Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

doi:10.3748/wjg.v19.i48.9282

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World Journal of Gastroenterology

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World J Gastroenterol. Dec 28, 2013; 19(48): 9282-9293
Published online Dec 28, 2013. doi: 10.3748/wjg.v19.i48.9282

Table 1 Tumour regression scoring according to Mandard et al[14]

Grade	Definition
TRG 1	No residual cancer
TRG 2	Rare residual cancer cells
TRG 3	Fibrosis outgrowing residual cancer
TRG 4	Residual cancer outgrowing fibrosis
TRG 5	Absence of regressive changes

TRG: Tumour Regression Grade.

Table 2 Clinical and pathological characteristics of the 218 patients operated on for esophageal and gastro-esophageal adenocarcinoma, according to treatment n (%)

Characteristic		Surgery only 82 (37.6)	Neoadjuvant chemotherapy and surgery 136 (62.4)	Pvalue
Preoperative status
Age (range)¹ yr		74.32 (42.08-85.41)	63.76 (32.77-81.28)	< 0.0001
Sex ratio (M:F)¹		68 (82.9):14 (17.1)	118 (86.8):18 (13.2)	0.439
cT stage	1	17 (20.7)	0 (0.0)	< 0.0001
	2	30 (36.6)	16 (16.0)
	3	34 (41.5)	114 (84.0)
	4	1 (1.2)	6 (4.4)
cN stage	0	36 (43.9)	19 (14.0)	< 0.0001
	1	46 (56.1)	117 (86.0)
cM stage	0	80 (97.6)	134 (98.5)	0.613
	1	1 (2.4)	2 (1.4)
Performance status	0	8 (11.6)	35 (25.7)	0.001
	1	51 (73.9)	96 (70.6)
	2	10 (14.5)	5 (3.7)
ASA	1	3 (3.7)	11 (8.1)	0.005
	2	56 (68.3)	106 (78.5)
	3	23 (28)	18 (13.3)
O-POSSUM		18 (12-30)	16 (12-26)	< 0.0001
Tumour site	Middle 1/3	1 (1.2)	1 (0.7)	0.418
	Lower 1/3	32 (39)	57 (41.9)
	GEJ-S1	19 (23.2)	23 (16.9)
	GEJ-S2	18 (22.0)	34 (25.0)
	GEJ-S3	12 (14.6)	20 (14.7)
Operative outcomes
Length of operation (min)¹		255 (120-480)	261 (120-471)	0.409
Blood loss (mL)¹		300 (0-2200)	318 (0-3000)	0.429
Clavien Dindo Max	0	26 (31.7)	53 (39.3)	0.59
	1	5 (6.1)	8 (5.9)
	2	35 (42.7)	40 (29.6)
	3	6 (7.3)	17 (12.6)
	4	6 (7.3)	17 (12.6)
	5	4 (4.9)	0 (0)
Anastomotic leaks		8 (9.8)	9 (6.7)	0.413
Pathological outcomes
pT or ypT	0	3 (3.6)	8 (5.9)	0.692
	1	23 (28)	23 (16.9)
	2	17 (20.7)	34 (25)
	3	34 (41.5)	66 (48.5)
	4	5 (6.1)	5 (3.7)
pN or ypN	0	40 (48.8)	73 (53.7)	0.758
	1	20 (24.4)	21 (15.4)
	2	11 (13.4)	25 (18.4)
	3	11 (13.4)	17 (12.5)
pM or ypM	0	82 (100)	136 (100)	1.00
Tumour regression grade	1	-	8 (5.8)	n/a
	2	-	28 (20.6)
	3	-	20 (14.7)
	4	-	45 (33.1)
	5	-	35 (25.7)
Nodal downstaged (cN1 to p or ypN1)		13 (15.9)	60 (44.1)	< 0.0001
Positive nodes¹		1 (0-21)	0 (0-24)	0.789
Nodal yield¹		18 (4-49)	18 (3-53)	0.242
Resection clearance	R0	65 (79.3)	110 (80.9)	0.772
Vascular invasion		24 (29.3)	41 (30.1)	0.891
Lymphatic invasion		9 (11)	22 (16.2)	0.28
Perineural invasion		8 (9.8)	20 (14.7)	0.291
Maximum tumour diameter (mm)¹		25 (0-90)	25 (0-155)	0.998
Morphology	Ulcer	48 (60)	96 (74.4)	0.029
	Polypoid	22 (27.5)	23 (17.8)
	Fungating	2 (2.5)	3 (2.3)
	Diffuse infiltrating	8 (10)	7 (5.4)
Grade	G1	6 (7.3)	16 (11.8)	0.669
	G2	30 (36.6)	37 (27.2)
	G3	46 (56.1)	82 (60.3)
	G4	0 (0)	1 (0.7)
Sites of recurrence	Local	3 (3.7)	8 (5.9)	0.461
	Nodal	5 (6.1)	14 (10.4)	0.281
	Distant	18 (22.0)	44 (32.6)	0.093

Values in parentheses are percentages unless indicated.

¹Values in parentheses are range. ASA: American society of anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity; GEJ-S1-3: Gastro-esophageal junction-Siewert type 1-3.

Table 3 Clinical and pathological characteristics of the 136 patients treated with neoadjuvant chemotherapy for esophageal and gastro-esophageal adenocarcinoma, classified as responders Tumour regression grade 1-2 or non-reponders tumour regression grade 3-5 n (%)

		TRG 1-2 36 (26.5)	TRG 3-5 100 (73.5)	Pvalue
Preoperative status
Age (range) yr¹		65.27 (26.99-76.04)	63.51 (32.77-81.28)	0.410
Sex ratio (M:F)¹		32 (88.9):4 (11.1)	86 (86):14 (14)	0.662
cT stage	1	0 (0)	0 (0)	0.396
	2	2 (5.6)	14 (14)
	3	33 (91.7)	81 (81)
	4	1 (2.8)	5 (5)
cN stage	0	5 (13.9)	14 (14)	0.987
	1	31 (86.1)	86 (86)
cM stage	0	35 (97.1)	99 (99)	0.456
	1	1 (2.8)	1 (1)
Performance status	0	12 (33.3)	23 (23)	0.225
	1	23 (63.9)	73 (73)
	2	1 (2.8)	4 (4.0)
ASA	1	2 (5.6)	9 (9.1)	0.408
	2	32 (88.9)	74 (74.7)
	3	2 (5.6)	16 (16.2)
O-POSSUM		15 (12-23)	16 (12-26)	0.476
Tumour site	Middle 1/3	1 (2.8)	0 (0)	0.738
	Lower 1/3	15 (41.7)	42 (42)
	GEJ-S1	7 (19.4)	16 (16)
	GEJ-S2	9 (25)	25 (25)
	GEJ-S3	4 (11.1)	16 (16)
Operative outcomes
Length of operation (min)¹		262 (163-427)	260 (120-471)	0.513
Blood loss (mL)¹		300 (0-3000)	325 (0-1700)	0.673
Clavien Dindo Max	0	14 (38.9)	39 (39.4)	0.531
	1	2 (5.6)	6 (6.1)
	2	14 (38.9)	26 (26.3)
	3	4 (11.1)	13 (13.1)
	4	2 (5.6)	15 (15.2)
	5	0 (0)	0 (0)
Anastomotic leaks		1 (2.8)	8 (8.1)	0.276
Pathological outcomes
yPT	0	8 (22.2)	0 (0)	< 0.0001
	1	11 (30.6)	12 (12)
	2	9 (25)	25 (25)
	3	8 (22.2)	58 (58)
	4	0 (0)	5 (5)
yPN	0	34 (94.4)	39 (39)	< 0.0001
	1	0 (0)	21 (21)
	2	2 (5.6)	23 (23)
	3	0 (0)	17 (17)
yPM	0	36 (100)	100 (100)	0.579
Nodal downstaged (cN1 to ypN0)		30 (83.3)	30 (30)	< 0.0001
Positive nodes¹		0 (0-5)	1 (0-24)	< 0.0001
Nodal yield¹		18 (4-25)	18 (3-53)	0.984
Resection clearance	R0	35 (97.2)	75 (75)	0.004
Vascular invasion		4 (11.1)	37 (37)	0.004
Lymphatic invasion		4 (11.1)	18 (18)	0.338
Perineural invasion		2 (5.6)	18 (18)	0.072
Maximum tumour diameter¹	(mm)	15 (0-110)	30 (0-155)	< 0.0001
Morphology	Ulcer	30 (93.8)	66 (68)	0.003
	Polypoid	2 (6.3)	21 (21.6)
	Fungating	0 (0)	3 (3.1)
	Diffuse infiltrating	0 (0)	7 (7.2)
Grade	G1	8 (22.2)	8 (8)	0.104
	G2	9 (25)	28 (28)
	G3	19 (52.8)	63 (63)
	G4	0 (0)	1 (1)
Sites of recurrence	Local	0 (0)	8 (8.1)	0.080
	Nodal	1 (2.8)	13 (13.1)	0.082
	Distant	2 (5.6)	42 (42.4)	< 0.0001

Values in parentheses are percentages unless indicated.

¹Values in parentheses are range. TRG: Tumour Regression Grade; ASA:American Society of Anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity; GEJ-S1-3: Gastro-esophageal junction-Siewert type 1-3.

Table 4 Univariate and multivariate Cox regression analyses of patient and tumour factors with disease free survival for patients undergoing neoadjuvant chemotherapy (n = 136)

		Univariate			Multivariate
		HR	95%CI	Pvalue	HR	95%CI	Pvalue
Patient factors
Age		0.972	(0.944-1.00)	0.054
Sex	Female	1.000	Ref
	Male	0.953	(0.453-2.005)	0.899
ASA	1	1.000	Ref
	2	0.696	(0.313-1.548)	0.374
	3	0.947	(0.352-2.546)	0.914
Performance status	0	1.000	Ref
	1	1.016	(0.578-1.789)	0.955
	2	0.950	(0.218-4.129)	0.945
O-POSSUM
Tumour response
TRG	1	1.000	Ref
	2	1.099	(0.099-12.148)	0.939
	3	8.404	(1.071-65.929)	0.043
	4	7.829	(1.054-58.163)	0.044
	5	15.422	(2.083-114.189)	0.007
TRG grouped	1-2	1.000	Ref		1.000	Ref
	3-5	9.504	(2.973-30.380)	< 0.0001	6.315	(1.261-31.616)	0.025
Lymph node response
Lymph nodes downstaged	Yes	1.000	Ref		1.000	Ref
	No	5.784	(3.064-10.919)	< 0.0001	6.161	(1.683-22.554)	0.006
Tumour factors
ypT stage	0	1.000	Ref		1.000	Ref
	1	2.085	(0.232-18.711)	0.512	0.281	(0.020-3.928)	0.345
	2	5.214	(0.687-39.549)	0.110	0.286	(0.022-3.705)	0.338
	3	9.490	(1.293-69.635)	0.027	0.469	(0.034-6.460)	0.571
	4	52.907	(6.008-465.873)	< 0.0001	1.519	(0.087-26.389)	0.774
ypN stage	0	1.000	Ref		1.000	Ref
	1	4.791	(2.434-9.431)	< 0.0001	0.476	(0.133-1.700)	0.253
	2	4.102	(2.005-8.392)	< 0.0001	0.254	0.070-0.927)	0.038
	3	7.449	(3.522-15.756)	< 0.0001	0.476	(0.129-1.755)	0.265
ypM stage	0	1.000	Ref		1.000	Ref
	1	3.172	(1.253-8.031)	0.015	2.693	(0.924-7.847)	0.069
Vascular invasion	No	1.000	Ref		1.000	Ref
	Yes	3.444	(2.080-5.702)	< 0.0001	1.929	(1.034-3.600)	0.039
Lymphatic invasion	No	1.000	Ref		1.000	Ref
	Yes	2.201	(1.268-3.821)	0.005	1.253	(0.637-2.462)	0.514
Perineural invasion	No	1.000	Ref		1.000	Ref
	Yes	5.073	(2.896-8.886)	< 0.0001	2.766	(1.444-5.300)	0.002
Resection clearance	R0	1.000	Ref		1.000	Ref
	R1	3.869	(2.272-6.588)	< 0.0001	1.805	(0.940-3.468)	0.076

TRG: Tumour Regression Grade; ASA: American Society of Anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity.

Table 5 Clinical and pathological characteristics of the 113 patients with pathological N0 stage, according to treatment n (%)

		pN0 Surgery alone 40 (35.4)	ypN0 Neoadjuvant chemotherapy and surgery 73 (64.6)	Pvalue
Preoperative status
Age (range) yr¹		73.62 (56.73-85.41)	65.59 (32.77-78.43)	< 0.0001
Sex ratio (M:F)¹		31 (77.5):9 (22.5)	66 (90.4):7 (9.8)	0.061
cT stage	1	13 (32.5)	0 (0)	< 0.0001
	2	17 (42.5)	9 (12.3)
	3	10 (25)	61 (83.6)
	4	0 (0)	3 (4.1)
cN stage	0	27 (67.5)	13 (17.8)	< 0.0001
	1	13 (32.5)	60 (82.2)
cM stage	0	40 (100)	71 (97.3)	0.293
	1	0 (0)	2 (2.8)
Performance status	0	3 (9.4)	16 (21.9)	0.045
	1	25 (78.1)	54 (74)
	2	4 (12.5)	3 (4.1)
ASA	1	2 (5)	6 (8.2)	0.268
	2	31 (77.5)	59 (80.8)
	3	7 (17.5)	8 (11)
O-POSSUM¹		17 (14-29)	16 (12-26)	0.015
Tumour site	Middle 1/3	0 (0)	1 (1.4)	0.190
	Lower 1/3	15 (37.5)	35 (47.9)
	OGJ-S1	11 (27.5)	12 (16.4)
	OGJ-S2	8 (20)	16 (21.9)
	OGJ-S3	6 (15)	9 (12.3)
Operative outcomes
Length of operation (min)¹		240 (120-360)	278 (120-471)	0.082
Blood loss (mL)¹		200 (0-2200)	350 (0-3000)	0.167
Clavien Dindo Max	0	14 (35)	24 (32.9)	0.709
	1	1 (2.5)	3 (4.1)
	2	17 (42.5)	27 (37)
	3	4 (10)	10 (13.7)
	4	2 (5)	9 (12.3)
	5	2 (5)	0 (0)
Anastomotic leaks		4 (10)	7 (9.6)	0.944
Pathological outcomes
TRG 1-2		-	34 (46.6)	NA
TRG 3-5		-	39 (53.4)
pT or ypT	0	2 (5)	11 (15.1)	0.224
	1	22 (55)	20 (27.4)
	2	5 (12.5)	20 (27.4)
	3	10 (25)	24 (32.9)
	4	0 (0)	1 (1.4)
Nodal Downstaged (cN1 to p or ypN0)		15 (37.5)	61 (83.6)	< 0.0001
Nodal yield¹		16 (4-49)	18 (3-52)	0.150
Resection clearance	R0	35 (87.5)	69 (94.5)	0.189
Vascular invasion		7 (17.5)	10 (13.7)	0.590
Lymphatic invasion		2 (5)	6 (8.2)	0.525
Perineural invasion		2 (5)	5 (6.8)	0.698
Maximum tumour diameter (mm)¹		24 (0-50)	24 (0-110)	0.324
Morphology	Ulcer	25 (65.8)	53 (79.1)	0.135
	Polypoid	10 (26.3)	11 (16.4)
	Fungating	1 (2.6)	1 (1.5)
	Diffuse infiltrating	2 (5.3)	2 (3)
Grade	G1	4 (10)	13 (17.8)	0.811
	G2	17 (42.5)	20 (27.4)
	G3	19 (47.5)	40 (54.8)
	G4	0 (0)	0 (0)
Site of recurrence	Local	0 (0)	2 (2.7)	0.293
	Nodal	1 (2.5)	4 (5.5)	0.463
	Distant	3 (7.5)	12 (16.4)	0.182

Values in parentheses are percentages unless indicated.

Citation: Noble F, Nolan L, Bateman AC, Byrne JP, Kelly JJ, Bailey IS, Sharland DM, Rees CN, Iveson TJ, Underwood TJ, Bateman AR. Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus. World J Gastroenterol 2013; 19(48): 9282-9293
URL: https://www.wjgnet.com/1007-9327/full/v19/i48/9282.htm
DOI: https://dx.doi.org/10.3748/wjg.v19.i48.9282