# Impact of Perioperative Blood Transfusion on Postoperative Complications and Prognosis of Gastric Adenocarcinoma Patients with Different Preoperative Hemoglobin Value

Authors: Lian Xue; Xiao-Long Chen; Zhang Wei-Han; Kun Yang; Xin-Zu Chen; Bo Zhang; Zhi-Xin Chen; Jia-Ping Chen; Zong-Guang Zhou; Jian-Kun Hu
Journal: Gastroenterology Research and Practice
 (2016)

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## Abstract

Background. The impact of perioperative blood transfusion on the prognosis of gastric adenocarcinoma patients is still controversial. The aim of this study was to elucidate the impact of perioperative blood transfusion on postoperative complications and prognosis of patients who underwent gastrectomy for gastric adenocarcinoma with different levels of preoperative hemoglobin value (POHb). Method. From 2003 to 2011, 1199 patients who underwent curative gastrectomy were retrospectively enrolled and followed up to December 2014. Clinicopathological features and survival outcomes were compared between transfused and nontransfused patients. Results. In this study, transfused patients had more postoperative complications than nontransfused ones (P=0.002). In survival analysis, the difference was not significant between transfused and nontransfused patients with POHb between 70 and 100 g/L (P=0.191). However, in patients with POHb >100 g/L, transfused patients had significantly worse prognosis (P<0.001), especially in TNM III stage patients (P=0.002). And intraoperative blood transfusion predicted poor prognosis (P=0.001). Conclusion. Perioperative blood transfusion might lead to poor survival in gastric adenocarcinoma patients with POHb >100 g/L and transfused patients had more postoperative complications; thus it is better to refrain from unnecessary perioperative blood transfusion especially intraoperative transfusion.


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## Body

## 1. Introduction

Gastric adenocarcinoma (GAC) is one of the most common malignant cancers in the world [1]. Surgery is considered to be the main treatment for GAC. Patients with cancers were prone to have anemia, and radical resection with extended lymphadenectomy might cause much blood loss during surgery; thus patients with low hemoglobin (Hb) value might receive perioperative blood transfusion.Whether perioperative blood transfusion impacted on the prognosis of patients with cancer was still under debate. Some studies reported that blood transfusion was related to poor prognosis of patients with colorectal cancer, renal cell carcinoma, lung cancer, and breast cancer [2–6]. The possible reason might be that blood transfusion could cause immunomodulation, which decreased the activities of natural killer cells and increased the activities of regulatory T cells [7]. However, other studies held the opposite opinion, indicating that blood transfusion did not affect patient’s outcomes [8, 9].With respect to gastric adenocarcinoma, several researches had been carried out in order to find out the relationship among perioperative blood transfusion, postoperative complications, and prognosis, but it still remained controversial. Although some reports did not support the fact that blood transfusion was related to poor prognosis, others claimed that it did exist [10–14]. Some reports showed that transfused patients had more postoperative complications [13, 15].In China, according to the clinical guideline of blood transfusion, patients with POHb lower than 70 g/L should be transfused, and there is no need of transfusion for patients with POHb >100 g/L [16]. However, there were few studies discussing prognosis of perioperative transfused patients with cancer grouped by different POHb. In our study, we divided the patients into different groups according to their POHb and tried to find out the relationship among blood transfusion, postoperative complications, and survival of patients in these different groups.


## 2. Methods

The West China Hospital research ethics committee approved retrospective analysis of anonymous data. Signed patient informed consent was waived per the committee approval, because it was a retrospective analysis.


### 2.1. Patients

From January 2003 to April 2011, 1199 patients who underwent curative gastrectomy with R0 resection for gastric adenocarcinoma at Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, were enrolled in our study. Patients with distant metastases, neoadjuvant chemoradiotherapy, previous neoplastic diseases, and hematological pathologies were excluded from our study. We divided patients into three groups according to their POHb value: Group 1: patients with POHb ≤70 g/L; Group 2: patients with POHb between 70 and 100 g/L; Group 3: patients with POHb >100 g/L. In Group 2 and Group 3, patients were divided into two subgroups according to whether they had perioperative blood transfusion. And all the patients in Group 1 had received blood transfusion. The clinicopathological features such as tumor size, tumor location, differentiation grade, and pathological TNM stage were recorded according to Japanese classification of gastric carcinoma by JGCA [17]. Other variables including operation time, intraoperative blood loss, and postoperative complications were also analyzed. Clinicopathological features and overall survival rates were compared among these groups.


### 2.2. Surgical Treatment

Gastrectomy plus lymphadenectomy was the mainstay treatment for patients with gastric adenocarcinoma. Patients with early gastric adenocarcinoma underwent D1/D1+, while patients with advanced gastric adenocarcinoma underwent D2/D2+ lymphadenectomy. All the operations were performed by expertise of surgeons specialized in gastrointestinal surgery according to Japanese Gastric Cancer Treatment Guidelines [18].


### 2.3. Perioperative Blood Transfusions

Perioperative blood transfusion was defined as either whole blood or packed red blood cells administered within 14 days before surgery, during surgery, or 14 days after surgery [14]. Usually, POHb ≤ 70 g/L and significant intraoperative blood loss were general indications for blood transfusion. The amount and time of perioperative blood transfusion were recorded.


### 2.4. Follow-Up

Regular outpatient visit was the first choice for follow-up, while telephones and mails were adopted as two main supplementary follow-up methods. Follow-up information was updated until December 2014. The main reasons for the loss of follow-up were the changes of phone number or home address and refusal of reexamination in our hospital.


### 2.5. Statistical Analysis

All the statistical analyses were performed with the statistical software SPSS 19.0 (SPSS, Chicago, Illinois, USA). All continuous values were presented as mean ± standard deviation (SD). Unordered categorical variable and ranked data were analyzed through chi-square test and rank sum test, respectively. Student’st-test was used to analyze continuous data if variance was homogeneity and distribution was normal. If not, rank sum test was used. Multivariate logistic regression analysis was performed to identify risk factors for need of perioperative blood transfusion. Survival curves were computed using Kaplan-Meier and compared by means of log-rank test. Multivariate analysis was performed by Cox regression test to find out independent prognostic factors. P value < 0.05 was considered statistically significant.


## 2.1. Patients

From January 2003 to April 2011, 1199 patients who underwent curative gastrectomy with R0 resection for gastric adenocarcinoma at Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, were enrolled in our study. Patients with distant metastases, neoadjuvant chemoradiotherapy, previous neoplastic diseases, and hematological pathologies were excluded from our study. We divided patients into three groups according to their POHb value: Group 1: patients with POHb ≤70 g/L; Group 2: patients with POHb between 70 and 100 g/L; Group 3: patients with POHb >100 g/L. In Group 2 and Group 3, patients were divided into two subgroups according to whether they had perioperative blood transfusion. And all the patients in Group 1 had received blood transfusion. The clinicopathological features such as tumor size, tumor location, differentiation grade, and pathological TNM stage were recorded according to Japanese classification of gastric carcinoma by JGCA [17]. Other variables including operation time, intraoperative blood loss, and postoperative complications were also analyzed. Clinicopathological features and overall survival rates were compared among these groups.


## 2.2. Surgical Treatment

Gastrectomy plus lymphadenectomy was the mainstay treatment for patients with gastric adenocarcinoma. Patients with early gastric adenocarcinoma underwent D1/D1+, while patients with advanced gastric adenocarcinoma underwent D2/D2+ lymphadenectomy. All the operations were performed by expertise of surgeons specialized in gastrointestinal surgery according to Japanese Gastric Cancer Treatment Guidelines [18].


## 2.3. Perioperative Blood Transfusions

Perioperative blood transfusion was defined as either whole blood or packed red blood cells administered within 14 days before surgery, during surgery, or 14 days after surgery [14]. Usually, POHb ≤ 70 g/L and significant intraoperative blood loss were general indications for blood transfusion. The amount and time of perioperative blood transfusion were recorded.


## 2.4. Follow-Up

Regular outpatient visit was the first choice for follow-up, while telephones and mails were adopted as two main supplementary follow-up methods. Follow-up information was updated until December 2014. The main reasons for the loss of follow-up were the changes of phone number or home address and refusal of reexamination in our hospital.


## 2.5. Statistical Analysis

All the statistical analyses were performed with the statistical software SPSS 19.0 (SPSS, Chicago, Illinois, USA). All continuous values were presented as mean ± standard deviation (SD). Unordered categorical variable and ranked data were analyzed through chi-square test and rank sum test, respectively. Student’st-test was used to analyze continuous data if variance was homogeneity and distribution was normal. If not, rank sum test was used. Multivariate logistic regression analysis was performed to identify risk factors for need of perioperative blood transfusion. Survival curves were computed using Kaplan-Meier and compared by means of log-rank test. Multivariate analysis was performed by Cox regression test to find out independent prognostic factors. P value < 0.05 was considered statistically significant.


## 3. Results

### 3.1. Demography of Patients

In this study, 1199 patients with different POHb were included, with 345 (28.8%) patients receiving perioperative blood transfusion and 854 (71.2%) receiving no transfusion. 54 (4.5%) patients were in POHb ≤ 70 g/L group while 257 (21.4%) ones were in POHb between 70 and 100 g/L group and 888 (74.1%) patients in POHb >100 g/L group. Among transfused patients, 177 (51.3%) patients received less than 2 units (200 mL/unit) of blood transfusion, 94 (27.2%) patients received 2–4 units, and 74 (21.5%) received more than 4 units. Ninety-six (27.8%) patients underwent preoperative transfusion; 210 (60.9%) ones underwent intraoperative transfusion while 39 (11.3%) patients underwent postoperative transfusion.Comparisons of clinicopathological features between transfused and nontransfused patients were shown in Table1. Of all the patients, transfused ones had significantly more combined organ resections (P<0.001), more patients with open surgery (P<0.001), and more intraoperative blood loss (P<0.001). Postoperative complications seemed to occur more frequently in transfused patients (P=0.002) especially pulmonary infection (transfused 18.8% versus nontransfused 13.7%). Table 2 showed the comparison between transfused and nontransfused patients in POHb between 70 and 100 g/L or POHb >100 g/L groups. Clinicopathological characteristics were similar with regard to sex, TNM stage, differentiation grade, macroscopic type, and tumor size in transfused and nontransfused subgroups of patients with POHb between 70 and 100 g/L (all P>0.05). However, in the patients with POHb >100 g/L group, transfused patients had more advanced TNM stage (P<0.001), larger tumor size (P=0.009), more poor differentiated grade (P=0.010), and more postoperative complications (P=0.027).Table 1
Comparison of clinicopathological features of all transfused and nontransfused patients.
Categories
Transfused
Nontransfused
P value
n
=
345 (%)
n
=
854 (%)
Age
Mean  ±  SD
58.4 ± 11.7
55.9 ± 11.5
0.001
Gender
Male
244  (70.7)
605  (70.8)
0.967
Female
101  (29.3)
245  (29.2)
Combined organ resection
Yes
41  (11.9)
31  (3.6)
<0.001
No
304  (88.1)
823  (96.4)
Type of gastrectomy
DG
193  (55.9)
519  (60.8)
0.055
TG
86  (24.9)
160  (18.7)
PG
66  (19.2)
175  (20.5)
Operation approach
Open surgery
325  (94.2)
725  (84.9)
<0.001
Laparoscopic assisted
20  (5.8)
129  (15.1)
Concomitant diseases
Yes
182  (52.8)
403  (47.2)
0.081
No
163  (47.2)
451  (52.8)
Longitudinal location
U
72  (20.9)
221  (25.9)
0.004
M
63  (18.3)
102  (11.9)
L
202  (58.6)
523  (61.2)
Whole
8  (2.2)
8  (1.0)
Differentiation grade
Well/moderate
48  (13.9)
171  (20.0)
0.013
Poor/undifferentiated
297  (86.1)
683  (80.0)
Macroscopic type
Types 0–2
210  (60.9)
569  (66.6)
0.058
Types 3–4
135  (39.1)
285  (33.4)
Tumor size (cm)
Mean  ±  SD
5.7 ± 2.6
4.6 ± 2.5
<0.001
≤4.5
120  (34.8)
461  (54.0)
<0.001
>4.5
225  (65.2)
393  (46.0)
T stage
T1
28  (8.1)
192  (22.5)
<0.001
T2
37  (10.7)
121  (14.2)
T3
14  (4.1)
44  (5.2)
T4
266  (77.1)
497  (58.1)
N stage
N0
84  (24.3)
319  (37.4)
<0.001
N1
69  (20.0)
154  (18.0)
N2
66  (19.1)
168  (19.7)
N3a
90  (26.1)
157  (18.4)
N3b
37  (10.5)
56  (6.5)
TNM stage
I/II
108  (31.3)
410  (48.0)
<0.001
III
237  (68.7)
444  (52.0)
Operation time (min)
Mean  ±  SD
241.0 ± 61.9
232.8 ± 49.9
0.169
Intraoperative blood loss (mL)
Mean  ±  SD
528.7 ± 282.2
414.2 ± 194.3
<0.001
Postoperative complications
Stomach without tension
2  (0.6)
19  (2.2)
0.002
Wound infection
7  (2.0)
10  (1.2)
Anastomotic leakage
8  (2.3)
6  (0.7)
Bleeding
9  (2.6)
3  (0.4)
Pulmonary infection
65  (18.8)
117  (13.7)
Others
14  (4.1)
16  (1.9)
Total patients
82  (23.8)
152  (17.8)
Postoperative hospital stay
Mean  ±  SD
12.4 ± 10.6
11.7 ± 9.8
0.261
SD: standard deviation, DG: distal gastrectomy, TG: total gastrectomy, PG: proximal gastrectomy, U: upper, M: middle, and L: lower.Table 2
Comparison of clinicopathological features of transfused and nontransfused patients in POHb between 70 and 100 g/L or >100 g/L subgroups.
Categories
Transfused ones with POHb between 70 and 100 g/L
Nontransfused with POHb between 70 and 100 g/L
P value
Transfused ones with POHb >100 g/L
Nontransfused with POHb >100 g/L
P value
n
=
150 (%)
n
=
107 (%)
n
=
141 (%)
n
=
747 (%)
Age
Mean ± SD
60.2 ± 10.8
57.4 ± 12.6
0.051
58.1 ± 11.2
55.7 ± 11.4
0.020
Gender
Male
108  (72.0)
69  (64.5)
0.200
100  (70.9)
536  (71.8)
0.841
Female
42  (28.0)
38  (35.5)
41  (29.1)
211  (28.2)
Combined organ resection
Yes
16  (10.7)
1  (0.9)
0.002
22  (15.6)
30  (4.0)
<0.001
No
134  (89.3)
106  (99.1)
119  (84.4)
717  (96.0)
Type of gastrectomy
DG
83  (55.3)
62  (57.9)
0.916
71  (50.4)
457  (61.2)
0.024
TG
39  (26)
26  (24.3)
38  (27.0)
134  (17.9)
PG
28  (18.7)
19  (17.8)
32  (22.6)
156  (20.9)
Open approach
Open surgery
141  (94.0)
93  (86.9)
0.050
138  (97.9)
632  (84.6)
<0.001
Laparoscopic assisted
9  (6.0)
14  (13.1)
3  (2.1)
115  (15.4)
Longitudinal location
U
30  (20.0)
27  (25.2)
0.279
34  (24.1)
194  (26.0)
0.024
M
26  (17.3)
16  (15.0)
27  (19.1)
86  (11.5)
L
90  (60.0)
64  (59.8)
76  (53.9)
459  (61.4)
Whole
4  (2.7)
0  (0)
4  (2.9)
8  (1.1)
Differentiation grade
Well/moderate
22  (14.7)
17  (15.9)
0.788
16  (11.3)
154  (20.6)
0.010
Poor/undifferentiated
128  (85.7)
90  (84.1)
125  (88.7)
593  (79.4)
Macroscopic type
Types 0–2
91  (60.7)
64  (59.8)
0.890
86  (61.0)
505  (67.6)
0.127
Types 3–4
59  (39.3)
43  (40.2)
55  (39.0)
242  (32.4)
Tumor size (cm)
Mean ± SD
5.9 ± 2.6
5.5 ± 3.0
0.262
5.1 ± 2.5
4.5 ± 2.3
0.009
≤4.5
47  (31.3)
41  (38.3)
0.245
60  (42.6)
420  (56.2)
>4.5
103  (68.7)
66  (61.7)
81  (57.4)
327  (43.8)
T stage
T1
12  (8.0)
15  (14.0)
0.227
15  (10.6)
177  (23.7)
<0.001
T2
20  (13.3)
16  (15.0)
12  (8.5)
105  (14.1)
T3
6  (4.0)
2  (1.9)
5  (3.5)
42  (5.6)
T4
112  (74.7)
74  (69.1)
109  (77.4)
423  (56.6)
N stage
N0
35  (23.4)
32  (29.9)
0.228
34  (24.1)
287  (38.4)
<0.001
N1
32  (21.3)
20  (18.7)
26  (18.4)
134  (18.0)
N2
32  (21.3)
26  (24.3)
27  (19.1)
142  (19.0)
N3a
36  (24.0)
21  (19.6)
38  (27.0)
136  (18.2)
N3b
15  (10.0)
8  (7.5)
16  (11.4)
48  (6.4)
TNM stage
I/II
49  (32.7)
46  (43.0)
0.091
44  (31.2)
364  (48.7)
<0.001
III
101  (67.3)
61  (57.0)
97  (68.8)
383  (51.3)
Operation time (min)
Mean ± SD
236.9 ± 55.2
228.4 ± 51.4
0.231
249.3 ± 64.6
233.5 ± 49.6
0.008
Intraoperative blood loss (mL)
Mean ± SD
498.5 ± 215.2
408.5 ± 212.1
0.001
625.9 ± 421.5
415.0 ± 191.7
0.002
Postoperative complications
Yes
32  (21.3)
18  (16.8)
0.426
37  (26.2)
134  (17.9)
0.027
No
118  (78.7)
89  (83.2)
104  (73.8)
613  (82.1)
Postoperative hospital stay
Mean ± SD
12.0 ± 8.4
11.2 ± 6.7
0.428
13.2 ± 13.7
11.7 ± 10.2
0.146
SD: standard deviation, DG: distal gastrectomy, TG: total gastrectomy, PG: proximal gastrectomy, U: upper, M: middle, and L: lower.


### 3.2. Risk Factors for Blood Transfusion

To identify risk factors for blood transfusion, univariate and multivariate analyses were performed in each group, respectively. The results of multivariate analysis of different groups were shown in Tables3 and 4. In logistic regression analysis, risk factors for blood transfusion in patients with POHb between 70 and 100 g/L were significantly associated with intraoperative blood loss (P=0.002) and combined organ resection (P=0.015). However, risk factors for blood transfusion in patients with POHb >100 g/L were associated with age (P=0.013), combined organ resection (P=0.033), TNM stage (P=0.005), and intraoperative blood loss (P<0.001).Table 3
Multivariate analysis of risk factors for blood transfusion in patients with POHb between 70 and 100 g/L.
Parameter estimate
SE
Adjusted OR
95% CI
P value
Age
0.073
Gender
0.097
Macroscopic type
0.256
Differentiation grade
0.786
Tumor size
0.302
TNM
0.438
Intraoperative blood loss
−0.002
0.001
0.998
0.997–0.999
0.002
Combined organ resection
2.540
1.047
12.674
1.629–98.640
0.015
Adjusted OR estimated by the Cox model.
95% CI: 95% confidence interval, OR: odd ratio, and SE: standard error.Table 4
Multivariate analysis of risk factors for blood transfusion in patients with POHb >100 g/L.
Parameter estimate
SE
Adjusted OR
95% CI
P value
Age
0.799
0.322
2.224
1.184–4.178
0.013
Gender
0.481
Macroscopic type
0.829
Differentiation grade
0.113
Tumor size
0.957
Type of gastrectomy
0.402
TNM stage
−1.028
0.367
0.358
0.174–0.734
0.005
Longitudinal location
0.867
Intraoperative blood loss
−0.003
0.001
0.997
0.995–0.998
<0.001
Combined organ resection
1.105
0.518
3.019
1.094–8.333
0.033
Adjusted OR estimated by the Cox model.
95% CI: 95% confidence interval, OR: odd ratio, and SE: standard error.


### 3.3. Survival Analyses

Finally, 999 patients (83.3%) were followed up and included in survival analysis. The median survival time of transfused and nontransfused group was 46.3 (0.07–141.9) months and 111.5 (0–141.9) months, respectively. Three-year survival rates were 51% and 61% in transfused and nontransfused patients with POHb between 70 and 100 g/L, respectively. In transfused and nontransfused patients with POHb >100 g/L, the 3-year survival rates were 44% and 65%, respectively. In univariate analysis, age (P=0.001), type of gastrectomy (P<0.001), combined organ resections (P=0.003), longitudinal location (P<0.001), differentiation grade (P=0.009), macroscopic type (P<0.001), tumor size (P<0.001), pT stage (P<0.001), pN stage (P<0.001), pTNM stage (P<0.001), and perioperative blood transfusion (P<0.001) were associated with overall survival in all patients with gastrectomy in our study (Table 5). The multivariate analysis revealed that age (P=0.005), tumor size (P<0.001), and TNM stage (P<0.001) were independent prognostic factors in gastric adenocarcinoma patients (Table 5).Table 5
Univariate and multivariate Cox analysis for prognostic factors.
Risk factors
Categories
3-year overall survival rate (%)
Univariate analysisP value
Multivariate analysis
P value
OR
95% CI
Age (years)
≤60
64
0.001
0.005
1.308
1.084–1.579
>60
56
Gender
Male
59
0.191
Female
63
Type of gastrectomy
DG
66
<0.001
0.254
TG
48
PG
54
Combined organ resection
Yes
44
0.003
0.104
No
61
Longitudinal location
U
53
<0.001
0.934
M
59
L
64
Whole
17
Differentiation grade
Well/ moderate
70
0.009
0.078
Poor/undifferentiated
58
Macroscopic type
Types 0–2
68
<0.001
0.083
Types 3–4
45
Tumor size
≤4.5 cm
72
<0.001
<0.001
1.460
1.190–1.791
>4.5 cm
48
T stage
T1
87
<0.001
T2
79
T3
65
T4
48
N stage
N0
84
<0.001
N1
68
N2
51
N3a
38
N3b
23
TNM stage
I/II
83
<0.001
<0.001
2.607
2.087–3.256
III
43
Postoperative complications
Yes
52
0.110
No
61
Perioperative blood transfusion
Yes
49
<0.001
0.079
No
64
SD: standard deviation, DG: distal gastrectomy, TG: total gastrectomy, PG: proximal gastrectomy, U: upper, M: middle, and L: lower.


### 3.4. Subgroup Analyses

Of all patients, Kaplan-Meier curve showed that transfused patients had significantly worse prognosis than nontransfused patients (Figure1(a), P<0.001). Nontransfused patients with POHb >100 g/L had better survival outcomes among the subgroups we divided in this study (Figure 1(b), P=0.001). When comparing prognosis between transfused and nontransfused patients in POHb between 70 and 100 g/L and POHb >100 g/L groups, respectively, we found out that there was no significant difference in prognosis between transfused and nontransfused ones in POHb between 70 and 100 g/L group (P=0.191, Figure 1(c)). However, in POHb >100 g/L group, the survival was significantly better in the nontransfused group than transfused group (P<0.001, Figure 1(d)). We further divided patients according to their TNM stage (I/II stage; III stage) in POHb >100 g/L subgroup, and constituent ratios of differentiation grade, macroscopic type, and tumor size between these two subgroups were similar. We found that, in stage I/II subgroup, the difference was not significant between transfused and nontransfused groups (P=0.674, Figure 2(a)); however, in TNM stage III subgroup, survival outcome was remarkably better in nontransfused group than that in transfused group (P=0.002, Figure 2(b)). In addition, a dose-response relationship between the amount of transfused blood and prognosis was not recognized (P=0.153, Figure 2(c)), and the patients with intraoperative transfusion had obviously worse prognosis than those who had preoperative or postoperative transfusion (P=0.001, Figure 2(d)).Figure 1
(a) Survival analysis of transfused and nontransfused patients. (b) Survival analysis of transfused and nontransfused patients with different POHb. (c) Survival analysis of transfused and nontransfused patients with POHb between 70 and 100 g/L. (d) Survival analysis of transfused and nontransfused patients with POHb >100 g/L.
(a)
(b)
(c)
(d)Figure 2
(a) Survival analysis of transfused and nontransfused TNM I/II stage patients with POHb >100 g/L. (b) Survival analysis of transfused and nontransfused TNM III stage patients with POHb >100 g/L. (c) Survival analysis of transfused patients with different units of blood. (d) Survival analysis of transfused patients with different transfusion time.
(a)
(b)
(c)
(d)


## 3.1. Demography of Patients

In this study, 1199 patients with different POHb were included, with 345 (28.8%) patients receiving perioperative blood transfusion and 854 (71.2%) receiving no transfusion. 54 (4.5%) patients were in POHb ≤ 70 g/L group while 257 (21.4%) ones were in POHb between 70 and 100 g/L group and 888 (74.1%) patients in POHb >100 g/L group. Among transfused patients, 177 (51.3%) patients received less than 2 units (200 mL/unit) of blood transfusion, 94 (27.2%) patients received 2–4 units, and 74 (21.5%) received more than 4 units. Ninety-six (27.8%) patients underwent preoperative transfusion; 210 (60.9%) ones underwent intraoperative transfusion while 39 (11.3%) patients underwent postoperative transfusion.Comparisons of clinicopathological features between transfused and nontransfused patients were shown in Table1. Of all the patients, transfused ones had significantly more combined organ resections (P<0.001), more patients with open surgery (P<0.001), and more intraoperative blood loss (P<0.001). Postoperative complications seemed to occur more frequently in transfused patients (P=0.002) especially pulmonary infection (transfused 18.8% versus nontransfused 13.7%). Table 2 showed the comparison between transfused and nontransfused patients in POHb between 70 and 100 g/L or POHb >100 g/L groups. Clinicopathological characteristics were similar with regard to sex, TNM stage, differentiation grade, macroscopic type, and tumor size in transfused and nontransfused subgroups of patients with POHb between 70 and 100 g/L (all P>0.05). However, in the patients with POHb >100 g/L group, transfused patients had more advanced TNM stage (P<0.001), larger tumor size (P=0.009), more poor differentiated grade (P=0.010), and more postoperative complications (P=0.027).Table 1
Comparison of clinicopathological features of all transfused and nontransfused patients.
Categories
Transfused
Nontransfused
P value
n
=
345 (%)
n
=
854 (%)
Age
Mean  ±  SD
58.4 ± 11.7
55.9 ± 11.5
0.001
Gender
Male
244  (70.7)
605  (70.8)
0.967
Female
101  (29.3)
245  (29.2)
Combined organ resection
Yes
41  (11.9)
31  (3.6)
<0.001
No
304  (88.1)
823  (96.4)
Type of gastrectomy
DG
193  (55.9)
519  (60.8)
0.055
TG
86  (24.9)
160  (18.7)
PG
66  (19.2)
175  (20.5)
Operation approach
Open surgery
325  (94.2)
725  (84.9)
<0.001
Laparoscopic assisted
20  (5.8)
129  (15.1)
Concomitant diseases
Yes
182  (52.8)
403  (47.2)
0.081
No
163  (47.2)
451  (52.8)
Longitudinal location
U
72  (20.9)
221  (25.9)
0.004
M
63  (18.3)
102  (11.9)
L
202  (58.6)
523  (61.2)
Whole
8  (2.2)
8  (1.0)
Differentiation grade
Well/moderate
48  (13.9)
171  (20.0)
0.013
Poor/undifferentiated
297  (86.1)
683  (80.0)
Macroscopic type
Types 0–2
210  (60.9)
569  (66.6)
0.058
Types 3–4
135  (39.1)
285  (33.4)
Tumor size (cm)
Mean  ±  SD
5.7 ± 2.6
4.6 ± 2.5
<0.001
≤4.5
120  (34.8)
461  (54.0)
<0.001
>4.5
225  (65.2)
393  (46.0)
T stage
T1
28  (8.1)
192  (22.5)
<0.001
T2
37  (10.7)
121  (14.2)
T3
14  (4.1)
44  (5.2)
T4
266  (77.1)
497  (58.1)
N stage
N0
84  (24.3)
319  (37.4)
<0.001
N1
69  (20.0)
154  (18.0)
N2
66  (19.1)
168  (19.7)
N3a
90  (26.1)
157  (18.4)
N3b
37  (10.5)
56  (6.5)
TNM stage
I/II
108  (31.3)
410  (48.0)
<0.001
III
237  (68.7)
444  (52.0)
Operation time (min)
Mean  ±  SD
241.0 ± 61.9
232.8 ± 49.9
0.169
Intraoperative blood loss (mL)
Mean  ±  SD
528.7 ± 282.2
414.2 ± 194.3
<0.001
Postoperative complications
Stomach without tension
2  (0.6)
19  (2.2)
0.002
Wound infection
7  (2.0)
10  (1.2)
Anastomotic leakage
8  (2.3)
6  (0.7)
Bleeding
9  (2.6)
3  (0.4)
Pulmonary infection
65  (18.8)
117  (13.7)
Others
14  (4.1)
16  (1.9)
Total patients
82  (23.8)
152  (17.8)
Postoperative hospital stay
Mean  ±  SD
12.4 ± 10.6
11.7 ± 9.8
0.261
SD: standard deviation, DG: distal gastrectomy, TG: total gastrectomy, PG: proximal gastrectomy, U: upper, M: middle, and L: lower.Table 2
Comparison of clinicopathological features of transfused and nontransfused patients in POHb between 70 and 100 g/L or >100 g/L subgroups.
Categories
Transfused ones with POHb between 70 and 100 g/L
Nontransfused with POHb between 70 and 100 g/L
P value
Transfused ones with POHb >100 g/L
Nontransfused with POHb >100 g/L
P value
n
=
150 (%)
n
=
107 (%)
n
=
141 (%)
n
=
747 (%)
Age
Mean ± SD
60.2 ± 10.8
57.4 ± 12.6
0.051
58.1 ± 11.2
55.7 ± 11.4
0.020
Gender
Male
108  (72.0)
69  (64.5)
0.200
100  (70.9)
536  (71.8)
0.841
Female
42  (28.0)
38  (35.5)
41  (29.1)
211  (28.2)
Combined organ resection
Yes
16  (10.7)
1  (0.9)
0.002
22  (15.6)
30  (4.0)
<0.001
No
134  (89.3)
106  (99.1)
119  (84.4)
717  (96.0)
Type of gastrectomy
DG
83  (55.3)
62  (57.9)
0.916
71  (50.4)
457  (61.2)
0.024
TG
39  (26)
26  (24.3)
38  (27.0)
134  (17.9)
PG
28  (18.7)
19  (17.8)
32  (22.6)
156  (20.9)
Open approach
Open surgery
141  (94.0)
93  (86.9)
0.050
138  (97.9)
632  (84.6)
<0.001
Laparoscopic assisted
9  (6.0)
14  (13.1)
3  (2.1)
115  (15.4)
Longitudinal location
U
30  (20.0)
27  (25.2)
0.279
34  (24.1)
194  (26.0)
0.024
M
26  (17.3)
16  (15.0)
27  (19.1)
86  (11.5)
L
90  (60.0)
64  (59.8)
76  (53.9)
459  (61.4)
Whole
4  (2.7)
0  (0)
4  (2.9)
8  (1.1)
Differentiation grade
Well/moderate
22  (14.7)
17  (15.9)
0.788
16  (11.3)
154  (20.6)
0.010
Poor/undifferentiated
128  (85.7)
90  (84.1)
125  (88.7)
593  (79.4)
Macroscopic type
Types 0–2
91  (60.7)
64  (59.8)
0.890
86  (61.0)
505  (67.6)
0.127
Types 3–4
59  (39.3)
43  (40.2)
55  (39.0)
242  (32.4)
Tumor size (cm)
Mean ± SD
5.9 ± 2.6
5.5 ± 3.0
0.262
5.1 ± 2.5
4.5 ± 2.3
0.009
≤4.5
47  (31.3)
41  (38.3)
0.245
60  (42.6)
420  (56.2)
>4.5
103  (68.7)
66  (61.7)
81  (57.4)
327  (43.8)
T stage
T1
12  (8.0)
15  (14.0)
0.227
15  (10.6)
177  (23.7)
<0.001
T2
20  (13.3)
16  (15.0)
12  (8.5)
105  (14.1)
T3
6  (4.0)
2  (1.9)
5  (3.5)
42  (5.6)
T4
112  (74.7)
74  (69.1)
109  (77.4)
423  (56.6)
N stage
N0
35  (23.4)
32  (29.9)
0.228
34  (24.1)
287  (38.4)
<0.001
N1
32  (21.3)
20  (18.7)
26  (18.4)
134  (18.0)
N2
32  (21.3)
26  (24.3)
27  (19.1)
142  (19.0)
N3a
36  (24.0)
21  (19.6)
38  (27.0)
136  (18.2)
N3b
15  (10.0)
8  (7.5)
16  (11.4)
48  (6.4)
TNM stage
I/II
49  (32.7)
46  (43.0)
0.091
44  (31.2)
364  (48.7)
<0.001
III
101  (67.3)
61  (57.0)
97  (68.8)
383  (51.3)
Operation time (min)
Mean ± SD
236.9 ± 55.2
228.4 ± 51.4
0.231
249.3 ± 64.6
233.5 ± 49.6
0.008
Intraoperative blood loss (mL)
Mean ± SD
498.5 ± 215.2
408.5 ± 212.1
0.001
625.9 ± 421.5
415.0 ± 191.7
0.002
Postoperative complications
Yes
32  (21.3)
18  (16.8)
0.426
37  (26.2)
134  (17.9)
0.027
No
118  (78.7)
89  (83.2)
104  (73.8)
613  (82.1)
Postoperative hospital stay
Mean ± SD
12.0 ± 8.4
11.2 ± 6.7
0.428
13.2 ± 13.7
11.7 ± 10.2
0.146
SD: standard deviation, DG: distal gastrectomy, TG: total gastrectomy, PG: proximal gastrectomy, U: upper, M: middle, and L: lower.


## 3.2. Risk Factors for Blood Transfusion

To identify risk factors for blood transfusion, univariate and multivariate analyses were performed in each group, respectively. The results of multivariate analysis of different groups were shown in Tables3 and 4. In logistic regression analysis, risk factors for blood transfusion in patients with POHb between 70 and 100 g/L were significantly associated with intraoperative blood loss (P=0.002) and combined organ resection (P=0.015). However, risk factors for blood transfusion in patients with POHb >100 g/L were associated with age (P=0.013), combined organ resection (P=0.033), TNM stage (P=0.005), and intraoperative blood loss (P<0.001).Table 3
Multivariate analysis of risk factors for blood transfusion in patients with POHb between 70 and 100 g/L.
Parameter estimate
SE
Adjusted OR
95% CI
P value
Age
0.073
Gender
0.097
Macroscopic type
0.256
Differentiation grade
0.786
Tumor size
0.302
TNM
0.438
Intraoperative blood loss
−0.002
0.001
0.998
0.997–0.999
0.002
Combined organ resection
2.540
1.047
12.674
1.629–98.640
0.015
Adjusted OR estimated by the Cox model.
95% CI: 95% confidence interval, OR: odd ratio, and SE: standard error.Table 4
Multivariate analysis of risk factors for blood transfusion in patients with POHb >100 g/L.
Parameter estimate
SE
Adjusted OR
95% CI
P value
Age
0.799
0.322
2.224
1.184–4.178
0.013
Gender
0.481
Macroscopic type
0.829
Differentiation grade
0.113
Tumor size
0.957
Type of gastrectomy
0.402
TNM stage
−1.028
0.367
0.358
0.174–0.734
0.005
Longitudinal location
0.867
Intraoperative blood loss
−0.003
0.001
0.997
0.995–0.998
<0.001
Combined organ resection
1.105
0.518
3.019
1.094–8.333
0.033
Adjusted OR estimated by the Cox model.
95% CI: 95% confidence interval, OR: odd ratio, and SE: standard error.


## 3.3. Survival Analyses

Finally, 999 patients (83.3%) were followed up and included in survival analysis. The median survival time of transfused and nontransfused group was 46.3 (0.07–141.9) months and 111.5 (0–141.9) months, respectively. Three-year survival rates were 51% and 61% in transfused and nontransfused patients with POHb between 70 and 100 g/L, respectively. In transfused and nontransfused patients with POHb >100 g/L, the 3-year survival rates were 44% and 65%, respectively. In univariate analysis, age (P=0.001), type of gastrectomy (P<0.001), combined organ resections (P=0.003), longitudinal location (P<0.001), differentiation grade (P=0.009), macroscopic type (P<0.001), tumor size (P<0.001), pT stage (P<0.001), pN stage (P<0.001), pTNM stage (P<0.001), and perioperative blood transfusion (P<0.001) were associated with overall survival in all patients with gastrectomy in our study (Table 5). The multivariate analysis revealed that age (P=0.005), tumor size (P<0.001), and TNM stage (P<0.001) were independent prognostic factors in gastric adenocarcinoma patients (Table 5).Table 5
Univariate and multivariate Cox analysis for prognostic factors.
Risk factors
Categories
3-year overall survival rate (%)
Univariate analysisP value
Multivariate analysis
P value
OR
95% CI
Age (years)
≤60
64
0.001
0.005
1.308
1.084–1.579
>60
56
Gender
Male
59
0.191
Female
63
Type of gastrectomy
DG
66
<0.001
0.254
TG
48
PG
54
Combined organ resection
Yes
44
0.003
0.104
No
61
Longitudinal location
U
53
<0.001
0.934
M
59
L
64
Whole
17
Differentiation grade
Well/ moderate
70
0.009
0.078
Poor/undifferentiated
58
Macroscopic type
Types 0–2
68
<0.001
0.083
Types 3–4
45
Tumor size
≤4.5 cm
72
<0.001
<0.001
1.460
1.190–1.791
>4.5 cm
48
T stage
T1
87
<0.001
T2
79
T3
65
T4
48
N stage
N0
84
<0.001
N1
68
N2
51
N3a
38
N3b
23
TNM stage
I/II
83
<0.001
<0.001
2.607
2.087–3.256
III
43
Postoperative complications
Yes
52
0.110
No
61
Perioperative blood transfusion
Yes
49
<0.001
0.079
No
64
SD: standard deviation, DG: distal gastrectomy, TG: total gastrectomy, PG: proximal gastrectomy, U: upper, M: middle, and L: lower.


## 3.4. Subgroup Analyses

Of all patients, Kaplan-Meier curve showed that transfused patients had significantly worse prognosis than nontransfused patients (Figure1(a), P<0.001). Nontransfused patients with POHb >100 g/L had better survival outcomes among the subgroups we divided in this study (Figure 1(b), P=0.001). When comparing prognosis between transfused and nontransfused patients in POHb between 70 and 100 g/L and POHb >100 g/L groups, respectively, we found out that there was no significant difference in prognosis between transfused and nontransfused ones in POHb between 70 and 100 g/L group (P=0.191, Figure 1(c)). However, in POHb >100 g/L group, the survival was significantly better in the nontransfused group than transfused group (P<0.001, Figure 1(d)). We further divided patients according to their TNM stage (I/II stage; III stage) in POHb >100 g/L subgroup, and constituent ratios of differentiation grade, macroscopic type, and tumor size between these two subgroups were similar. We found that, in stage I/II subgroup, the difference was not significant between transfused and nontransfused groups (P=0.674, Figure 2(a)); however, in TNM stage III subgroup, survival outcome was remarkably better in nontransfused group than that in transfused group (P=0.002, Figure 2(b)). In addition, a dose-response relationship between the amount of transfused blood and prognosis was not recognized (P=0.153, Figure 2(c)), and the patients with intraoperative transfusion had obviously worse prognosis than those who had preoperative or postoperative transfusion (P=0.001, Figure 2(d)).Figure 1
(a) Survival analysis of transfused and nontransfused patients. (b) Survival analysis of transfused and nontransfused patients with different POHb. (c) Survival analysis of transfused and nontransfused patients with POHb between 70 and 100 g/L. (d) Survival analysis of transfused and nontransfused patients with POHb >100 g/L.
(a)
(b)
(c)
(d)Figure 2
(a) Survival analysis of transfused and nontransfused TNM I/II stage patients with POHb >100 g/L. (b) Survival analysis of transfused and nontransfused TNM III stage patients with POHb >100 g/L. (c) Survival analysis of transfused patients with different units of blood. (d) Survival analysis of transfused patients with different transfusion time.
(a)
(b)
(c)
(d)


## 4. Discussion

Variety of experiments had demonstrated that perioperative blood transfusion could result in immunological changes which might contribute to poor survival of patients [19, 20]. Although many studies had been carried out to evaluate the influence of perioperative blood transfusion on the prognosis of gastric adenocarcinoma patients, the results were still varied. Sánchez-Bueno et al.’s study showed that perioperative blood transfusion did not influence the survival of patients with gastric adenocarcinoma [11]. A study by Moriguchi et al. also revealed the lack of any relationship between perioperative blood transfusion and survival of patients with gastric cancer [21]. On the other hand, other studies had opposite opinion that blood transfusion resulted in worse prognosis of gastric cancer patients. Ojima et al. demonstrated that perioperative blood transfusion had a negative influence on survival of patients with gastric cancer [22]. A large retrospective study with 1710 patients by Hyung et al. found that blood transfusion was an independent risk factor for recurrence and poor survival [14]. However, all the studies mentioned above discussed the relationship between perioperative blood transfusion and prognosis without concerning POHb of patients. Clinical decision for blood transfusion was driven more by hemoglobin threshold. Whether patients with POHb >70 g/L should be transfused and whether perioperative transfusion could influence postoperative complications and prognosis of gastric adenocarcinoma patients with different POHb still remain unknown. Therefore, in our study, we divided gastric adenocarcinoma patients into different groups according to their POHb and tried to find out the impact of transfusion on postoperative complications and prognosis.Our retrospective study showed that transfused patients had more postoperative complications than nontransfused ones. Other studies also demonstrated that transfused gastric cancer patients had more postoperative complications [13, 15]. We also found that pulmonary infection happened more frequently in transfused patients than nontransfused ones (transfused 18.8% versus nontransfused 13.7%). Maybe transfusion could disturb the immune system and cause high morbidity of pulmonary infection.In our study, perioperative blood transfusion resulted in poor prognosis of patients with gastric adenocarcinoma but not an independent prognostic factor. However, this might be influenced by different distributions of clinicopathological features or operation approach between transfused and nontransfused subgroups. When patients were divided according to POHb, we found out that difference was not significant between prognosis of transfused and nontransfused patients with POHb between 70 and 100 g/L (P=0.191). Survival outcome was significantly worse in transfused group than nontransfused group in patients with POHb >100 g/L; however, this difference might be caused by more advanced TNM stage patients in transfused group. Hence, we carried out survival analysis grouped by TNM stage (I/II stage; III stage) in patients with POHb >100 g/L. Distributions were similar with regard to sex, differentiation grade, macroscopic type, and tumor size in both subgroups. We found that transfused TNM III stage patients had worse prognosis than nontransfused patients, while differences were not significant between transfused and nontransfused patients in I/II stage subgroups. We concluded that perioperative blood transfusion contributed to poor prognosis, especially in stage III gastric adenocarcinoma patients.Blood transfusion may regulate immunity system which may be harmful for patients with cancer. The explanation for the adverse effect of transfusion is probably immunosuppression which may be caused by decreased natural killer cell activity and increased suppressor T lymphocytes activity. Other suppressor factors such as anti-idiotypic antibodies may also be generated after blood transfusion [7, 23]. Heiss held the opinion that transfusion might have effect on minimal residual disease in resected-cancer patients which might lead to poor prognosis of them [24]. They witnessed a significant quantitative increase of tumor cells in bone marrow of transfused patients only during follow-up. In advanced stage, immunosuppression caused by transfusion may lead to progression of residual foci and also fail to clear cancer cells in bone marrow. Their finding supported our results that transfused patients had worse prognosis and more postoperative complications such as pulmonary infections, especially in TNM stage III patients.There were some reports focused on the relationship between prognosis and amount of transfused blood. Hyung’s study described significant differences in the prognosis between patients transfused with different units of blood [14]. However, in this study, we revealed that transfused patients with different units of blood did not show significant difference in survival outcomes which was similar to Ojima’s and Kanda’s results [15, 22]. Maybe it was transfusion itself which caused immunosuppression and poor prognosis rather than amount of blood transfused. We also found that patients with intraoperative transfusion seemed to have worse survival than preoperative and postoperative transfused patients. Surgical stress inhibited the immune system and might result in immunosuppression which led to poor prognosis of patients with intraoperative blood transfusion [25]. If we cannot avoid perioperative transfusion, we may avoid intraoperative transfusion at least.This present study, which is one of the largest retrospective researches on Chinese patients, aims to excavate the relationship among Hb value, transfusion, and prognosis. In patients with POHb between 70 and 100 g/L, the difference was not significant between transfused and nontransfused patients. However, in patients with POHb >100 g/L especially TNM III stage, perioperative blood transfusion related to poor outcomes. Although transfusion did not affect much prognosis of patients with POHb between 70 and 100 g/L, blood transfusion still should be avoided for transfused patients who had more postoperative complications. And we also should avoid intraoperative blood transfusion for the adverse effect on prognosis. In our study, intraoperative blood loss was an independent risk factor for transfusion. Thus, as to surgeons, the best method to avoid perioperative transfusion is to reduce intraoperative blood loss, for example, careful anatomical dissection to avoid injury of blood vessels; using some technology or devices to reduce blood loss such as electrocoagulation, ultrasonic, laser devices, and collagen-sealing devices; reducing the length of incision and suture carefully.Our study is a retrospective study which included 1199 Chinese patients in one center, and we did not analyze the effect of postoperative treatment such as adjuvant chemotherapy or radiotherapy on the long-term survival of our patients in this study. Thus it is necessary to carry out some prospective, randomized, controlled studies to examine the prognostic value of blood transfusion in gastric adenocarcinoma.In conclusion, perioperative blood transfusion was related to poor prognosis of patients with gastric adenocarcinoma, especially in TNM III stage patients with POHb >100 g/L. Transfused patients also had more postoperative complications than nontransfused ones; thus it is better to refrain from unnecessary perioperative blood transfusion especially intraoperative transfusion.



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*Source: 6470857-2015-12-27.xml*