Patients and Characteristics
A total of 2,010 patients were enrolled in this study. (Table 1, Supp. Table 1) The median age was 64 years old while the male proportion was 62.1%. The median BMI was 22.67 kg/m2. 56.5% patients were treated with chemotherapy. The whole cohort consisted of 192 Ia (9.6%), 478 Ib (23.8%), 155 IIa (7.7%), 532 IIb (26.5%), 432 III (21.5%) and 221 IV (11%) stage patients. For Xtile categorizing, the Underweight, Normal and Overweight groups contained 216 (10.7%), 968 (48.2%) and 826 (41.1%) patients respectively. And for WHO categorizing, three categories included 157 (7.8%), 943 (46.9%) and 910 (45.3%) patients. Significant differences were observed in age, gender, FBG and chemotherapy administration among categories for both categorizing standards.
Table 1
Demographic and baseline characteristics of study cohort. (categorized by X-tile cutoffs.)
|
Underweight
(n=216)
|
Normal
(n=968)
|
Overweight
(n=826)
|
total
|
P value
|
Age
|
65 (59-72)
|
63 (57-69)
|
64 (57-69)
|
63 (58-69)
|
0.004
|
Male (%)
|
117 (54.2)
|
583 (60.3)
|
551 (66.7)
|
1251 (62.2)
|
0.001
|
ALB
|
38 (35-42)
|
39 (36-42)
|
40 (36-43)
|
39 (36-42)
|
0.001
|
FBG
|
5.68 (5.00-6.79)
|
6.04 (5.35-7.41)
|
6.10 (5.43-7.55)
|
6.03 (5.32-7.40)
|
<0.001
|
CA199
|
165.3 (37.1-766.9)
|
152.2 (39.0-484.6)
|
163.8 (41.7-563.7)
|
161.1 (40.2-552.2)
|
0.34
|
TB
|
16.9 (11.4-75.8)
|
17.0 (11.3-76.7)
|
16.6 (11.8-70.3)
|
16.8 (11.6-72.6)
|
0.935
|
Biliary drainage (%)
|
38 (24.5)
|
152 (20.8)
|
134 (21.8)
|
324 (21.6)
|
0.486
|
ASA Score (%)
|
|
|
|
|
0.394
|
1
|
130 (61.6)
|
530 (56.5)
|
433 (53.9)
|
1093 (56)
|
|
2
|
65 (30.8)
|
334 (35.6)
|
297 (37)
|
696 (35.7)
|
|
3
|
14 (6.6)
|
63 (6.7)
|
67 (8.4)
|
144 (7.4)
|
|
4
|
2 (0.9)
|
11 (1.2)
|
6 (0.7)
|
19 (1)
|
|
Tumor location (%)
|
|
|
|
|
0.495
|
Head
|
129 (59.7)
|
538 (55.6)
|
473 (57.2)
|
1140 (56.7)
|
|
Body/Tail
|
87 (40.3)
|
430 (44.4)
|
353 (42.8)
|
870 (43.3)
|
|
Diagnostic year (%)
|
|
|
|
|
0.758
|
2013
|
9 (4.2)
|
35 (3.6)
|
32 (3.9)
|
76 (3.8)
|
|
2014
|
19 (8.8)
|
57 (5.9)
|
56 (6.8)
|
132 (6.6)
|
|
2015
|
22 (10.2)
|
105 (10.8)
|
80 (9.7)
|
207 (10.3)
|
|
2016
|
30 (13.4)
|
146 (15.1)
|
137 (16.6)
|
313 (15.6)
|
|
2017
|
48 (22.7)
|
199 (20.6)
|
149 (18.0)
|
396 (19.7)
|
|
2018
|
47 (21.8)
|
205 (21.3)
|
174 (21.1)
|
426 (21.2)
|
|
2019
|
41 (19)
|
221 (22.8)
|
198 (24.0)
|
460 (22.9)
|
|
Stage
|
|
|
|
|
0.162
|
Ia
|
17 (8.9)
|
88 (9.2)
|
87 (10.4)
|
192 (9.6)
|
|
Ib
|
48 (22.2)
|
222 (22.9)
|
208 (25.2)
|
478 (23.8)
|
|
IIa
|
19 (8.8)
|
72 (7.4)
|
64 (7.8)
|
155 (7.7)
|
|
IIb
|
59 (27.3)
|
248 (25.6)
|
225 (27.3)
|
532 (26.5)
|
|
III
|
48 (22.2)
|
238 (24.6)
|
146 (17.7)
|
432 (21.5)
|
|
IV
|
25 (11.3)
|
100 (10.3)
|
96 (11.6)
|
221 (11)
|
|
Differentiation (%)
|
|
|
|
|
0.252
|
I
|
0 (0)
|
6 (0.6)
|
1 (0.1)
|
7 (0.3)
|
|
II
|
67 (31)
|
325 (33.6)
|
258 (31.2)
|
650 (32.3)
|
|
III
|
149 (69)
|
633 (65.3)
|
567 (68.7)
|
1349 (67.1)
|
|
IV
|
0 (0)
|
1 (0.1)
|
0 (0)
|
1 (0)
|
|
Unknown
|
0 (0)
|
3 (0.3)
|
0 (0)
|
3 (0.1)
|
|
Chemotherapy (%)
|
93 (43.1)
|
57 (56.9)
|
500 (60.5)
|
1144 (56.9)
|
<0.001
|
Surgical interventions (%)
|
152 (70.4)
|
669 (69.1)
|
598 (72.4)
|
1419 (70.6)
|
0.313
|
ALB, albumin; FBG, fasten blood glucose; TB, total bilirubin.
|
Relationship of BMI with OS
The association of BMI at diagnosis and OS is depicted in RCS curves adjusted by Cox model. (Figure 1). The P value of total correlation and non-linear correlation were 0.004 and 0.124 respectively, suggesting that there existed a negatively correlated linear relationship between BMI and OS. The sharp slope was observed at the beginning of the curve, and the curve tends to be smooth when BMI exceeded around 23 kg/m2.
BMI was a Positive Prognostic Predictor in Multivariable Risk Adjustment Analysis.
As a continuous data, BMI was tested fitting PH assumption with the Pearson relevance being 0.036 and significance being P=0.198. (Supp. Figure 2)
In univariate Cox survival analysis, BMI was analyzed as continuous data, Xtile categorical data and WHO categorical data separately. And they were all significantly related with OS. (continuous: hazard ratio (HR)=0.964 , P<0.001; Xtile: HR (Normal vs. Underweight)= 0.745, P=0.001, HR (Overweight vs. Underweight)=0.664, P<0.001, HR (Overweight vs. Normal)=0.892, P=0.058; WHO: HR (Normal vs. Underweight)= 0.625, P<0.001, HR (Overweight vs. Underweight)=0.563, P<0.001, HR (Overweight vs. Normal)=0.901, P=0.076). (Table 2)
Table 2
Univariate analysis of risks of OS
|
Univariate
|
|
HR
|
P value
|
Age
|
1.012 (1.006-1.018)
|
<0.001
|
Male
|
1.044 (0.932-1.170)
|
0.453
|
ALB
|
0.991 (0.981-1.002)
|
0.106
|
FBG
|
0.998 (0.992-1.004)
|
0.59
|
logCA199
|
1.318 (1.236-1.406)
|
<0.001
|
TB
|
1.000 (1.000-1.001)
|
0.164
|
Biliary drainage
|
1.057 (0.929-1.203)
|
0.398
|
Body/tail
|
1.085 (0.971-1.212)
|
0.149
|
Diagnostic year
|
|
0.103
|
2013
|
Ref.
|
|
2014
|
1.029 (0.762-1.389)
|
0.852
|
2015
|
1.204 (0.910-1.594)
|
0.194
|
2016
|
0.937 (0.715-1.228)
|
0.637
|
2017
|
1.120 (0.858-1.460)
|
0.405
|
2018
|
1.153 (0.880-1.512)
|
0.301
|
2019
|
0.960 (0.707-1.304)
|
0.795
|
ASA Score
|
|
0.798
|
1
|
Ref.
|
|
2
|
0.977 (0.867-1.102)
|
0.709
|
3
|
0.926 (0.748-1.148)
|
0.485
|
4
|
1.180 (0.707-1.968)
|
0.527
|
Stage
|
|
<0.001
|
Ia
|
Ref.
|
|
Ib
|
1.168 (1.508-1.946)
|
0.002
|
IIa
|
1.618 (1.186-2.207)
|
0.002
|
IIb
|
2.197 (1.717-2.811)
|
<0.001
|
III
|
3.213 (2.512-4.110)
|
<0.001
|
IV
|
6.307 (4.831-8.235)
|
<0.001
|
Differentiation
|
|
<0.001
|
I
|
Ref.
|
|
II
|
2.645 (0.372-18.835)
|
0.331
|
III
|
3.941 (0.554-28.008)
|
0.171
|
IV
|
41.974 (2.616-673.418)
|
0.008
|
Unknown
|
1.399 (0.127-15.446)
|
0.784
|
Chemotherapy
|
0.511 (0.458-0.570)
|
<0.001
|
Surgical intervention
|
0.254 (0.207-0.309)
|
<0.001
|
BMI
|
0.964 (0.946-0.983)
|
<0.001
|
X-Tile categorizing
|
|
<0.001
|
<18.9
|
Ref.
|
|
18.9-23.3
|
0.745 (0.626-0.886)
|
0.001
|
≥23.3
|
0.665 (0.556-0.794)
|
<0.001
|
WHO categorizing
|
|
<0.001
|
<18.5
|
Ref.
|
|
18.5-23
|
0.625 (0.514-0.759)
|
<0.001
|
≥23
|
0.563 (0.462-0.685)
|
<0.001
|
ALB, albumin; FBG, fasten blood glucose; TB, total bilirubin; HR, hazard ratio. Ref. reference.
|
Multivariable Cox regression models were established based on continuous, Xtile categorical and WHO categorical BMI separately. (continuous: adjusted hazard ratio (aHR)=0.972, P=0.004; Xtile: aHR (Normal vs. Underweight)= 0.821, P=0.038, aHR (Overweight vs. Underweight)=0.723, P=0.001, aHR (Overweight vs. Normal)=0.880, P=0.045; WHO: aHR (Normal vs. Underweight)= 0.759, P=0.010, aHR (Overweight vs. Underweight)=0.685, P<0.001, aHR (Overweight vs. Normal)=0.903, P=0.102) (Figure 2, Table 3) AJCC stages, differentiation, CA199 and chemotherapy was discovered significantly relevant with OS in all Cox models. (Table 3) Both continuous and categorical BMI was discovered associated with chemotherapy (continuous BMI: association P<0.001, Xtile categorical BMI: association P<0.001, WHO categorical BMI: association P<0.001). Moreover, the product term of categorical BMI and chemotherapy manifested significantly relevant with OS (interaction PXtile=0.004; interaction PWHO=0.020), suggesting the multiplicative interactions in models. The additive interaction between BMI and chemotherapy was explored and certified then.(RERIXtile: 0.50 (0.30-0.70), APXtile: 0.58 (0.29-0.86), SXtile: 0.21 (0.06-0.75); RERIWHO: 0.56 (0.37-0.74), APWHO: 0.70 (0.37-1.02), SWHO: 0.26 (0.12-0.57)) Nevertheless, neither the association (Table 1, Supp. Table 1, PXtile=0.162, PWHO=0.099), nor the interaction (PXtile=0.699, PWHO=0.966) of categorical BMI and TNM stages was observed.
Patients with Higher BMI Was Discovered to Gain More OS Benefits from Chemotherapy
For different BMI categories, the ratio of patients receiving chemotherapy differed significantly. (UnderweightXtile: 43.1%, NormalXtile: 57.0%, OverweightXtile: 60.5%, P<0.001; UnderweightWHO: 40.8%, NormalWHO: 56.0%, OverweightWHO: 60.7%, P<0.001). And in different Cox models stratified by categorical BMI, chemotherapy manifested different prognostic impact, indicating that patients with higher BMI probably gained more OS improvement from chemotherapy. (aHR: UnderweightXtile: 0.565 (0.389-0.819), NormalXtile: 0.474 (0.395-0.567), OverweightXtile: 0.409 (0.337-0.496); UnderweightWHO: 0.613 (0.401-0.940), NormalWHO: 0.464 (0.387-0.557), OverweightWHO: 0.425 (0.353-0.512)). Stratified with chemotherapy administration, it was discovered that, in multivariable Cox models, categorical BMI was no longer associated with OS among chemotherapy-absence patients (Xtile: aHR (Normal vs. Underweight)= 0.911, P=0.442, aHR (Overweight vs. Underweight)=0.826, P=0.133, aHR (Overweight vs. Normal)=0.907, P=0.287; WHO: aHR (Normal vs. Underweight)= 0.835, P=0.175, aHR (Overweight vs. Underweight)=0.782, P=0.071, aHR (Overweight vs. Normal)=0.937, P=0.463), while was more significantly associated among chemotherapy patients (Xtile: aHR (Normal vs. Underweight)= 0.562, P<0.001, aHR (Overweight vs. Underweight)=0.458, P<0.001, aHR (Overweight vs. Normal)=0.815, P=0.024; WHO: aHR (Normal vs. Underweight)=0.488, P<0.001, aHR (Overweight vs. Underweight)=0.416, P<0.001, aHR (Overweight vs. Normal)=0.854, P=0.076). (Supp. Table 2, Supp. Table 3)
Table 3
Multivariate analyses of risks of OS
|
Continuous BMI
|
WHO Model
|
X-tile Model
|
|
aHR
|
P value
|
aHR
|
P value
|
aHR
|
P value
|
Age
|
1.004 (0.998-1.011)
|
0.223
|
1.004 (0.997-1.01)
|
0.279
|
1.004 (0.997-1.011)
|
0.234
|
Male
|
1.120 (0.992-1.266)
|
0.068
|
1.124 (0.995-1.271)
|
0.060
|
1.122 (0.993-1.268)
|
0.064
|
ALB
|
1.004 (0.992-1.017)
|
0.51
|
1.004 (0.992-1.016)
|
0.541
|
1.005 (0.993-1.017)
|
0.43
|
FBG
|
1.018 (0.997-1.039)
|
0.086
|
1.017 (0.996-1.038)
|
0.111
|
1.018 (0.998-1.039)
|
0.084
|
logCA199
|
1.164 (1.093-1.240)
|
<0.001
|
1.161 (1.09-1.236)
|
<0.001
|
1.162 (1.091-1.237)
|
<0.001
|
TB
|
1.000 (0.999-1.001)
|
0.986
|
1 (0.999-1.001)
|
0.902
|
1 (0.999-1.001)
|
0.899
|
Biliary drainage
|
1.113 (0.941-1.316)
|
0.213
|
1.109 (0.938-1.311)
|
0.227
|
1.114 (0.942-1.318)
|
0.205
|
ASA Score
|
|
0.142
|
|
0.163
|
|
0.151
|
1
|
Ref.
|
|
Ref.
|
|
Ref.
|
|
2
|
0.926 (0.817-1.050)
|
0.231
|
0.926 (0.817-1.05)
|
0.231
|
0.927 (0.818-1.051)
|
0.239
|
3
|
1.182 (0.934-1.495)
|
0.164
|
1.179 (0.931-1.493)
|
0.171
|
1.184 (0.935-1.498)
|
0.16
|
4
|
1.317 (0.753-2.305)
|
0.334
|
1.272 (0.727-2.228)
|
0.400
|
1.298 (0.742-2.271)
|
0.36
|
Stage
|
|
<0.001
|
|
<0.001
|
|
<0.001
|
Ia
|
Ref.
|
|
Ref.
|
|
Ref.
|
|
Ib
|
1.587 (1.210-2.080)
|
0.001
|
1.58 (1.205-2.072)
|
0.001
|
1.574 (1.2-2.064)
|
0.001
|
IIa
|
1.704 (1.226-2.370)
|
0.002
|
1.681 (1.209-2.337)
|
0.002
|
1.691 (1.216-2.351)
|
0.002
|
IIb
|
2.399 (1.846-3.117)
|
<0.001
|
2.384 (1.834-3.098)
|
<0.001
|
2.391 (1.84-3.107)
|
<0.001
|
III
|
3.568 (2.744-4.640)
|
<0.001
|
3.542 (2.724-4.607)
|
<0.001
|
3.558 (2.736-4.627)
|
<0.001
|
IV
|
6.478 (4.856-8.641)
|
<0.001
|
6.442 (4.831-8.591)
|
<0.001
|
6.501 (4.874-8.671)
|
<0.001
|
Differentiation
|
|
<0.001
|
|
<0.001
|
|
<0.001
|
I
|
Ref.
|
|
Ref.
|
|
Ref.
|
|
II
|
4.642 (0.649-33.205)
|
0.126
|
4.725 (0.66-33.815)
|
0.122
|
4.762 (0.665-34.092)
|
0.12
|
III
|
6.444 (0.903-46.008)
|
0.063
|
6.562 (0.918-46.882)
|
0.061
|
6.637 (0.929-47.436)
|
0.059
|
IV
|
\
|
|
\
|
|
\
|
\
|
Unknown
|
1.652 (0.147-18.599)
|
0.684
|
1.744 (0.155-19.613)
|
0.652
|
1.744 (0.155-19.61)
|
0.652
|
Chemotherapy
|
0.458 (0.405-0.518)
|
<0.001
|
0.462 (0.408-0.522)
|
<0.001
|
0.462 (0.408-0.522)
|
<0.001
|
BMI
|
0.972 (0.953-0.991
|
0.004
|
|
|
|
|
BMI Stage
|
|
|
|
0.002
|
|
0.003
|
Underweight
|
|
|
Ref.
|
|
Ref.
|
|
Normal
|
|
|
0.759 (0.617-0.935)
|
0.010
|
0.821 (0.682-0.989)
|
0.038
|
Overweight
|
|
|
0.685 (0.555-0.847)
|
0.000
|
0.723 (0.597-0.875)
|
0.001
|
ALB, albumin; FBG, fasten blood glucose; TB, total bilirubin. aHR, adjusted hazard ratio. Ref., reference.
|
Propensity Score Analysis Revealed the Role of BMI Additionally
Not only between Underweight category and Normal category, IPTW and SMRW analyses were performed between Overweight category and Normal category as well. The characteristics of weighted cohorts were shown.(Table 4, Supp. Table 4, Supp. Table 5, Supp. Table 6) It was discovered that BMI was still an independent prognostic predicter with chemotherapy factor balanced. (Figure 3, Figure 4, UnderweightXtile vs. NormalXtile P=0.003, OverweightXtile vs. NormalXtile P=0.019; UnderweightWHO vs. NormalWHO P<0.001, OverweightWHO vs. NormalWHO P=0.024)
Table 4
Baseline data comparisons after IPTW analysis. (categorized by X-tile cutoffs)
|
Underweight (1089.88)
|
Normal (1091.45)
|
P value
|
SMD
|
Normal (1672.01)
|
Overweight (1668.85)
|
P value
|
SMD
|
Age
|
64 (58-70)
|
63 (58-70)
|
0.534
|
0.055
|
63.00 (57.77-69.00)
|
64.00 (57.00-69.00)
|
0.982
|
0.001
|
Female (%)
|
463.5 (42.5)
|
451.5 (41.4)
|
0.783
|
0.023
|
615.5 (36.8)
|
613.3 (36.7)
|
0.978
|
0.001
|
Asa (%)
|
|
|
1
|
0.01
|
|
|
1
|
0.003
|
1
|
631.8 (58.0)
|
635.6 (58.2)
|
|
|
934.9 (55.9)
|
934.5 (56.0)
|
|
|
2
|
383.3 (35.2)
|
379.3 (34.8)
|
|
|
599.6 (35.9)
|
597.6 (35.8)
|
|
|
3
|
65.0 (6.0)
|
66.5 ( 6.1)
|
|
|
123.3 ( 7.4)
|
122.3 ( 7.3)
|
|
|
4
|
9.8 ( 0.9)
|
10.0 ( 0.9)
|
|
|
14.3 ( 0.9)
|
14.5 ( 0.9)
|
|
|
Differentiation (%)
|
|
|
0.266
|
0.109
|
|
|
0.985
|
0.009
|
I
|
0.0 ( 0.0)
|
6.0 ( 0.5)
|
|
|
7.0 ( 0.4)
|
6.1 ( 0.4)
|
|
|
II
|
345.2 (31.7)
|
358.7 (32.9)
|
|
|
534.5 (32.0)
|
531.6 (31.9)
|
|
|
III
|
744.7 (68.3)
|
726.7 (66.6)
|
|
|
1130.5 (67.6)
|
1131.2 (67.8)
|
|
|
Stage (%)
|
|
|
0.989
|
0.064
|
|
|
1
|
0.003
|
Ia
|
97.7 ( 9.0)
|
98.4 ( 9.0)
|
|
|
162.2 ( 9.7)
|
162.6 ( 9.7)
|
|
|
Ib
|
237.0 (21.7)
|
247.4 (22.7)
|
|
|
401.2 (24.0)
|
401.3 (24.0)
|
|
|
IIa
|
86.1 ( 7.9)
|
85.2 ( 7.8)
|
|
|
128.6 ( 7.7)
|
128.6 ( 7.7)
|
|
|
IIb
|
256.9 (23.6)
|
272.3 (24.9)
|
|
|
431.5 (25.8)
|
431.3 (25.8)
|
|
|
III
|
269.5 (24.7)
|
265.5 (24.3)
|
|
|
359.5 (21.5)
|
357.6 (21.4)
|
|
|
IV
|
142.7 (13.1)
|
122.6 (11.2)
|
|
|
188.9 (11.3)
|
187.5 (11.2)
|
|
|
Biliary drainage (%)
|
188.1 (17.3)
|
179.0 (16.4)
|
0.785
|
0.023
|
275.4 (16.5)
|
274.0 (16.4)
|
0.978
|
0.001
|
TB
|
17.10 (11.36- 65.50)
|
16.60 (11.20- 66.31)
|
0.675
|
0.018
|
16.70 (11.22-65.63)
|
16.33 (11.70-66.45)
|
0.989
|
0.001
|
AIB
|
39.00 (36.00-42.00)
|
39.00 (36.00-42.00)
|
0.711
|
0.011
|
39.00 (37.00-42.00)
|
39.00 (36.00-43.00)
|
0.958
|
0.003
|
FBG
|
5.82 (5.08-7.26)
|
5.99 (5.30-7.35)
|
0.489
|
0.065
|
6.06 (5.36-7.43)
|
6.14 (5.45-7.55)
|
1
|
<0.001
|
chemotherapy (%)
|
587.3 (53.9)
|
598.8 (54.9)
|
0.816
|
0.02
|
989.8 (59.2)
|
990.0 (59.3)
|
0.959
|
0.003
|
CA199
|
167.53 (41.57-736.56)
|
152.50 (39.30-481.59)
|
0.225
|
0.016
|
149.90 (39.30-465.31)
|
164.78 (41.49-561.24)
|
0.925
|
0.005
|
ALB, albumin; FBG, fasten blood glucose; TB, total bilirubin; SMD, standard deviation mean difference.
|