Chemotherapy plus bevacizumab with or without anti-programmed death 1 immunotherapy as the second-line therapy in colorectal cancer

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

Characteristics	Levels	Control group (n = 77)	Experiment group (n = 26)	P value
Age	> 60	33 (42.9)	12 (46.2)	0.949
	≤ 60	44 (57.1)	14 (53.8)
Gender	Male	55 (71.4)	18 (69.2)	1.000
	Female	22 (28.6)	8 (30.8)
ECOG	0-1	69 (89.6)	22 (84.6)	0.739
	2	8 (10.4)	4 (15.4)
Primary tumor location	Right colon	20 (26)	9 (34.6)	0.552
	Left colon and rectum	57 (74)	17 (65.4)
Primary tumor surgery	No	15 (19.5)	3 (11.5)	0.533
	Yes	62 (80.5)	23 (88.5)
Number of metastatic organs	1	26 (33.8)	8 (30.8)	0.968
	≥ 2	51 (66.2)	18 (69.2)
Liver metastasis	No	19 (24.7)	8 (30.8)	0.724
	Yes	58 (75.3)	18 (69.2)
Lung metastasis	No	41 (53.2)	11 (42.3)	0.461
	Yes	36 (46.8)	15 (57.7)
RAS mutation type	Unknown	15 (19.5)	5 (19.2)	0.872
	Wild-type	12 (15.6)	3 (11.5)
	Mutation	50 (64.9)	18 (69.2)

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	DCR (%)
Control group	77	7	34	36	57.14
Experimental group	26	3	17	6	76.92
χ2 value	-	-	2.706	3.585	3.5847
P value	-	0.711	0.1	0.058	0.058

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; DCR: Disease control rate.

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

Dependent: Survival (PFS/30, status)		All patients (n = 131)	HR (univariable)	HR (multivariable)
Gender	Male	76 (58.0)	-	-
	Female	55 (42.0)	0.87 (0.60-1.26, P = 0.458)	-
Age	> 60	66 (50.4)	-	-
	≤ 60	65 (49.6)	0.73 (0.50-1.07, P = 0.110)	-
ECOG	0-1	116 (88.5)	-	-
	2	15 (11.5)	1.34 (0.73-2.47, P = 0.340)	-
Number of metastatic organs	1	55 (42.0)	-	-
	≥ 2	76 (58.0)	1.96 (1.32-2.90, P < 0.001)	1.90 (1.27-2.84, P = 0.002)
Primary tumor location	Right colon	32 (24.4)	-	-
	Left colon and rectum	99 (75.6)	0.92 (0.61-1.40, P = 0.697)	-
Liver metastasis	No	46 (35.1)	-	-
	Yes	85 (64.9)	1.57 (1.04-2.36, P = 0.032)	1.28 (0.84-1.96, P = 0.254)
Lung metastasis	No	70 (53.4)	-	-
	Yes	61 (46.6)	1.23 (0.85-1.78, P = 0.274)	-
RAS mutation type	Unknown	25 (19.1)	-	-
	Wild type	20 (15.3)	0.97 (0.51-1.85, P = 0.930)	-
	Mutation	86 (65.6)	1.37 (0.84-2.24, P = 0.202)	-
Group	Control group	105 (80.2)	-	-
	Experimental group	26 (19.8)	0.51 (0.31-0.82, P = 0.006)	0.49 (0.30-0.80, P = 0.004)

n = 131, events = 115, likelihood ratio test = 22.56 on 3 df (P < 0.001). ECOG: Eastern Cooperative Oncology Group; PFS: Progression-free survival; HR: Hazard ratio.

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

Toxicities	Experimental group (n = 26)			Control group (n = 77)			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	8 (30.8)	15 (57.7)	3 (11.5)	47 (61.0)	29 (37.7)	1 (1.3)	0.1197a	0.2451b
Neutropenia	18 (69.2)	7 (26.9)	1 (3.8)	58 (75.3)	14 (18.2)	5 (6.5)	0.4996a	1b
Leukocytopenia	14 (53.8)	11 (42.3)	1 (3.8)	55 (71.4)	18 (23.4)	4 (5.2)	0.1088a	0.3667b
Thrombocytopenia	17 (65.4)	9 (34.6)	0 (0.0)	62 (80.5)	15 (19.5)	0 (0.0)	0.1902a	1b
Proteinuria	21 (80.8)	5 (19.2)	0 (0.0)	70 (90.9)	7 (9.1)	0 (0.0)	0.2984a	1b
Aspartate transaminase increased	18 (69.2)	7 (26.9)	1 (3.8)	56 (72.7)	20 (26.0)	1 (1.3)	1a	1b
Alanine transaminase increased	20 (76.9)	5 (19.2)	1 (3.8)	65 (84.4)	12 (15.6)	0 (0.0)	0.8985a	1b
Alkaline phosphatase increased	21 (80.8)	5 (19.2)	0 (0.0)	69 (89.6)	7 (9.1)	1 (1.3)	0.1732b	1b
Blood bilirubin increased	20 (76.9)	5 (19.2)	1 (3.8)	61 (79.2)	16 (20.8)	0 (0.0)	1a	1b
Triglycerides increased	20 (76.9)	4 (15.4)	2 (7.7)	67 (87.0)	10 (13.0)	0 (0.0)	0.7475b	0.4967 b
Nausea	18 (69.2)	8 (30.8)	0 (0.0)	47 (61.0)	30 (39.0)	0 (0.0)	0.6076a	1b
Vomiting	19 (73.1)	7 (26.9)	0 (0.0)	61 (79.2)	16 (20.8)	0 (0.0)	0.7054a	1b
Fatigue	18 (69.2)	8 (30.8)	0 (0.0)	68 (88.3)	9 (11.7)	0 (0.0)	0.0332b	1b
Fever	24 (92.3)	2 (7.7)	0 (0.0)	73 (94.8)	4 (5.2)	0 (0.0)	0.6407b	1b
Diarrhea	24 (92.3)	1 (3.8)	1 (3.8)	71 (92.2)	6 (7.8)	0 (0.0)	0.6759b	1b
Peripheral neurotoxicity	25 (96.2)	1 (3.8)	0 (0.0)	77 (100.0)	0 (0.0)	0 (0.0)	0.2524b	1b
Hand-foot syndrome	23 (88.5)	3 (11.5)	0 (0.0)	73 (94.8)	4 (5.2)	0 (0.0)	0.3648b	1b
Hypertension	24 (92.3)	1 (3.8)	1 (3.8)	72 (93.5)	4 (5.2)	1 (1.3)	1b	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 1immunotherapy, mean ± SD

Characteristics	Stats	Normal range
Height (cm)	168.3 ± 8.0	140-190
Weight (kg)	67.7 ± 12.0	40-100
ALLC (109/L)	6.0 ± 1.9	3.5-9.5
RDW (%)	15.2 ± 3.8	11.6-14.8
PLT (109/L)	178.2 ± 63.7	125-350
ANC (109/L)	4.1 ± 1.4	1.8-6.3
ALC (109/L)	1.4 ± 0.5	1.1-3.2
AMC (109/L)	0.4 ± 0.1	0.1-0.6
AEC (109/L)	0.2 ± 0.2	0.02-0.52
ALB (g/L)	41.4 ± 4.0	40-55
LDH (IU/L)	240.0 ± 154.9	109-245
FIB (g/L)	3.6 ± 0.7	2-4
Dimer (ng/ml)	257.3 ± 647.3	0-500
CEA (ng/mL), n (%)	6 (24.0%)	0-5
	19 (76.0%)	-
CA199 (IU/mL), n (%)	13 (52.0%)	0-37
	12 (48.0%)	-

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

Dependent: Survival (PFS/30, status)		All	HR (univariable)	HR (multivariable)
Age	> 60	11 (44.0)	-	-
	≤ 60	14 (56.0)	0.20 (0.07-0.62, P = 0.005)	0.27 (0.05-1.48, P = 0.133)
Gender	Male	18 (72.0)	-	-
	Female	7 (28.0)	1.01 (0.40-2.54, P = 0.979)	-
ECOG	1	21 (84.0)	-	-
	2	4 (16.0)	1.01 (0.23-4.55, P = 0.985)	-
Location	Right colon	9 (36.0)	-	-
	Left colon and rectum	16 (64.0)	0.73 (0.31-1.74, P = 0.477)	-
Liver metastasis	No	7 (28.0)	-	-
	Yes	18 (72.0)	5.23 (1.48-18.50, P = 0.010)	8.15 (1.39-47.83, P = 0.020)
Lung metastasis	No	10 (40.0)	-	-
	Yes	15 (60.0)	0.62 (0.25-1.51, P = 0.291)	-
RAS mutation type	Unknown	5 (20.0)	-	-
	Wild type	3 (12.0)	0.75 (0.13-4.20, P = 0.742)	-
	Mutation	17 (68.0)	2.30 (0.74-7.14, P = 0.151)	-
CEA	Normal	6 (24.0)	-	-
	Abnormal	19 (76.0)	0.59 (0.21-1.67, P = 0.316)	-
CA199	Normal	13 (52.0)	-	-
	Abnormal	12 (48.0)	3.16 (1.12-8.88, P = 0.029)	1.06 (0.23-4.90, P = 0.942)
NLR	≤ 2.9	13 (52.0)	-	-
	> 2.9	12 (48.0)	1.45 (0.60-3.55, P = 0.410)	-
LMR	≤ 3.63	13 (52.0)	-	-
	> 3.63	12 (48.0)	0.57 (0.23-1.39, P = 0.216)	-
PLR	≤ 121	13 (52.0)	-	-
	> 121	12 (48.0)	1.43 (0.58-3.48, P = 0.436)	-
BMI	≤ 24.9	12 (48.0)	-	-
	> 24.9	13 (52.0)	1.02 (0.43-2.42, P = 0.963)	-
ALI	≤ 260.9	13 (52.0)	-	-
	> 260.9	12 (48.0)	0.30 (0.10-0.85, P = 0.023)	0.50 (0.15-1.64, P = 0.252)
SII	≤ 426.8	13 (52.0)	-	-
	> 426.8	12 (48.0)	1.74 (0.72-4.25, P = 0.220)	-
ALLC	≤ 6.0	13 (52.0)	-	-
	> 6.0	12 (48.0)	1.31 (0.53-3.20, P = 0.559)	-
ANC	≤ 4.1	13 (52.0)	-	-
	> 4.1	12 (48.0)	1.31 (0.53-3.20, P = 0.559)	-
ALC	≤ 1.4	13 (52.0)	-	-
	> 1.4	12 (48.0)	0.61 (0.25-1.50, P = 0.285)	-
AMC	≤ 0.4	13 (52.0)	-	-
	> 0.4	12 (48.0)	0.71 (0.28-1.82, P = 0.473)	-
AEC	≤ 0.2	13 (52.0)	-	-
	> 0.2	12 (48.0)	1.59 (0.65-3.89, P = 0.309)	-
RDW	≤ 15.2	13 (52.0)	-	-
	> 15.2	12 (48.0)	1.04 (0.42-2.57, P = 0.938)	-
LDH	≤ 240.0	13 (52.0)	-	-
	> 240.0	12 (48.0)	3.09 (1.16-8.22, P = 0.024)	5.72 (1.58-20.72, P = 0.008)

n = 25, events = 21, likelihood ratio test = 25.81 on 5 df (P < 0.001). ECOG: Eastern Cooperative Oncology Group; PFS: Progression-free survival; HR: Hazard ratio; CEA: Carcinoembryonic antigen; CA199: Carbohydrate antigen 199; NLR: Neutrophil-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; PLR: Platelet-to-lymphocyte 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.