Predictive factors of histological response of colorectal liver metastases after neoadjuvant chemotherapy

Table 1 Preoperative criteria

	NR	R	P-value	Total
	N = 76, n (%)	N = 74, n (%)		N = 150, n (%)
Gender
F	33 (43.4)	38 (51.4)	0.33	71 (47.3)
M	43 (56.6)	36 (48.6)		79 (52.7)
Age, in yr
Median	631	641	0.91	63.31
ASA
1	3 (3.9)	4 (5.4)	0.33	7 (4.7)
2	70 (92.1)	70 (94.6)		140 (93.3)
3	3 (3.9)	0 (0)		3 (2)
Number of lesions before treatment
Median	31	31	0.35	31
Bilobar lesions
No	26 (34.2)	30 (40.5)	0.42	56 (37.3)
Yes	50 (65.8)	44 (59.5)		94 (62.7)
Synchronous liver metastases
No	21 (27.6)	17 (23)	0.51	38 (25.3)
Yes	55 (72.4)	57 (77)		112 (74.7)
Metachronous livers metastases
No	55 (72.4)	57 (77)	0.51	112 (74.7)
Yes	21 (27.6)	17 (23)		38 (25.3)
Time period if metachronous, in mo
Median	141	151	0.96	141
Extra-hepatic metastases
N	56 (73.7)	57 (77)	0.63	113 (75.3)
Yes	20 (26.3)	17 (23)		37 (24.7)
Primary cancer
Colon	57 (75.0)	39 (52.7)	0.004	96 (64)
Rectum	19 (25.0)	35 (47.3)		54 (36)
N+ status primary tumor
No	20 (28.2)	27 (37)	0.26	47 (32.6)
Yes	51 (71.8)	46 (63)		97 (67.4)
Cytotoxic chemotherapy
5-FU	72 (94.7)	69 (93.2)	0.74	141 (94)
Oxaliplatin	33 (43.4)	31 (41.9)	0.85	64 (42.7)
Irinotecan	54 (71.1)	54 (73)	0.79	108 (72)
Capecitabine	1 (1.3)	1 (1.4)	1	2 (1.3)
Raltitrexed	0 (0.0)	1 (1.4)	0.49	1 (0.7)
Targeted preoperative therapy
No	24 (31.6)	23 (31.1)	0.95	47 (31.3)
Yes	52 (68.4)	51 (68.9)		103 (68.7)
Type of targeted therapy
None	24 (31.6)	23 (31.1)	0.056	47 (31.3)
Bevacizumab	33 (43.4)	43 (58.1)		76 (50.7)
Cetuximab	17 (22.4)	6 (8.1)		23 (15.3)
Panitumumab	1 (1.3)	2 (2.7)		3 (2)
Aflibercept	1 (1.3)	0 (0)		1 (0.7)
Number of preoperative treatment sessions
Median	8*	6*	0.038	7.5*
Response to preoperative chemotherapy
No	25 (32.9)	13 (17.6)		38 (25.3)
Yes	51 (67.1)	61 (82.4)	0.031	112 (74.7)
Liver-first strategy
No	74 (97.4)	61 (82.4)	0.002	135 (90)
Yes	2 (2.6)	13 (17.6)		15 (10)
Combined surgery
No	72 (94.7)	68 (91.9)	0.53	140 (93.3)
Yes	4 (5.3)	6 (8.1)		10 (6.7)
Two-stage procedure
No	54 (71.1)	60 (81.1)	0.15	114 (76)
Yes	22 (28.9)	14 (18.9)		36 (24)
Repeat hepatectomy
No	63 (82.9)	69 (93.2)	0.051	132 (88)
Yes	13 (17.1)	5 (6.8)		18 (12)
Hepatectomy
Minor	39 (51.3)	33 (44.6)	0.41	72 (48)
Major	37 (48.7)	41 (55.4)		78 (52)

¹Median. NR: Non-responders; R: Responders; F: Female; M: Male; ASA: American Society of Anes-thesiologist’s score; 5-FU: 5-Fluorouracil.

Table 2 Pathological criteria

	NR	R	P-value	Total
	N = 76,n (%)	N = 74,n (%)		N = 150,n (%)
Dissociated histological response
No	33 (43.4)	55 (74.3)	0.0001	88 (58.7)
Yes	43 (56.6)	19 (25.7)		62 (41.3)
Number of lesions on specimen
Median	31	21	0.07	31
Lesions on specimen
Single	18 (23.7)	24 (32.4)	0.23	42 (28)
Multiple	58 (76.3)	50 (67.6)		108 (72)
Lesions on specimen
≤ 3	46 (60.5)	53 (71.6)	0.15	99 (66)
> 3	30 (39.5)	21 (28.4)		51 (34)
Resection
R0	52 (68.4)	65 (87.8)	0.004	117 (78)
R1	24 (31.6)	9 (12.2)		33 (22)
Emboli
No	60 (78.9)	68 (91.9)	0.025	128 (85.3)
Yes	16 (21.1)	6 (8.1)		22 (14.7)
Size of the largest metastasis
Median	2.91	31	0.43	31
Differentiation
Unclassifiable	2 (2.6)	5 (6.8)	0.45	7 (4.7)
Undifferentiated/barely differentiated	5 (6.6)	3 (4.1)		8 (5.3)
Moderately differentiated	30 (39.5)	34 (45.9)		64 (42.7)
Well-differentiated	39 (51.3)	32 (43.2)		71 (47.3)

¹Median; NR: Non-responders; R: responders.

Table 3 Postoperative criteria

	NR	R	P-value	Total
	N = 76, n (%)	N = 74, n (%)		N = 150, n (%)
Complication
No	45 (59.2)	48 (64.9)	0.48	93 (62)
Yes	31 (40.8)	26 (35.1)		57 (38)
Medical complication
No	53 (69.7)	54 (73)	0.66	107 (71.3)
Yes	23 (30.3)	20 (27)		43 (28.7)
Surgical complication
No	57 (75)	61 (82.4)	0.27	118 (78.7)
Yes	19 (25)	13 (17.6)		32 (21.3)
Length of the hospitalization
Median	111	111	0.36	111
Postoperative chemotherapy
Absent	36 (47.4)	31 (41.9)	0.33	67 (44.7)
Similar	31 (40.8)	38 (51.4)		69 (46)
Different	9 (11.8)	5 (6.8)		14 (9.3)
Recurrence
No	5 (6.6)	12 (16.2)	0.06	17 (11.3)
Yes	71 (93.4)	62 (83.8)		133 (88.7)
Recurrence
Hepatic	59 (77.6)	39 (52.7)	0.001	98 (65.3)
Extra-hepatic	51 (67.1)	46 (62.2)	0.53	97 (64.7)
Multiple sites	43 (56.6)	33 (44.6)	0.14	76 (50.7)

¹Median. NR: Non-responders; R: responders.

Table 4 Predictive factors of the histological response

	Odds ratio	95%CI	P-value
Number of preoperative treatment sessions
≤ 7	1	-	-
> 7	0.47	[0.23; 0.98]	0.044
Radiological response to preoperative chemotherapy
Yes	1	-	-
No	0.33	[0.14; 0.79]	0.013
Liver-first strategy
No	1	-	-
Yes	5.11	[1.06; 24.73]	0.042
Repeat hepatectomy
No	1	-	-
Yes	0.30	[0.09; 0.97]	0.045
Primary cancer
Colon	1	-	-
Rectal	2.81	[1.28; 6.14]	0.010

Table 5 Prognostic factors of overall survival

No vascular neoplastic microemboli on histology
	Hazard ratio	95%CI	P-value
Responder
NR	1	[0.35; 0.86]	0.010
R	0.55
Gender
F	1	[1.11; 2.58]	0.014
M	1.70
Targeted preoperative therapy
No	1	[1.40; 3.62]	0.001
Yes	2.25
Two-stage procedure
No	1	[1.18; 3.06]	0.008
Yes	1.90
N+ status of the primary tumor
No	1	[1.10; 2.84]	0.018
Yes	1.77
Presence of vascular neoplastic microemboli on histology
	Hazard ratio	95%CI	P-value
Gender
F	1	[1.11; 2.58]	0.014
M	1.70
Targeted preoperative therapy
No	1	[1.40; 3.62]	0.001
Yes	2.25
Two-stage procedure
No	1	[1.18; 3.06]	0.008
Yes	1.90
N+ status of the primary tumor
No	1	[1.10; 2.84]	0.018
Yes	1.77

NR: Non-responders; R: responders; F: Female; M: Male.