Real-world comparison of chemotherapy plus bevacizumab with or without immunotherapy as first-line therapy in colorectal cancer

Table 1 Baseline characteristics and treatment details of patients in the matched cohort, n (%)

Characteristics	Levels	Control group (n = 78)	Experiment group (n = 25)	P value
Age	> 60	33 (42.3)	10 (40)	1.000
	≤ 60	45 (57.7)	15 (60)	-
Gender	Male	48 (61.5)	15 (60)	1.000
	Female	30 (38.5)	10 (40)	-
ECOG	1	75 (96.2)	23 (92)	0.759
	2	3 (3.8)	2 (8)	-
Primary tumor location	Right colon	27 (34.6)	12 (48)	0.335
	Left colon and rectum	51 (65.4)	13 (52)	-
Primary tumor surgery	No	12 (15.4)	3 (12)	1.000
	Yes	66 (84.6)	22 (88)	-
Number of metastatic organs	1	55 (70.5)	19 (76)	0.783
	≥ 2	23 (29.5)	6 (24)	-
Liver metastasis	No	37 (47.4)	9 (36)	0.441
	Yes	41 (52.6)	16 (64)	-
Lung metastasis	No	58 (75.3)	19 (76)	1.000
	Yes	19 (24.7)	6 (24)	-
RAS	Unknown	16 (20.5)	8 (32)	0.496
	Wild-type	15 (19.2)	4 (16)	-
	Mutation	47 (60.3)	13 (52)	-

The control group received chemotherapy combined with bevacizumab. The experimental group received chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy. ECOG: Eastern Cooperative Oncology Group.

Table 2 Comparison of short-term efficacy between two groups of microsatellite stable metastatic colorectal cancer

Group	Number	PR	SD	PD	ORR (%)	DCR (%)
Control group	78	18	53	7	23.08	91.03
Experimental group	25	9	15	1	36.00	96.00
χ2 value	-	1.0348	0.2377	-	1.0348	-
P value	-	0.309	0.6258	0.67591	0.309	0.67591

¹Fisher’s exact test.

The control group received chemotherapy combined with bevacizumab. The experimental group received chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy. PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate.

Table 3 Univariate and multivariate Cox analysis of the effect of prognostic factors in the original cohort, n (%)

Dependent: Survival (OS/30, status OS)		All patients	HR (univariable)	HR (multivariable)
Gender	Male	87 (64.0)	-	-
	Female	49 (36.0)	0.83 (0.45-1.50, P = 0.531)	1.02 (0.56-1.91, P = 0.928)
Age	> 60	60 (44.1)	-	-
	≤ 60	76 (55.9)	1.20 (0.67-2.14, P = 0.540)	1.00 (0.56-1.80, P = 0.995)
ECOG	1	125 (91.9)	-	-
	2	11 (8.1)	1.14 (0.41-3.19, P = 0.803)	-
Number of metastatic organs	1	80 (58.8)	-	-
	≥ 2	56 (41.2)	1.50 (0.85-2.64, P = 0.163)	-
Primary tumor location	Right colon	51 (37.5)	-	-
	Left colon and rectum	85 (62.5)	1.15 (0.64-2.07, P = 0.631)	-
Liver metastasis	No	53 (39.0)	-	-
	Yes	83 (61.0)	3.34 (1.73-6.46, P < 0.001)	3.36 (1.71-6.60, P < 0.001)
Lung metastasis	No	94 (69.1)	-	-
	Yes	42 (30.9)	0.65 (0.34-1.24, P = 0.192)	-
RAS	Unknown	26 (19.1)	-	-
	Wild type	24 (17.6)	1.00 (0.41-2.43, P = 0.993)	-
	Mutation	86 (63.2)	0.89 (0.42-1.90, P = 0.767)	-
Group	Control group	108 (79.4)	-	-
	Experimental group	28 (20.6)	0.80 (0.34-1.89, P = 0.607)	0.80 (0.34-1.91, P = 0.620)

OS: Overall survival; HR: Hazard ratio; ECOG: Eastern Cooperative Oncology Group.

Table 4 Treatment-emergent adverse events in the 103 patients of the matched dataset, n (%)

Toxicities	Experimental group (n = 25)			Control group (n = 78)			P value for grade 1-2	P value for grade 3-4
	Grade 0	Grade 1-2	Grade 3-4	Grade 0	Grade 1-2	Grade 3-4
Anemia	13 (50.0)	12 (50.0)	0 (0)	53 (70.6)	24 (28.2)	1 (1.2)	0.1831a	1b
Neutropenia	18 (69.2)	6 (26.9)	1 (3.8)	40 (51.8)	30 (38.8)	8 (9.4)	0.2807a	0.4488b
Leukocytopenia	19 (73.1)	5 (23.1)	1 (3.8)	47 (60.0)	28 (36.5)	3 (3.5)	0.2164a	1b
Thrombocytopenia	18 (69.2)	7 (30.8)	0 (0)	44 (55.3)	30 (40.0)	4 (4.7)	0.4782a	0.5698b
Proteinuria	23 (92.3)	2 (7.7)	0 (0)	64 (81.2)	14 (18.8)	0 (0)	0.3454b	1b
Aspartate transaminase increased	12 (46.2)	13 (53.8)	0 (0)	46 (57.6)	30 (40.0)	2 (2.4)	0.3363a	1b
Alanine transaminase increased	14 (53.8)	11 (46.2)	0 (0)	50 (63.5)	26 (35.3)	1 (1.2)	0.4667a	1b
Alkaline phosphatase increased	18 (69.2)	7 (30.8)	0 (0)	62 (77.6)	16 (22.4)	0 (0)	0.6126a	1b
Blood bilirubin increased	22 (84.6)	3 (15.4)	0 (0)	57 (64.7)	20 (34.1)	1 (1.2)	0.07312b	1b
Triglycerides increased	13 (50.0)	10 (42.3)	2 (7.7)	53 (67.1)	22 (29.4)	3 (3.5)	0.3894a	0.5926b
Hypothyroidism	23 (92.3)	2 (7.7)	0 (0)	78 (100)	0 (0)	0 (0)	0.0571b	1b
Nausea	11 (42.3)	14 (57.7)	0 (0)	31 (41.2)	46 (57.6)	1 (1.2)	0.9765a	1b
Vomiting	11 (42.3)	14 (57.7)	0 (0)	47 (58.8)	30 (40.0)	1 (1.2)	0.1901a	1b
Fatigue	23 (92.3)	2 (7.7)	0 (0)	58 (72.9)	20 (27.1)	0 (0)	0.09078b	1b
Fever	24 (96.2)	1 (3.8)	0 (0)	77 (98.8)	1 (1.2)	0 (0)	0.4283b	1b
Rash	23 (92.3)	2 (7.7)	0 (0)	78 (100)	0 (0)	0 (0)	0.05711b	1b
Diarrhea	24 (96.2)	1 (3.8)	0 (0)	72 (92.9)	4 (4.7)	2 (2.4)	1b	1b
Peripheral neurotoxicity	24 (96.2)	1 (3.8)	0 (0)	75 (96.5)	2 (2.4)	1 (1.2)	0.5698b	1b
Hand-foot syndrome	23 (92.3)	1 (3.8)	1 (3.8)	72 (92.9)	5 (5.9)	1 (1.2)	1b	0.4283b
Hypertension	24 (96.2)	1 (3.8)	0 (0)	77 (98.8)	0 (0)	1 (1.2)	0.2427b	1b

^aP values were calculated by χ² test.

^bP values were calculated by Fisher’s exact test.

The control group received chemotherapy combined with bevacizumab. The experimental group received chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy.

Table 5 Baseline hematological prognostic indicators markers for patients receiving chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy, mean ± SD

Characteristics	Stats	Normal range
Height (cm)	162.6 ± 8.2	140-190
Weight (kg)	61.0 ± 8.9	40-100
ALLC (109/L)	6.1 ± 2.2	3.5-9.5
ANC (109/L)	5.9 ± 11.1	1.8-6.3
ALC (109/L)	1.6 ± 0.6	1.1-3.2
AMC (109/L)	0.4 ± 0.2	0.1-0.6
PLT (109/L)	253.5 ± 79.7	125-350
AEC (109/L)	0.3 ± 0.5	0.02-0.52
RDW (%)	14.7 ± 3.2	11.6-14.8
FIB (g/L)	3.7 ± 1.5	2-4
Dimer (ng/mL)	879.3 ± 1162.6	0-500
LDH (IU/L)	257.5 ± 150.4	109-245
ALB (g/L)	41.5 ± 4.0	40-55
CEA (ng/mL), n (%)	10 (35.7)	0-5
	18 (64.3)
CA199 (IU/mL), n (%)	19 (67.9)	0-37
	9 (32.1)

ALLC: Absolute leukocyte count; ANC: Absolute neutrophil count; ALC: Absolute lymphocyte count; AMC: Absolute monocyte count; PLT: Platelet; AEC: Absolute eosinophil count; RDW: Red blood cell distribution width; FIB: Fibrinogen; LDH: Lactate dehydrogenase; ALB: Albumin; CEA: Carcinoembryonic antigen; CA199: Carbohydrate antigen 199.

Table 6 Univariate and multivariate Cox analysis of prognostic factors in microsatellite stable metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy, n (%)

Dependent: Survival (PFS/30, status)		All	HR (univariable)	HR (multivariable)
Age	> 60	10 (35.7)	-	-
	≤ 60	18 (64.3)	1.47 (0.52-4.15, P = 0.466)	-
Gender	Male	15 (53.6)	-	-
	Female	13 (46.4)	1.34 (0.52-3.41, P = 0.543)	-
Location	Right colon	15 (53.6)	-	-
	Left colon and rectum	13 (46.4)	4.02 (1.38-11.70, P = 0.011)	1.34 (0.25-7.36, P = 0.733)
Number of metastatic organs	1	22 (78.6)	-	-
	≥ 2	6 (21.4)	0.90 (0.26-3.14, P = 0.870)	-
Liver metastasis	No	10 (35.7)	-	-
	Yes	18 (64.3)	0.73 (0.27-1.99, P = 0.540)	-
Lung metastasis	No	21 (75.0)	-	-
	Yes	7 (25.0)	1.20 (0.42-3.42, P = 0.727)	-
RAS	Unknown	8 (28.6)	-	-
	Wild type	5 (17.9)	1.61 (0.34-7.57, P = 0.544)	-
	Mutation	15 (53.6)	1.52 (0.42-5.52, P = 0.524)	-
CEA	1	10 (35.7)	-	-
	2	18 (64.3)	2.11 (0.74-6.01, P = 0.161)	-
CA199	1	19 (67.9)	-	-
	2	9 (32.1)	3.70 (1.27-10.77, P = 0.016)	2.56 (0.43-15.18, P = 0.301)
NLR	≤ 3.96	23 (82.1)	-	-
	> 3.96	5 (17.9)	4.72 (1.24-17.88, P = 0.023)	1.79 (0.19-17.36, P = 0.614)
LMR	≤ 6.45	25 (89.3)	-	-
	> 6.45	3 (10.7)	2.44 (0.67-8.84, P = 0.174)	-
BMI	≤ 18.73	3 (10.7)	-	-
	> 18.73	25 (89.3)	4.38 (0.56-34.10, P = 0.159)	-
ALI	≤ 205.20	9 (32.1)	-	-
	> 205.20	19 (67.9)	0.37 (0.14-1.00, P = 0.049)	0.33 (0.14-13.15, P = 0.805)
SII	≤ 926.18	21 (75.0)	-	-
	> 926.18	7 (25.0)	3.11 (1.10-8.81, P = 0.033)	2.54 (0.32-20.29, P = 0.379)
ALLC	≤ 4.85	8 (28.6)	-	-
	> 4.85	20 (71.4)	3.51 (1.12-11.04, P = 0.032)	11.52 (0.52-256.63, P = 0.123)
ANC	≤ 3.13	13 (46.4)	-	-
	> 3.13	15 (53.6)	2.56 (0.95-6.89, P = 0.064)	0.51 (0.07-3.53, P = 0.493)
ALC	≤ 1.15	7 (25.0)	-	-
	> 1.15	21 (75.0)	1.87 (0.53-6.60, P = 0.332)	-
AMC	≤ 0.32	7 (25.0)	-	-
	> 0.32	21 (75.0)	3.38 (0.96-11.90, P = 0.058)	1.30 (0.15-11.13, P = 0.814)
AEC	≤ 0.15	16 (57.1)	-	-
	> 0.15	12 (42.9)	2.52 (0.98-6.46, P = 0.055)	0.54 (0.10-3.07, P = 0.488)
RDW	≤ 13	6 (21.4)	-	-
	> 13	22 (78.6)	0.23 (0.07-0.76, P = 0.016)	0.26 (0.04-1.51, P = 0.133)
LDH	≤ 199	13 (46.4)	-	-
	> 199	15 (53.6)	3.44 (1.24-9.54, P =0 .018)	4.11 (1.02-16.55, P = 0.046)

PFS: Progression-free survival; HR: Hazard ratio; CEA: Carcinoembryonic antigen; CA199: Carbohydrate antigen 199; NLR: Neutrophil-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; BMI: Body mass index; ALI: Advanced lung cancer inflammation index; SII: Systemic immune-inflammation index; ALLC: Absolute leukocyte count; ANC: Absolute neutrophil count; ALC: Absolute lymphocyte count; AMC: Absolute monocyte count; AEC: Absolute eosinophil count; RDW: Red blood cell distribution width; LDH: Lactate dehydrogenase.

Table 7 The predictive value of lactate dehydrogenase in microsatellite stable metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy

Time	AUC	95%CI	Cut-off	Sensitivity	Specificity
9 months	0.81	0.63-0.98	154	0.89	0.75
12 months	0.71	0.47-0.95	343	0.84	0.73
15 months	0.79	0.54-1.04	232	0.93	0.71

AUC: Area under the curve; CI: Confidence interval.