 CDDP 16 5-FU 16 5-FU + CDDP	Stomach	Proper D2 in all patients of both arms	No differences for all arms	NR
Biffi et al[39], 2010	240/70 Tot 35 S 34 NAC + S	Stomach 59% EGJ 41% (Siewert II, III)	Proper D2 in almost all cases	not evaluated premature interruption for low accrual	NR
Ychou et al[18], 2011	224 Tot 111 S 113 NAC + S	LE 11%, EGJ 64%, Stomach 25%	D2 recommended No data on LND performed	OS (NAC + S/S) 38/24 HR = 0.69 P = 0.02 DFS (NAC + S/S) 34/19 HR = 0.65 P = 0.003	HR LE 1.14 EGJ 0.57 Stomach 0.92

S: Surgery; NAC: Neoadjuvant chemotherapy; Adv: Advantage; LND: Lymph node dissection; OS: Overall survival; DFR: Disease free survival; HR: Hazard ratio; LN+: Lymph node positive; D2: D2 lymph node dissection; NR: Not reported; LE: Lower esophagus; EGJ: Esophagogastric junction; pN+: Positive lymph nodes at pathological examinations.

Table 4 Survival results after surgery alone in reference centers

Study, country	Period	Setup	No. of patients	Node dissection	5-yr OS rates
Cunningham et al[17] United Kingdom	1994-2002	MC RCT	503	D2 in 40% S/42% NAC	NAC + S 36.3% Surgery alone 23%
Ychou et al[18] France	1995-2003	MC RCT	224	No data on type of LND	NAC + S 38% Surgery alone 24%
Maruyama et al[48] Japan	1991-2009	MC Retr	11261	D2	AJCC Stage II 73.1% AJCC stage III 44.5%
Wu et al[53] Taiwan	1993-1999	MC RCT	110/111	D1 vs D3	D1 53.6%/ D3 59.5%
Kim et al[49] South Korea	2009-2011	MC Retr	1561	D2	AJCC Stage II 86.5% AJCC Stage III 63.7%
Siewert et al[50] Germany	1986-1989	MC Prosp	1096	D2	46.60%
Sue-Ling et al[51] United Kingdom	1970-1989	SI Prosp	207	D2	55%
Viste et al[54] Norway	1980-1990	SI Retr	105	D2	47%
Robertson et al[55] Hong Kong	1987-1991	SI RCT	25/30	D1 vs D2	D1 45%/D2 35%
Dent et al[56] South Africa	1982-1985	SS RCT	22/21	D1 vs D2	D1 69%/D2 67%
Bonenkamp et al[57] The Netherlands	1989-1993	MC RCT	380/331	D1 vs D2	D1/D2: 45%/47% D2, pT2: 44% D2, pT3: 22% D2, LN-/LN+: 69%/30%
Degiuli et al[13] Italy	1998-2006	MC RCT	133/134	D1 vs D2	D1 /D2: 66.5%/64.2% D2 pT2-T4: 59% D2 pT2-pT4 N+: 51%

MC: Multicenter; RCT: Randomized control trial; Retr: Retrospective study; NAC: Neoadjuvant chemoterapy; S: Surgery; Prosp: Prospective study; SI: Single institution; SS: Single surgeon; LND: Lymph node dissection; OS: Overall survival; AJCC: American Joint Committee on Cancer; LN+: Lymph node positive; LN-: Lymph node negative; D1: D1 lymph node dissection; D2: D2 lymph node dissection; D3: D3 lymph node dissection; NR: Not reported; pT2: Pathological TNM T2 stage; pT3: Pathological TNM T3 stage.