Efficacy and safety of immune checkpoint inhibitors plus chemotherapy in esophageal cancer patients with liver metastases

Table 1 Demographic and clinical characteristics of the study cohort, n (%)

Demographic and clinical characteristics	Total number of cases (n = 126)	CMT group (n = 87)	CMT + ICI group (n = 39)	χ² value	P value
Age (years)				0.451	0.502
> 60	59 (46.8)	39 (44.8)	20 (51.3)
≤ 60	67 (53.2)	48 (55.2)	19 (48.7)
Sex				0.079	0.779
Male	119 (94.4)	83 (95.4)	36 (92.3)
Female	7 (5.6)	4 (4.6)	3 (7.7)
Underlying diseases				0.016	0.900
Yes	43 (34.1)	30 (34.5)	13 (33.3)
No	83 (65.9)	57 (65.5)	26 (66.7)
Dysphagia or cancer-related symptoms				0.182	0.669
Yes	106 (84.1)	74 (85.1)	32 (682.1)
No	20 (15.9)	13 (14.9)	7 (17.9)
KPS score				-	0.094
≥ 70	124 (98.4)	87 (100.0)	37 (94.9)
< 70	2 (1.6)	0 (0.0)	2 (5.1)
Histology				2.098	0.321
ESCC	111 (88.1)	74 (85.1)	37 (94.9)
EAC	3 (2.4)	3 (3.4)	2 (5.1)
Other	12 (9.5)	10 (11.5)	0 (0.0)
Primary tumor location				1.649	0.428
Upper	4 (3.2)	3 (3.4)	1 (2.6)
Middle	51 (40.5)	32 (36.8)	19 (48.7)
Lower	71 (56.3)	52 (59.8)	19 (48.7)
Tumor differentiation grade				1.476	0.452
G1	6 (4.8)	5 (5.7)	1 (2.6)
G2	46 (36.5)	34 (39.1)	12 (30.8)
G3-G4	74 (58.7)	48 (55.2)	26 (66.7)
Tumor stage				0.961	0.327
T1-2	17 (13.5)	10 (11.5)	7 (17.9)
T3-4	109 (86.5)	77 (88.5)	32 (82.1)
Nodal stage				0.007	0.932
N0	15 (11.9)	11 (12.6)	4 (10.3)
N+	111 (88.1)	76 (87.4)	35 (89.7)
Synchronous liver metastasis at initial diagnosis				0.487	0.485
Yes	62 (49.2)	41 (47.1)	21 (53.8)
No	64 (50.8)	46 (52.9)	18 (46.2)
Distant lymph node metastasis				0.054	0.816
Yes	53 (42.1)	36 (41.4)	17 (43.6)
No	73 (57.9)	51 (58.6)	22 (56.4)
Primary lesion surgery				0.184	0.668
Yes	52 (41.3)	37 (42.5)	15 (38.5)
No	74 (58.7)	50 (57.5)	24 (61.5)
Primary lesion radiotherapy				0.227	0.634
Yes	51 (40.5)	34 (39.1)	17 (43.6)
No	75 (59.5)	53 (60.9)	22 (56.4)
Pre-hepatic metastasis chemotherapy				0.483	0.487
Yes	41 (32.5)	30 (34.5)	11 (28.2)
No	85 (67.5)	57 (65.5)	28 (71.8)
Pre-hepatic metastasis targeted therapy				-	0.552
Yes	3 (2.4)	84 (96.6)	0 (0.0)
No	123 (97.6)	3 (3.4)	39 (100.0)
Child-Pugh score				-	1.000
> 6	2 (1.6)	2 (97.7)	0 (0.0)
≤ 6	124 (98.4)	85 (2.3)	39 (100.0)
Oligometastatic liver disease				0.491	0.483
Yes	24 (19)	18 (20.7)	6 (15.4)
No	102 (81)	69 (79.3)	33 (84.6)
Number of liver metastases				1.680	0.195
> 3	80 (63.5)	52 (59.8)	28 (71.8)
≤ 3	46 (36.5)	35 (40.2)	11 (28.2)
Hepatic lobe involvement				5.638	0.060
Left	8 (6.3)	4 (4.6)	4 (10.3)
Right	40 (31.7)	33 (37.9)	7 (17.9)
Bilateral	78 (61.9)	50 (57.5)	28 (71.8)
Extrahepatic metastasis				3.739	0.060
Yes	55 (43.7)	33 (37.9)	22 (56.4)
No	71 (56.3)	54 (62.1)	17 (43.6)
Lung metastasis				2.321	0.128
Yes	60 (32.1)	18 (20.7)	13 (33.3)
No	127 (67.9)	69 (79.3)	26 (66.7)
Bone metastasis				0.182	0.669
Yes	20 (15.9)	13 (14.9)	7 (17.9)
No	106 (84.1)	74 (85.1)	32 (82.1)
Brain metastasis				-	1.000
Yes	3 (2.4)	2 (2.3)	1 (2.6)
No	123 (97.6)	85 (97.7)	38 (97.4)

Statistical significance was set at P < 0.05. For certain variables, the Fisher’s exact test was applied in the absence of χ² values. G1: Well-differentiated; G2: Moderately differentiated; G3: Poorly differentiated; G4: Undifferentiated; T: Tumor; N: Node; CMT: Chemotherapy; ICI: Immune checkpoint inhibitor; KPS: Karnofsky Performance Status; ESCC: Esophageal squamous cell carcinoma; EAC: Esophageal adenocarcinoma.

Table 2 Treatment-related characteristics of participants, n (%)

Treatment-related characteristics	Total number of cases (n = 126)	CMT group (n = 87)	CMT + ICI group (n = 39)	χ² value	P value
Chemotherapy regimen				0.852	0.653
Taxane-based ± platinum	75 (59.5)	49 (56.3)	26 (66.7)
Fluoropyrimidine ± platinum	31 (24.6)	23 (26.4)	8 (20.5)
Other	20 (15.9)	15 (17.3)	5 (12.8)
Chemotherapy cycle				0.081	0.776
≥ 4	105 (83.3)	72 (82.8)	33 (84.6)
< 4	21 (16.7)	15 (17.2)	6 (15.4)
Immunotherapy cycle				120.395	< 0.001a
≥ 4	38 (30.2)	0 (0.0)	38 (97.4)
< 4	88 (69.8)	87 (100.0)	1 (2.6)
Liver local treatment				0.746	0.388
Yes	39 (31.0)	29 (33.3)	10 (25.6)
No	87 (69.0)	58 (66.7)	29 (74.4)
Local treatment modalities				2.626	0.662
None	87 (69.0)	58 (66.7)	29 (74.4)
Ablation	24 (19.0)	18 (20.7)	6 (15.4)
Surgery	4 (3.2)	3 (3.4)	1 (2.6)
TACE	4 (3.2)	4 (4.6)	0 (0.0)
Radiotherapy	7 (5.6)	4 (4.6)	3 (7.7)

^aP < 0.05, statistical significance between the two groups.

CMT: Chemotherapy; ICI: Immune checkpoint inhibitor; TACE: Transarterial chemoembolization.

Table 3 Comparison of objective response rate and disease control rate between the two groups, n (%)

Healing effect	Total number of cases (n = 126)	CMT group (n = 87)	CMT + ICI group (n = 39)	P value
ORR	88 (69.8)	51 (58.6)	37 (94.9)	< 0.001
DCR	104 (82.5)	65 (74.7)	39 (100.0)	< 0.001

P < 0.05 was indicative of statistical significance between the two groups. CMT: Chemotherapy; ICI: Immune checkpoint inhibitor; ORR: Objective response rate; DCR: Disease control rate.

Table 4 Comparison of treatment-related adverse events between the two groups, n (%)

TRAEs	Total number of cases (n = 126)	CMT group (n = 87)	CMT + ICI group (n = 39)	χ² value	P value
Any TRAEs	116 (92.1)	80 (92.0)	36 (92.3)	0.000	1.000
TRAEs ≥ 10%
Hematologic toxicity	112 (88.9)	76 (87.4)	36 (92.3)	0.261	0.609
Anemic	104 (82.5)	71 (81.6)	33 (84.6)	0.169	0.681
Leucopenia	71 (56.3)	49 (56.3)	22 (56.4)	0.000	0.993
Neutropenia	57 (45.2)	40 (46.0)	17 (43.6)	0.062	0.803
Thrombocytopenia	52 (41.3)	33 (37.9)	19 (48.7)	1.293	0.256
Hypoalbuminemia	71 (56.3)	50 (57.5)	21 (53.8)	0.144	0.704
Liver dysfunction	40 (31.7)	32 (36.8)	8 (20.5)	3.289	0.070
Increased γ-GT	15 (11.9)	13 (14.9)	2 (5.1)	1.626	0.202
Increased AST	21 (16.7)	16 (18.4)	5 (12.8)	0.602	0.438
Nausea and vomiting	43 (34.1)	35 (40.2)	8 (20.5)	4.657	0.031a
Fatigue	36 (28.6)	25 (28.7)	11 (28.2)	0.004	0.951
≥ 3 TRAEs	41 (32.5)	32 (36.8)	9 (23.1)	2.304	0.129
Hematologic toxicity	37 (29.4)	28 (32.2)	9 (23.1)	1.077	0.299
Neutropenia	17 (13.5)	14 (16.1)	3 (7.7)	1.628	0.202

^aP < 0.05, statistical significance in pairwise multiple comparisons between two groups.

CMT: Chemotherapy; ICI: Immune checkpoint inhibitor; TRAEs: Treatment-related adverse events; γ-GT: Gamma-glutamyl transferase; AST: Aspartate aminotransferase.

Table 5 Results of univariate Cox regression analysis

Influential factors (independent variables)	P value	HR	95%CI for HR
			Lower bound	Upper bound
Age (> 60/≤ 60 years)	0.537	1.124	0.775	1.630
Sex (male/female)	0.781	1.124	0.493	2.560
Underlying diseases (yes/no)	0.324	1.220	0.822	1.810
Dysphagia or cancer-related symptoms (yes/no)	0.217	0.737	0.454	1.196
KPS score (≥ 70/< 70)	0.013a	6.117	1.463	25.573
Histology
ESCC, dummy variable	0.164
EAC	0.163	1.563	0.835	2.928
Other	0.168	2.269	0.709	7.267
Tumor location
Upper, dummy variable	0.819
Middle	0.595	1.317	0.478	3.628
Lower	0.798	0.952	0.652	1.390
Tumor differentiation grade
Grade 1, dummy variable	0.298
Grade 2	0.140	2.044	0.791	5.281
Grade 3-4	0.121	2.110	0.821	5.427
Tumor stage (T1-2/T3-4)	0.121	1.539	0.892	2.656
Nodal stage (N0/N+)	0.758	1.092	0.623	1.915
Synchronous liver metastasis at initial diagnosis (yes/no)	0.795	1.050	0.726	1.519
Distant lymph node metastasis (yes/no)	0.036a	1.492	1.027	2.168
Primary lesion surgery (yes/no)	0.080	0.712	0.488	1.041
Primary lesion radiotherapy (yes/no)	0.765	0.944	0.649	1.373
Pre-hepatic metastasis chemotherapy (yes/no)	0.441	0.854	0.571	1.277
Pre-hepatic metastasis targeted therapy (yes/no)	0.009a	4.809	1.477	15.656
Child-Pugh score (> 6/≤ 6)	0.107	3.224	0.778	13.361
Number of liver metastases (> 3/≤ 3)	0.012a	1.650	1.115	2.441
oligometastatic liver disease (yes/no)	0.001a	0.434	0.261	0.725
Hepatic lobe involvement
Bilateral lobes, dummy variable	0.024a
Left lobe	0.070	0.462	0.200	1.066
Right lobe	0.021a	0.616	0.409	0.929
Extrahepatic metastasis (yes/no)	0.334	1.201	0.828	1.743
Lung metastasis (yes/no)	0.614	1.118	0.724	1.728
Bone metastasis (yes/no)	0.299	1.300	0.792	2.135
Brain metastasis (yes/no)	0.161	0.366	0.090	1.491
Chemotherapy regimen
Taxane-based ± platinum, dummy variable	0.012a
Fluoropyrimidine ± platinum	0.627	1.115	0.720	1.727
Other	0.003a	2.231	1.313	3.792
Chemotherapy cycle (≥ 4/< 4)	< 0.001a	0.261	0.160	0.425
Immunotherapy (yes/no)	0.005a	0.551	0.364	0.836
Immunotherapy cycle (≥ 4/< 4)	0.004a	0.538	0.353	0.820
Liver local treatment (yes/no)	0.005a	0.546	0.358	0.833
Local treatment modalities
None, dummy variable	0.047a
Ablation	0.027a	0.565	0.340	0.937
Surgery	0.217	0.528	0.192	1.455
TACE	0.409	1.530	0.557	4.203
Radiotherapy	0.064	0.424	0.171	1.050

^aP < 0.05, statistical significance included in multifactor Cox regression analysis.

HR: Hazard ratio; 95%CI: 95% confidence interval; TACE: Transarterial chemoembolization; KPS: Karnofsky Performance Status; ESCC: Esophageal squamous cell carcinoma; EAC: Esophageal adenocarcinoma.

Table 6 Results of multivariate Cox regression analysis

Influential factors (independent variables)	P value	HR	95%CI for HR
			Lower bound	Upper bound
KPS score (≥ 70/< 70)	0.049a	5.452	1.008	29.479
Oligometastatic liver disease (yes/no)	0.156	0.592	0.286	1.222
Distant lymph node metastasis (yes/no)	0.843	1.046	0.670	1.633
Pre-hepatic metastasis targeted therapy (yes/no)	0.378	1.853	0.470	7.310
Hepatic lobe involvement
Bilateral lobes, dummy variable	0.449
Left-sided lobe	0.736	0.858	0.353	2.088
Right-sided lobe	0.206	0.686	0.382	1.231
Chemotherapy regimen
Taxane-based ± platinum, dummy variable	0.187
Fluoropyrimidine ± platinum	0.498	0.849	0.528	1.363
Other	0.123	1.570	0.885	2.785
Chemotherapy cycle (≥ 4/< 4)	< 0.001a	0.139	0.072	0.266
Immunotherapy cycle (≥ 4/< 4)	< 0.001a	0.225	0.132	0.383
Liver local treatment (yes/no)	0.021a	0.549	0.330	0.913

^aP < 0.05, statistical significance.

HR: Hazard ratio; 95%CI: 95% confidence interval; KPS: Karnofsky Performance Status.