Extent of lymphadenectomy and perioperative therapies: Two open issues in gastric cancer

Table 1 Regional lymph nodes as defined by the Japanese Research Society for Gastric Cancer (JGCA, 1998)[10]

No. 1 Right paracardial LN

No. 2 Left paracardial LN

No. 3 LN along the lesser curvature

No. 4 LN along greater curve (short gastric vessels, left and right gastroepiploic vessels)

No. 5 Suprapyloric LN

No. 6 Infrapyloric LN

No. 7 LN along the left gastric artery

No. 8 LN along the common hepatic artery (anterosuperior and posterior group)

No. 9 LN around the celiac artery

No. 10 LN at the splenic hilum

No. 11 LN along the splenic artery (proximal and distal tract)

No. 12 LN in the hepatoduodenal ligament (along hepatic artery, bile duct and portal vein)

No. 13 LN retropancreatic

No. 14 LN along superior mesenteric vessels (vein and artery)

No. 15 LN along the middle colic vessels

No. 16 LN paraaortic (of upper, middle and lower abdominal aorta, in relation to the intragastric tumor site)

The classification includes also the following lymph node compartments:

No. 17 LN on the anterior surface of the pancreatic head

No. 18 LN along the inferior margin of the pancreas

No. 19 Infradiaphragmatic LN1

No. 20 LN in the esophageal hiatus of the diaphragm1

No. 110 Paraesophageal LN in the lower thorax1

No. 111 Supradiaphragmatic LN1

No. 112 Posterior mediastinal LN1

¹When the gastric carcinoma also invades the esophagus. LN: Lymph nodes.

Table 2 Nodal compartments to be removed for each type of lymph node dissection as defined by the Japanese Research Society for Gastric Cancer (JGCA, 1998)[10]

Tumor site	LN D1 dissection	LN D2 dissection	LN D3 dissection
Upper stomach	1, 2, 3, 4	4, 7, 8, 9, 10, 11	5, 6, 8, 12, 16
Middle stomach	1, 3, 4, 5, 6	7, 8, 9, 11, 12	4, 8, 10, 11, 12, 13, 14, 16
Lower stomach	3, 4, 5, 6	1, 7, 8, 9, 11, 12, 14	4, 8, 12, 13, 16

LN: Lymph nodes.

Table 3 Main data regarding the extent of nodal dissection

Ref.	Study design	No. of patients	Post-operative mortality (P value)	Post-operative morbidity (P value)	Survival (P value)	Recurrence (P value)
Dent et al[21], 1988	RCT D1 vs D2	D1: 22; D2: 21	None	D1 < D2 (nv)	At 3 yr (NS)	-
Bonenkamp et al[22], 1995 Dutch D1D2 trial	RCT D1 vs D2	D1: 380; D2: 331	D1 < D2 (0.004)	D1 < D2 (0.001)	-	-
Cuschieri et al[23], 1996	RCT D1 vs D2	D1: 200; D2: 200	D1 < D2 (0.04)	D1 < D2 (0.001)	-	-
MRC ST01
Bonenkamp et al[25], 1999	RCT D1 vs D2	D1: 380; D2: 331	-	-	At 5 yr D1 vs D2 (NS)	At 5 yr D1 vs D2 (NS)
Dutch D1D2 trial
Cuschieri et al[26], 1999	RCT D1 vs D2	D1: 200; D2: 200	-	-	At 5 yr D1 vs D2 (NS)	At 5 yr D1 vs D2 (NS)
MRC ST01
Sano et al[30], 2004	RCT D2 vs D3	D2: 263; D3: 260	D2 vs D3 (NS)	D2 < D3 (NS)	-	-
JCOG Study 9501
Sasako et al[32], 2008	RCT D2 vs D3	D2: 263; D3: 260	-	-	At 5 yr D2 vs D3 (NS)	At 5 yr D2 vs D3 (NS)
JCOG Study 9501
Wu et al[33], 2004	RCT D1 vs D3	D1: 110; D3: 111	None	D1 < D3 (0.012)	-	-
Wu et al[34], 2006	RCT D1 vs D3	D1: 110; D3: 111	-	-	At 5 yr D1 < D3 (0.041)	At 5 yr D1 vs D2 (NS)
Hartgrink et al[36], 2004	RCT D1 vs D2	D1: 380; D2: 331	-	-	At 11 yr D1 vs D2 (NS)	At 11 yr D1 vs D2 (NS)
Dutch D1D2 trial
Songun et al[37], 2010	RCT D1 vs D2	D1: 380; D2: 331	-	-	At 15 yr D1 vs D2 (NS)	At 15 yr D1 > D2 (0.005)
Dutch D1D2 trial
Degiuli et al[38], 2010	RCT D1 vs D2	D1: 133; D2: 134	D1 vs D2 (NS)	D1 vs D2 (NS)	-	-
IGCSG
Yang et al[39], 2009	Meta-analysis	D1: 907; D2: 875	D1 < D2 (0.001)	D1 < D2 (0.0001)	At 3 and 5 yr D1 vs D2 (NS)	-
	D1 vs D2
	Meta-analysis D2 vs D3	D2: 599; D3: 588	D2 vs D3 (NS)	D2 vs D3 (NS)	-	-
Memon et al[40], 2011	Meta-analysis D1 vs D2	D1: 946; D2: 930	D1 < D2 (0.005)	D1 < D2 (0.0002)	At 5 yr D1 vs D2 (NS)	-
Seevaratnam et al[41], 2012	Meta-analysis	D1: 845; D2 797	D1 < D2 (0.002)	D1 < D2 (0.0001)	At 5 yr D1 vs D2 (NS)	-
	D1 vs D2

RCT: Randomized controlled trial; NS: Not significant; nv: Not valued.

Table 4 Main data regarding adjuvant chemoradiotherapy for gastric cancer

Ref.	Study design	No. of patients	Survival (P value)	Disease free survival (P value)	Recurrence (P value)	Loco-regional recurrence (P value)
Moertel et al[44], 1984	RCT surgery alone (S) vs surgery + chemoradiotherapy (SCRT)	S: 39	At 5 yr	At 5 yr	-	S vs SCRT
		SCRT: 23	S < SCRT	S < SCRT		(NS)
			(0.05)	(0.02)
Allum et al[45], 1989 BSCG	RCT surgery alone (S) vs surgery + chemoradiotherapy (SCRT) vs surgery + chemotherapy (SCT)	S: 145	At 5 yr	-	-	S vs SCRT (NS)
		SCRT: 153	S vs SCRT			S vs SCT (NS)
		SCT: 138	vs CT (NS)
Hallissey et al[46], 1994 BSCG	RCT surgery alone (S) vs surgery + chemoradiotherapy (SCRT) vs surgery + chemotherapy (SCT)	S: 145	At 5 yr	-	-	-
		SCRT: 153	S vs SCRT
		SCT: 138	vs CT (NS)
Macdonald et al[42], 2001INT-0116	RCT surgery alone (S) vs surgery + chemoradiotherapy (SCRT)	S: 275	At 3 yr	At 3 yr	At 3 yr	At 3 yr
		SCRT: 281	S < SCRT	S < SCRT	S > SCRT	S > SCRT
			(0.005)	(0.001)	(0.001)	(0.0001)
Dikken et al[49], 2010	Retrospective surgery alone (S) vs surgery + chemoradiotherapy (SCRT)	S: 694	At 24 mo S vs SCRT (NS)	At 24 mo	-	At 24 mo
		SCRT: 91		S vs SCRT (NS)		S > SCRT (0.0015)
Kim et al[51], 2005	Observational surgery alone (S) vs surgery + chemoradiotherapy (SCRT)	S: 446	At 5 yr	At 5 yr	-	At 5 yr
		SCRT: 544	S < SCRT	S < SCRT		S > SCRT
			(0.01)	(0.01)		(0.005)
Smalley et al[53], 2012	RCT surgery alone (S) vs surgery + chemoradiotherapy (SCRT)	S: 227	At 10 yr	At 10 yr	At 10 yr	Ar 10 yr
INT-0116		SCRT: 282	S < SCRT	S < SCRT	S > SCRT	S > SCRT
			(0.0046)	(0.001)	(0.006)	(0.0001)
Fiorica et al[54], 2007	Meta-analysis surgery alone (S) vs surgery + chemoradiotherapy (SCRT)	S: 424	At 5 yr	-	-	-
		SCRT: 444	S < SCRt
			(0.00001)
Lee et al[55], 2011	RCT surgery + chemoradiotherapy (SCRT) vs surgery + chemotherapy (SC)	SCRT: 230	-	At 3 yr	SCRT vs SC (NS)	SCRT vs SC (NS)
		SC: 228		SCRT vs SC (NS)

RCT: Randomized controlled trial; NS: Not significant.

Table 5 Main data regarding adjuvant chemotherapy for gastric cancer

Ref.	Study design	n	Survival	Disease free	Recurrence (P value)	Loco-regional
			(P value, HR, RR)	Survival (P value, HR, RR)		Recurrence (P value)
Sakuramoto et al[59], 2007	RCT	S: 530	At 3 yr	At 3 yr	At 3 yr	At 3 yr
	Surgery alone (S) vs surgery + chemoterapy (SC)	SC: 529	S < SC (0.003)	S < SC (0.001)	S > SC (0.001)	S > SC (0.006)
Sasako et al[60], 2011	RCT	S: 530	At 5 yr	At 5 yr	At 5 yr	At 5 yr
	Surgery alone (S) vs surgery + chemoterapy (SC)	SC: 529	SC benefit vs S	SC benefit vs S	S > SC (0.008)	S > SC (0.005)
			HR = 0.66	HR = 0.65
Bang et al[61], 2012	RCT	S: 515	At 3 yr	At 3 yr	At 3 yr	At 3 yr
	Surgery alone (S) vs surgery + chemoterapy (SC)	SC: 520	SC benefit vs S	SC benefit vs S	S > SC (0.0006)	S > SC (0.0003)
			HR = 0.72 (0.049)	HR = 0.56 (0.0001)
Liu et al[64], 2008	Meta-analysis	S: 2313	At median 5 yr	At median 5 yr	At median 5 yr	At median 5 yr
	Surgery alone (S) vs	SC: 2286	SC benefit vs S	SC benefit vs S	SC benefit vs S	SC benefit vs S
	surgery + chemoterapy (SC)		RR = 0.85 (0.00001)	RR = 0.85 (0.04)	RR = 0.78	RR between 0.62-0.65
Sun et al[62], 2009	Meta-analysis	S: 1914	At 5 yr
	Surgery alone (S) vs surgery + chemoterapy (SC)	SC: 1931	SC benefit vs S
			HR = 0.78 (0.001)
Paoletti et al[63], 2010	Meta-analysis	S: 1885	At 10 yr	At 10 yr
	Surgery alone (S) vs surgery + chemoterapy (SC)	SC: 1953	SC benefit vs S	SC benefit vs S
			HR = 0.82 (0.001)	HR = 0.82 (0.001)

RCT: Randomized controlled trial.