Inhibition Effect of Pancreatic Exocrine Insufficiency on Immune Checkpoint Inhibitor Treatment in Pancreatic Cancer: A Retrospective Study

Figures & data

Figure 1 Flow diagram of patient selection.

Table 1 Characteristics of Cohorts (n = 359)

Demographics
Age, years, median (IQR)	63.0 (55.0, 70.0)
Male, n (%)	205 (57.1)
BMI (kg/m^2), median (IQR)	22.5 (20.5, 24.7)
Smoking, n (%)	122 (34.0)
Alcohol drinking, n (%)	89 (24.8)
Tumor location, n (%)
Head of pancreas	268 (74.7)
Body-tail of pancreas	91 (25.3)
Tumor stage (M0/M1)	271/88
CA 19–9 at diagnosis ≥ 1000 U/mL	85 (23.7)
PEI, n (%)	243 (67.7)
PERT, n (%)	149 (41.5)
Complicating diseases, n (%)
Diabetes	102 (28.4)
Cardiovascular diseases	134 (37.3)
Treatment, n (%)
Unresectable	186 (51.8)
Surgical resection	173 (48.2)
Anti-tumor therapy, n (%)
None	74 (20.6)
Chemotherapy	181 (50.4)
Chemotherapy + Immunotherapy	104 (29.0)

Abbreviations: IQR, interquartile range; BMI, body mass index; PEI, pancreatic exocrine insufficiency; PERT, pancreatic enzyme replacement treatment.

Table 2 Clinical Characteristics of Patients with or Without PEI (n = 359)

Characteristic	PEI	Non-PEI	P value
Total No. of patients, n (%)	243 (67.7)	116 (32.3)
Demographics
Age, years, median (IQR)	63 (55.0, 70.0)	62 (54.0, 71.8)	0.974^a
Gender (male to female)	142/101	63/53	0.460^b
BMI (kg/m^2), median (IQR)	22.6 (20.5, 24.8)	22.3 (20.6, 24.6)	0.686^a
Smoking, n (%)	79 (64.8)	43 (35.2)	0.394^b
Alcohol drinking, n (%)	58 (65.2)	31 (34.8)	0.558^b
CA 19–9 at diagnosis			0.513^a
< 1000 U/mL, n (%)	183 (66.8)	91 (33.2)
≥ 1000 U/mL, n (%)	60 (70.6)	25 (29.4)
Tumor location, n (%)			0.087^b
Head of pancreas (n = 268)	188 (70.1)	80 (29.9)
Body-tail of pancreas (n = 91)	55 (60.4)	36 39.6)
Surgical treatment, n (%)			0.044^b,*
Unresectable (n = 186)	117 (62.9)	69 (37.1)
Surgical resection (n = 173)	126 (72.8)	47 (27.2)
Anti-tumor therapy, n (%)			0.004^b,**
Chemotherapy	109 (60.2)	72 (39.8)
Chemotherapy + Immunotherapy	80 (76.9)	24 (23.1)
Comorbidities, n (%)
Diabetes (n = 102)	79 (77.5)	23 (22.5)	0.013^b,*
Cardiovascular diseases (n = 134)	90 (67.2)	44 (32.8)	0.870^b

Notes: ^aMann–Whitney U-test, ^bChi-Squared Test. *P < 0.05, **P < 0.01.

Table 3 Logistic Regression Variables Analysis of Risk Factors for PEI in PDAC (n = 285)

Characteristic	Univariate Analysis OR (95% CI)	P value	Multivariate Analysis OR (95% CI)	P value
Age at diagnosis	1.00 (0.980–1.027)	0.782
BMI (kg/m^2)	1.05 (0.966–1.134)	0.261
CA 19–9 at diagnosis
< 1000 U/mL, n (%)	1.00	0.591
≥ 1000 U/mL, n (%)	0.85 (0.475–1.528)
Comorbidities
Diabetes	2.08 (1.155–3.726)	0.015*	2.32 (1.268–4.227)	0.006**
Surgical treatment
Unresectable	1.00	0.048*	1.00	0.020*
Surgical resection	1.65 (1.003–2.699)		1.85 (1.102–3.099)
Anti-tumor therapy
Chemotherapy	1.00	0.005**	1.00	0.001**
Chemotherapy + Immunotherapy	2.20 (1.277–3.796)		2.63 (1.492–4.626)

Notes: *P < 0.05, **P < 0.01.

Table 4 Characteristics of Cohorts (n = 285)

Characteristic	Chemotherapy (n = 181)	Chemotherapy + Immunotherapy (n = 104)	P value
Demographics
Age, years, median (IQR)	63 (55.0, 70.0)	60 (54.0, 67.0)	0.223^a
Gender (male to female)
BMI (kg/m^2), median (IQR)	22.6 (20.5, 24.7)	22.2 (20.4, 25.0)	0.802^b
Smoking, n (%)	57 (62.0)	35 (38.0)	0.707^a
Drinking, n (%)	41 (59.4)	28 (40.6)	0.418^b
CA 19–9 at diagnosis			0.375^b
< 1000 U/mL, n (%)	138 (62.2)	84 (37.8)
≥ 1000 U/mL, n (%)	43 (68.3)	20 (31.7)
Tumor location, n (%)			0.898^b
Head of pancreas (n = 207)	131 (63.3)	76 (36.7)
Body-tail of pancreas (n = 78)	50 (64.1)	28 (35.9)
Surgical treatment, n (%)			0.043^b,*
Unresectable (n = 131)	75 (57.3)	56 (42.7)
Surgical resection (n = 154)	106 (68.8)	48 (31.2)
PEI incidence, n (%)	109 (60.2)	80 (76.9)	0.004^b,**
Comorbidities, n (%)
Diabetes (n = 83)	59 (71.1)	24 (28.9)	0.089^b
Cardiovascular diseases (n = 134)	67 (63.8)	38 (36.2)	0.936^b
PERT, n (%)	71 (39.2)	52 (50.0)	0.077 ^b

Notes: ^aMann–Whitney U-test, ^bChi-Squared Test. *P < 0.05, **P < 0.01.

Table 5 Cox Proportional Hazard Regression Analysis of Risk Factors Associated with Overall Survival Among Patients with Pancreatic Cancer (n = 285)

Characteristic	Univariate Analysis HR (95% CI)	P value	Multivariate Analysis HR (95% CI)	P value
Age at diagnosis	1.02 (1.005–1.031)	0.006**	1.01 (0.997–1.023)	0.148
BMI (kg/m^2)	0.99 (0.953–1.035)	0.738
PEI	1.228 (0.938–1.607)	0.135
CA 19–9 at diagnosis
< 1000 U/mL, n (%)	1.00	< 0.001***	1.00	0.096
≥ 1000 U/mL, n (%)	1.72 (1.273–2.317)		1.30 (0.954–1.780)
Anti-tumor therapy
Chemotherapy	1.00	0.534
Chemotherapy + Immunotherapy	0.92 (0.707–1.197)
Surgical treatment
Unresectable	1.00	< 0.001***	1.00	< 0.001***
Surgical resection	0.43 (0.331–0.555)		0.51 (0.383–0.669)
PERT
No	1.00	0.001**	1.00	0.022*
Yes	0.63 (0.487–0.818)		0.73 (0.561–0.956)

Notes: *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 2 Cox proportional hazards analysis evaluating the association between chemotherapy plus immunotherapy (ChIM) treatment and risk factors of patients with PDAC. Hazard ratio (HR) was expressed as ChIM-to-chemotherapy risk ratio.

Abbreviations: BMI, body mass index; PEI, pancreatic exocrine insufficiency; PERT, pancreatic enzyme replacement therapy.

Figure 3 Kaplan–Meier survival analysis of patients with PDAC in different groups. (A) Kaplan–Meier curves of 1-year OS of patients receiving chemotherapy or ChIM. (B) Kaplan–Meier curves of 1-year OS of patients with or without PERT.

Data Sharing Statement

All the data in this study are available upon request from the corresponding author.