Comparison of tumor regression grading systems for locally advanced gastric adenocarcinoma after neoadjuvant chemotherapy

Table 1 Criteria of five tumor regression grading systems

TRG system	Description
JGCA/JGCA2017-TRG
0	No response
1a	67%-99% residual tumor/tumor bed
1b	34%-66% residual tumor/tumor bed
2/2a	10%-33% residual tumor/tumor bed
/2b	< 10% residual tumor/tumor bed
3	Complete response
Becker-TRG
1a	Complete response
1b	< 10% residual tumor/tumor bed
2	10%-50% residual tumor/tumor bed
3	> 50% residual tumor/tumor bed
AJCC/CAP-TRG
0	No residual tumor
1	Single cells or rare small groups of cancer cells
2	More than single cells or rare small groups of cancer cells with evident tumor regression
3	Extensive residual tumor or no response
Mandard-TRG
1	No residual tumor
2	Rare residual tumor
3	Fibrosis outgrowing residual tumor
4	Residual tumor outgrowing fibrosis
5	No response

TRG: Tumor regression grade; JGCA: Japanese Gastric Cancer Association; AJCC: American Joint Committee on Cancer; CAP: College of American Pathologists.

Table 2 Clinical and demographic characteristics of the study population

Characteristics	n (%)
No. of patients	413
Age, median (IQR), yr	61 (54-67)
BMI, median (IQR), (kg/m2)	23.04 (20.83-25.10)
Male	304 (73.61)
ASA score
1	102 (24.70)
2	255 (61.74)
3	56 (13.56)
ECOG
0	229 (55.45)
1	168 (40.68)
2	16 (3.87)
Location
Upper	166 (40.19)
Middle	51 (12.35)
Lower	170 (41.16)
Diffuse	26 (6.30)
Diameter (cm)	3.0 (1.5-4.0)
Differentiation
Well	27 (6.54)
Moderate	176 (42.86)
Poor	209 (50.61)
Mucinous or signet cell	85 (20.58)
LVI	132 (31.96)
Cycles of treatment	2 (2-3)
ypT
ypT0	37 (8.96)
ypT1	25 (6.05)
ypT2	55 (13.32)
ypT3	66 (15.98)
ypT4	230 (55.69)
ypN
N0	169 (40.92)
N1	64 (15.50)
N2	70 (16.95)
N3	110 (26.63)
ypStage
pCR	32 (7.75)
I	57 (13.80)
II	116 (28.09)
III	208 (50.36)
Total gastrectomy	180 (43.58)
Regimen
Platin-based	364 (88.14)
Taxol-based	25 (6.05)
Triplet	24 (5.81)
Adjuvant chemotherapy	308 (74.58)
Postoperative complications
Grade 0-1	277 (67.07)
Grade 2	78 (18.89)
Grade 3-4	58 (14.04)
JGCA2017-TRG
Grade 3 (no residual)	36 (8.72)
Grade 2b (< 10%)	39 (9.44)
Grade 2a (10%-33%)	29 (7.02)
Grade 1b (34%-66%)	78 (18.89)
Grade 1a (67%-99%)	205 (49.64)
Grade 0 (no response)	26 (6.30)
JGCA-TRG
Grade 3 (no residual)	36 (8.72)
Grade 2 (< 33%)	68 (16.46)
Grade 1b (34%-66%)	78 (18.89)
Grade 1a (67%-99%)	205 (49.64)
Grade 0 (no response)	26 (6.30)
Becker-TRG
1a (no residual)	36 (8.72)
1b (< 10%)	39 (9.44)
2 (10%-50%)	65 (15.74)
3 (> 50%)	273 (66.10)
AJCC-TRG
0 (complete response)	36 (8.72)
1 (moderate response)	48 (11.62)
2 (minimal response)	89 (21.55)
3 (poor response)	240 (58.11)
Mandard-TRG
1 (complete response)	36 (8.72)
2 (Fibrosis + scattered tumor cells)	48 (11.62)
3 (Fibrosis predominance + tumor cells)	89 (21.55)
4 (Tumor cells preponderance + fibrosis)	214 (51.82)
5 (No response)	26 (6.30)

BMI: Body mass index; ASA: American Society of Anesthesiologists; ECOG: Eastern Cooperative Oncology Group; LVI: Lymphovascular invasion; NACT: Neoadjuvant chemotherapy; TRG: Tumor regression grade.

Table 3 Univariate analyses for overall survival and progression-free survival using a Cox proportional hazards model

Variables	OS		DFS
	HR (95%CI)	P value	HR (95%CI)	P value
Age
≤ 65
> 65	1.12 (0.84-1.51)	0.439	1.12 (0.84-1.49)	0.4351
BMI
≤ 23.9	1.39 (1.04-1.87)	0.027	1.31 (0.98-1.74)	0.065
> 23.9
Gender
Male
Female	1.14 (0.84-1.56)	0.393	1.06 (0.78-1.45)	0.690
ASA score
1-2
3	1.00 (0.67-1.49)	0.993	0.97 (0.65-1.43)	0.874
ECOG
0
1-2	1.29 (0.98-1.70)	0.073	1.30 (0.99-1.71)	0.056
Location
Diffuse vs Upper	3.32 (2.07-5.31)	< 0.001	2.97 (1.86-4.73)	< 0.001
Diffuse vs Middle	2.63 (1.51-4.56)	< 0.001	2.28 (1.32-3.94)	0.003
Diffuse vs Lower	3.94 (2.45-6.35)	< 0.001	3.52 (2.19-5.65)	< 0.001
Diffuse	1.00		1.00
Diameter (cm)
≤ 5
> 5	2.79 (2.00-3.88)	< 0.001	2.99 (2.17-4.13)	< 0.001
Differentiation
Well-Moderate
Poor	1.43 (1.08-1.90)	0.012	1.51 (1.15-1.99)	0.003
Histology
Non-mucinous
Mucinous or signet cell	1.86 (1.39-2.53)	< 0.001	1.77 (1.31-2.40)	< 0.001
Lymphovascular invasion
No
Yes	2.75 (2.08-3.64)	< 0.001	2.91 (2.21-3.83)	< 0.001
ypT
ypT0-2
ypT3-4	3.54 (2.35-5.36)	< 0.001	3.66 (2.44-5.49)	< 0.001
ypN
ypN0
ypN+	3.50 (2.50-4.90)	< 0.001	3.59 (2.58-4.98)	< 0.001
Resection type
Subtotal
Total	1.79 (1.35-2.36)	< 0.001	1.74 (1.32-2.28)	< 0.001
Cycle of NACT
≤ 2
> 2	1.18 (0.89-1.56)	0.247	1.18 (0.90-1.55)	0.233
NACT regimen
Platin-based	1.00		1.00
Paclitaxel-based	1.10 (0.62-1.92)	0.752	1.27 (0.75-2.15)	0.373
Triplet drug	1.05 (0.59-1.89)	0.862	1.03 (0.57-1.84)	0.930
Adjuvant chemotherapy
Received
Not received	1.36 (1.00-1.85)	0.050	1.18 (0.87-1.60)	0.286
Complications
Clavien-dindo 0-2
Clavien-dindo 3-4	1.15 (0.78-1.69)	0.491	1.11 (0.76-1.63)	0.585
JGCA2017-TRG
Grade 3 (no residual)	1.00		1.00
Grade 2b (< 10%)	8.97 (2.06-39.02)	0.003	8.75 (2.01-38.09)	0.004
Grade 2a (10%-33%)	13.55 (3.11-58.93)	0.001	14.03 (3.23-61.06)	< 0.001
Grade 1b (34%-66%)	12.83 (3.10-53.18)	< 0.001	14.05 (3.40-58.09)	< 0.001
Grade 1a (67%-99%)	15.15 (3.74-61.42)	< 0.001	15.55 (3.84-62.97)	< 0.001
Grade 0 (no response)	20.24 (4.67-87.68)	< 0.001	21.15 (4.88-91.67)	< 0.001
JGCA-TRG
Grade 3 (no residual)	1.00		1.00
Grade 2 (< 33%)	10.79 (2.59-45.05)	0.001	10.79 (2.58-45.05)	0.001
Grade 1b (34%-66%)	12.83 (3.10-53.18)	< 0.001	14.04 (3.40-58.05)	< 0.001
Grade 1a (67%-99%)	15.15 (3.74-61.42)	< 0.001	15.54 (3.84-62.93)	< 0.001
Grade 0 (no response)	20.24 (4.67-87.66)	< 0.001	21.18 (4.89-91.78)	< 0.001
Becker-TRG
1a (no residual)	1.00		1.00
1b (< 10%)	8.98 (2.06-39.06)	0.003	8.74 (2.01-38.05)	0.004
2 (10%-50%)	12.19 (2.92-50.87)	0.001	12.72 (3.05-53.06)	< 0.001
3 (> 50%)	15.50 (3.84-62.62)	< 0.001	16.15 (4.00-65.22)	< 0.001
AJCC-TRG
0 (complete response)	1.00		1.00
1 (moderate response)	10.46 (2.46-44.48)	0.001	10.31 (2.42-43.90)	0.002
2 (minimal response)	11.21 (2.71-46.34)	0.001	11.67 (2.83-48.22)	0.001
3 (poor response)	16.31 (4.03-65.97)	< 0.001	16.94 (4.19-68.49)	< 0.001
Mandard-TRG
1 (complete response)	1.00		1.00
2 (Fibrosis + scattered tumor cells)	10.46 (2.46-44.48)	0.001	10.33 (2.43-43.95)	0.002
3 (Fibrosis predominance + tumor cells)	11.20 (2.71-46.30)	0.001	11.66 (2.82-48.16)	0.001
4 (Tumor cells preponderance + fibrosis)	15.85 (3.91-64.19)	< 0.001	16.48 (4.07-66.71)	< 0.001
5 (No response)	20.27 (4.68-87.81)	< 0.001	21.22 (4.90-91.96)	< 0.001

BMI: Body mass index; ASA: American Society of Anesthesiologists; ECOG: Eastern Cooperative Oncology Group; NACT: Neoadjuvant chemotherapy; TRG: Tumor regression grade; HR: Hazard ratio; DFS: Disease-free survival; OS: Overall survival.

Table 4 Multivariate Cox hazards regression model for the predictable risk of overall survival and disease-free survival in different covariate inclusion in whole patients

	Whole patients (n = 413)
Covariates	OS		DFS
	HR	P value	HR	P value
BMI ≤ 23.9	1.37 (1.01-1.87)	0.045	1.28 (0.95-1.72)	0.109
ECOG > 0	1.19 (0.87-1.61)	0.271	1.18 (0.88-1.60)	0.272
Linitis plastica	1.74 (0.97-3.13)	0.063	1.30 (0.74-2.30)	0.362
Diameter > 5 cm	1.20 (0.77-1.88)	0.426	1.43 (0.93-2.19)	0.102
Poorly differentiated	1.16 (0.85-1.57)	0.345	1.24 (0.92-1.66)	0.160
Mucinous or signet cell	1.45 (1.03-2.05)	0.036	1.32 (0.94-1.84)	0.111
Lymphovascular invasion	1.53 (1.12-2.10)	0.008	1.61 (1.18-2.19)	0.002
ypT3-4	1.45 (0.92-2.28)	0.113	1.52 (0.97-2.37)	0.065
ypN+	1.96 (1.35-2.85)	< 0.001	1.94 (1.34-2.82)	< 0.001
Total gastrectomy	1.30 (0.94-1.79)	0.118	1.23 (0.90-1.69)	0.202
Without AC	1.35 (0.98-1.87)	0.066	Not included	NA
JGCA2017-TRG (Model 1)
Grade 3 (no residual)	1.00		1.00
Grade 2b (< 10%)	4.69 (1.04-21.08)	0.044	4.50 (1.00-20.27)	0.050
Grade 2a (10%-33%)	5.48 (1.19-25.23)	0.029	5.50 (1.20-25.26)	0.028
Grade 1b (34%-66%)	5.32 (1.22-23.30)	0.026	5.73 (1.32-24.88)	0.020
Grade 1a (67%-99%)	6.69 (1.55-28.96)	0.011	6.22 (1.44-26.81)	0.014
Grade 0 (no response)	8.60 (1.87-39.58)	0.006	8.44 (1.84-38.76)	0.006
JGCA-TRG (Model 2)
Grade 3 (no residual)	1.00
Grade 2 (< 33%)	5.00 (1.15-21.78)	0.032	4.90 (1.13-21.30)	0.034
Grade 1b (34%-66%)	5.27 (1.21-23.05)	0.027	5.67 (1.30-24.61)	0.021
Grade 1a (67%-99%)	6.63 (1.53-28.66)	0.011	6.16 (1.43-26.52)	0.015
Grade 0 (no response)	8.48 (1.84-39.00)	0.006	8.31 (1.81-38.15)	0.006
Becker-TRG (Model 3)
1a (no residual)	1.00		1.00
1b (< 10%)	4.74 (1.05-21.30)	0.043	4.57 (1.02-20.57)	0.047
2 (10%-50%)	5.11 (1.16-22.51)	0.031	5.13 (1.17-22.49)	0.030
3 (> 50%)	6.77 (1.57-29.14)	0.010	6.64 (1.55-28.46)	0.011
AJCC-TRG (Model 4)
0 (complete response)	1.00		1.00
1 (moderate response)	5.39 (1.22-23.78)	0.026	5.34 (1.21-23.50)	0.027
2 (minimal response)	5.01 (1.15-21.85)	0.032	5.05 (1.16-21.93)	0.031
3 (poor response)	6.72 (1.56-28.97)	0.011	6.53 (1.52-28.05)	0.012
Mandard-TRG (Model 5)
1 (complete response)	1.00		1.00
2 (Fibrosis + scattered tumor cells)	5.37 (1.22-23.68)	0.026	5.31 (1.21-23.39)	0.027
3 (Fibrosis predominance + tumor cells)	4.95 (1.14-21.60)	0.033	4.98 (1.15-21.62)	0.032
4 (Tumor cells preponderance + fibrosis)	6.44 (1.49-27.87)	0.013	6.26 (1.45-26.93)	0.014
5 (No response)	8.44 (1.83-38.86)	0.006	8.41 (1.83-38.60)	0.006

BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; AC: Adjuvant chemotherapy; TRG: Tumor regression grade; HR: Hazard ratio; DFS: Disease-free survival; OS: Overall survival.

Table 5 The pairwise comparison of C-indexes between different tumor regression grade based on Cox regression for overall survival

	JGCA2017	JGCA	Becker	AJCC/CAP	Mandard	Modified
Overall survival
JGCA2017	1.000	0.308	0.006	0.018	0.053	< 0.001
JGCA		1.000	0.007	0.021	0.063	< 0.001
Becker			1.000	0.397	0.148	0.073
AJCC/CAP				1.000	0.039	0.062
Mandard					1.000	0.005
Modified						1.000
Disease-free survival
JGCA2017	1.000	0.320	0.002	0.021	0.033	< 0.001
JGCA		1.000	0.003	0.025	0.040	< 0.001
Becker			1.000	0.273	0.136	0.046
AJCC/CAP				1.000	0.112	0.024
Mandard					1.000	0.002
Modified						1.000

JGCA: Japanese Gastric Cancer Association; AJCC: American Joint Committee on Cancer; CAP: College of American Pathologists.