Original Article

Yonago Acta medica 2016;59:210–216

Intra-Abdominal Complications after Curative Gastrectomies Worsen Prognoses
of Patients with Stage II–III Gastric Cancer
A.T.M. Abdul Kader,* Yuki Murakami,* Miwa Yoshimoto,* Kazunari Onishi,† Hirohiko Kuroda,* Tomoyuki
Matsunaga,* Yoji Fukumoto,* Shuichi Takano,* Naruo Tokuyasu,* Tomohiro Osaki,* Hiroaki Saito* andMasahide Ikeguchi**Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503,
Japan and †Division of Health Administration and Promotion, Department of Social Medicine, School of Medicine, Tottori University
Faculty of Medicine, Yonago 683-8503, Japan

ABSTRACT

go-jejunostomy after total gastrectomy are technicallydemanding, some patients suffered from postoperativecomplications,3 which can worsen their short-term outcome (such as lengthening their hospital stay, or requiring longer fasting). Furthermore, some complications,such as anastomotic leakage and pancreatic fistula, may
become serious or even life-threatening.
Reportedly, postoperative complications also negatively affect long-term outcomes for a wide range ofcancers,4–7 including GC.8, 9 However, reports regarding
GC have included only infectious complications andexcluded non-infectious complication in their analyses.
Adjuvant chemotherapy (AC) is an indispensable component of treatment, aimed at preventing recurrence inpatients with resectable advanced GC. The Japanese
Gastric Cancer Treatment Guideline recommends adjuvant therapy by S-1 for 1 year after curative surgery,2based on the Adjuvant Chemotherapy Trial of TS-1 for
Gastric Cancer (ACTS-GC), which showed a survival
benefit from AC after D2 gastrectomy compared withsurgery alone for patients with stage II–III GC.10 They
also recommend starting AC within 6 weeks after operation. Late initiation of AC has been significantly associated to poor prognosis in patients with stage II–III GC.11
Therefore, both non-infectious and infectious complications are likely to worsen their prognoses, owing to lateinitiation of AC. However, few reports have yet showna correlation between non-infectious complications andprognosis in GC patients. This retrospective study was
designed to determine the effect of postoperative intra-abdominal complications (IACs), including both infectious and non-infectious complications on long-term
outcomes in patients with stage II–III GC.

Background

Postoperative complications have beenshown to worsen prognoses of various cancer types.
Methods We retrospectively analyzed 265 patientswith stage II-III gastric cancer who underwent curative
gastrectomies between 1991 and 2010 at Tottori University Hospital to determine the effect of postoperative
intra-abdominal complication (IAC) on prognosis.
Results Of the 265 patients, 38 (14.3%) developed
postoperative IACs of grade ≥ 2, of whom significantly
more patients were male. Patients in the IAC group weresignificantly older than patients in the non-complication(NC) group. The NC group had significantly better survival than did the IAC group (P < 0.0001). Within the
IAC group, 5-year survival rates did not significantly
differ between patients with infectious complication subgroup (24.6%) and the non-infectious subgroup (46.2%).
Grade of complication was not related to prognosis.
Lengths of time before starting adjuvant chemotherapy(AC) after surgery were significantly longer for the IAC
group (55.3 ± 34.7 days) than for the NC group: (26.6 ±11.9 days; P = 0.0023). Prognosis of patients who took
AC within 6 weeks after surgery tended to be better thanthat of patients who took AC > 6 weeks after surgery (P= 0.071). In multivariate analysis, IAC was an independent predictor of prognosis, as were age, invasion depth,
and lymph node metastasis.
Conclusion Postoperative IACs were related to poorer
survival for patients with stage II–III gastric cancer.
Key words gastrectomy; gastric cancer; postoperativecomplication; prognosis
Although the prognosis of patients with gastric carcinoma has improved with increased availability of diagnostic techniques and better intraoperative and postoperative care, death from gastric cancer (GC) still ranks
second among all cancer deaths worldwide.1
Gastrectomy with D2 lymph node dissection has
been the standard treatment for advanced GC in Japan,2and has led to lower morbidity and mortality rates.
However, as D2 lymph node dissection and esopha-

Corresponding author: Hiroaki Saito, MD, PhD
sai10@med.tottori-u.ac.jp
Received 2016 June 24
Accepted 2016 July 20
Abbreviations: AC, adjuvant chemotherapy; CD, Clavien–Dindo;
CI, confidence interval; DSS, disease-specific survival; GC, gastriccancer; IAC, intra-abdominal complication; NC, non-complication;
POD, postoperative day; S-1, tegafur-gimeracil-oteracil; UFT, tegafur-uracil

210

Complications in gastric cancer

MATERIALS AND METHODSRESULTS
Table 1 shows details of complications in patients included in the current study. Thirty-eight patients (14.3%)
developed postoperative IACs of grade 2 or higher
according to CD classification. Of these patients, 5.3%
developed grade III IACs and 1.5% had grade IV or V
IACs.
Table 2 shows the differences in clinicopathologicalcharacteristics between the IAC group (n = 38) and theNC group (n = 227). The IAC had a significantly higher
percentage of male patients, and had a significantly older
median age, than did the NC group. The IAC and NC
groups did not significantly differ in tumor size, depth ofinvasion, lymph node metastasis, pathological stage of
disease, tumor location, type of gastrectomy, and splenectomy.
Five-year survival rates differed significantly between the IAC group (34.5%) and the NC group (70.7%;
P < 0.0001; Fig. 1). Within the IAC group, 5-year survival rates did not significantly differ between the subgroupwith infectious IACs (24.6%) and those with non-infectious IACs (46.2%; P = 0.4; Fig. 2). Five-year survival
also did not significantly differ between the subgroupwith grade 2 IACs (40.2%) and those with grade 3–5
IACs (33.9%; P = 0.39; Fig. 3).
Intervals before starting AC after surgery differedsignificantly between the IAC group (55. 3 ± 34.7 days;n = 10) and the NC group (26.6 ± 11.9 days; n = 62; P =0.0023). Because the Japanese Gastric Cancer Treatment
Guideline recommends starting AC with S-1 within 6
weeks post-surgery in patients with stage II–III GC,
we divided patients who took AC into the non-delayedgroup (patients who started AC within 6 weeks of surgery), and the delayed group (who started AC later than
6 weeks after surgery). In the NC group, only 4 patients(6.5%) were in the delayed group, while 5 patients (50%)
were in the delayed group in the IAC group and thedifference was statistically significant (P = 0.0001). The
prognosis of patients in non-delayed group tended to bebetter than that in delayed group, but not significantly
so (P = 0.071; Fig. 4). Two anti-cancer drugs, UFT and
S-1, were used for AC in the current study. Patients who
took UFT and those who took S-1 showed no significant
difference in prognosis (P = 0.24, Fig. 5).
We finally applied Cox proportional hazard model anda stepwise procedure on age, sex, tumor size, histology,
tumor location, depth of invasion, lymph node metastasis,
lymphatic vessel invasion, blood vessel invasion, type ofgastrectomy, splenectomy, AC, and IAC, to identify independent prognostic factors. Multivariate analysis indicatedthat IAC was an independent prognostic indicator, as wereage, depth of invasion, and lymph node metastasis (Table 3).

Patients

This study included consecutive 265 patients with stage
II–III gastric adenocarcinoma who underwent curative gastrectomies (R0 resections) between 1991 and2010 at the Tottori University Hospital. Institutional
review board approval was obtained (1607A052), andthe informed consent requirement was waived for thisstudy. All patients underwent distal partial gastrectomy,
proximal partial gastrectomy or total gastrectomy with
regional lymph node dissection. At the time of analysis,
the median follow-up for the 129 remaining survivors
was 91 months. Of the 136 deaths, 86 were related torecurrence of GC, two to another malignancy and 48 toanother disease or accident.
With regard to AC, 72 patients underwent chemotherapy, while the remainder did not. Uracil-tegafur(UFT, Taiho, Tokyo, Japan) was used in 16 patients andtegafur-gimeracil-oteracil (S-1, Taiho) was used in 56
patients. These patients received 200–400 mg of UFT,
2–3 × daily orally, or 80 mg/m2/day oral S-1. These regimens were administered for 6 months to a year postoperatively. Because S-1 became available for the treatmentof gastric cancer in 1999, UFT was mainly used before
1999 and S-1 was used after 1999.
Clinicopathological findings were generally determined according to the 14th edition of the JapaneseClassification of Gastric Carcinoma.12 With regard to thedefinition of postoperative IACs, the Clavien–Dindo (CD)system was used to classify each patient’s postoperative
IAC.13, 14 If an individual patient had multiple complications, the highest grade was used in the analysis. Grade
1 complications were not evaluated to exclude the possibility of a description bias in the patient records.
Statistical analysis

For statistical analyses, chi-square and Fisher’s exact
probability tests were used to compare distribution ofindividual variables between patient groups. Differences
between the two groups were evaluated using the Mann–
Whitney U test. Disease-specific survival (DSS) was
calculated by the Kaplan–Meier method and comparedusing the log-rank test. Patients who died of causes otherthan GC were considered lost to follow-up at the time ofdeath for DSS. We used multivariate analysis of factors
considered prognostic of DSS, with a Cox’s proportional hazards model and a stepwise procedure. P < 0.05
was considered significant. Statistical analyses were
performed with SPSS for Windows version 19.0 (SPSS,
Chicago, IL).

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A. Kader et al.
Table 1. Details of postoperative intra-abdominal complications
Type of complication
Infectious complication
Pancreatic fistula
Anastomotic leakage
Wound infection
Non-infectious complication
Stenosis
Ileus
Afferent loop syndrome
Total
CD, Clavien–Dindo.

Grade of CD classifications
IIIb
IVa
IVb

II

IIIa

3
8
2

2
6
0

1
0
0

1
0
0

4
3
0
20

4
0
0
12

0
0
1
2

0
0
0
1

V

Total

0
0
0

1
1
0

8
15
2

0
0
0
0

0
1
0
3

8
4
1
38

Table 2. Clinicopathologic characteristics of patients with stage II–III gastric cancer by the presence of
intra-abdominal complications
Complication group (n = 38)

Non-complication group (n = 227)

P value

Gender
0.014
Male
30
132
Female895
Age (years)
71.2 + 11.5
65.9 + 12
0.011
Tumor size (cm)
7.6 + 4.2
6.5 + 3.5
0.18
Tumor location
0.52
Upper
14
64
Middle
11
82
Lower
13
81
Tumor depth
0.7
T1
3
10
T2
6
43
T3
12
61
T4
17
113
Histology
0.74
Differentiated16
89
Undifferentiated22
138
Lymph node metastasis
0.2
N0
5
47
N1
9
79
N2
10
40
N3
14
61
Pathological stage
0.67
II
15
98
III
23
129
Gastrectomy
0.25
Distal13
109
Proximal
1
8
Total
24
110
Splenectomy
0.36
Performed
1045
Not performed
28
182
Adjuvant chemotherapy
0.89
Performed
1062
Not performed
28
165
N0, no regional lymph node metastases; N1, metastasis in 1–2 regional lymph nodes; N2, metastasis in 3–6 regional lymph nodes; N3,
metastasis in 7 or more regional lymph nodes; T1, tumor has invaded lamina propria or submucosa; T2, tumor has invaded the muscularis
propria; T3, tumor has invaded the subserosa; T4, tumor invasion is contiguous to or exposed beyond the serosa or tumor invades adjacentstructures.

212Complications in gastric cancer
Table 3. Multivariate analysis using Cox’s proportional hazards model and a stepwise procedure to identify
independent prognostic factors for disease-specific survival

P value

Covariates

Hazard ratio

95% CI

Age*
0.019
1.024
1.004–1.045
Depth of invasion (T1–T4)†< 0.0001
1.942
1.437–2.625
Lymph node metastasis (N0–N3)‡< 0.0001
1.545
1.265–1.887
Intra-abdominal complication
0.00012.633
1.610–4.305*Continuous variable. †T1: tumor has invaded lamina propria or submucosa; T2: tumor has invaded the muscularis propria; T3: tumor
has invaded the subserosa; T4: tumor invasion is contiguous to or exposed beyond the serosa or tumor invades adjacent structures. ‡N0:
no regional lymph node metastases; N1: metastasis in 1–2 regional lymph nodes; N2: metastasis in 3–6 regional lymph nodes; N3: metastasis in 7 or more regional lymph nodes. CI, confidence interval.

Kader et al. Figure 1
100

Percent survival

Non-complication (n = 227; 70.7%)50Complication (n = 38; 34.5% )P < 0.0001
1

2

3

4

KaderYearset al.
Figure 2
after operation

5

Fig. 1. Survival curves for patients withstage II–III gastric cancer, based on presence of postoperative intra-abdominal
complications. Patients without intra-abdominal complication had significantly
better prognosis than did patients with intra-abdominal complications (P < 0.0001).

Percent survival

100
Non-infectious complication (n = 13 ; 46.2%)
50

Infectious complication (n = 25 ; 24.6% )P = 0.4
1

2

3

4

5

Years after operation

213

Fig. 2. Survival curves for patients withstage II–III gastric cancer and postoperative intra-abdominal complications. Outcomes did not significantly differ between
patient subgroups with infectious andnon-infectious intra-abdominal complication (P = 0.4).

Kader et al. Figure 3

A. Kader et al.

Percent survival

100
Grade 2 (n = 21; 40.2%)50

Grade 3 and more (n = 17; 33.9% )P = 0.39

3
Kader 2et al. Figure
44

1

5

Fig. 3. Survival curves for patients withstage II–III gastric cancer with postoperative intra-abdominal complication bygrade of complication (CD classification).
Outcomes did not significantly differ between patients with grade 2 intra-abdominal complications and those with grade ≥3 complications (P = 0.39). CD, Clavien–
Dindo.

Years after operation

100

Percent survival< 6weeks (n = 63; 77.7%)50> 6weeks (n = 9; 44.4% )P = 0.071

Kader 2et al. Figure
54
3

1

5

Years after operation

Fig. 4. Survival curves for patients withstage II–III gastric cancer with postoperative intra-abdominal complication basedon length of time before starting AC. Prognosis of patients who started AC within 6
weeks after surgery tended to be better (butnot significantly so) than that of patients
who started AC more than 6 weeks after
surgery (P = 0.071). AC, adjuvant chemotherapy.

100

Percent survival

S-1 (n = 56; 57.8%)

50
UFT (n = 16; 62.5% )P = 0.24
1

2

3

4

Years after operation

2145

Fig. 5. Survival curves for patients withstage II–III gastric cancer and postoperative intra-abdominal complication by drugs
used for adjuvant chemotherapy. Prognosis
did not significantly differ between patients
who took UFT and those who took S-1 (P= 0.24). S-1, tegafur-gimeracil-oteracil;
UFT, tegafur-uracil.

Complications in gastric cancer

DISCUSSION
Gastric surgery has had lower morbidity and mortality
rates in recent years because of advances in treatment
techniques, surgical devices, and perioperative management.15–17 In fact, a recent clinical trial indicates thatthe rate of overall surgery-related complications among
patients who underwent gastrectomy with D2 lymphadenectomy—the current standard operation for advanced GC—is 20.9%, including 2.3 % for anastomotic
leakages, 5.3% for pancreatic fistulae, 5.3% for abdominal abscesses, and 4.6% for pneumonia, and with an 0.8%
hospital death rate.3
Postoperative complications inversely affect patients’short-term outcomes, and some complications, such as
anastomotic leakage and pancreatic fistula, can become
life-threatening. Therefore, every effort should be madeto avoid their development. They have also been shown
to affect long-term outcomes of patients with various
cancer types.4–7 We have clearly demonstrated that postoperative IAC is significantly associated with poorer
survival of patients with stage II–III GC in this current
study. Other reports have also associated infectious complications to poor prognosis in GC patients.8, 9 Tokunaga
et al. compared the prognosis of patients with stage II–
III GC with and without infectious IACs and found that
postoperative infectious IACs adversely affected overall
and relapse-free survival of these patients9; Tokunaga et al. considered pancreas-related complications,
anastomotic leakages, and intra-abdominal abscesses
as infectious IACs, but excluded ileus and wound infections, whereas all type of IACs were included in thecurrent study. Notably, we found that both infectious
and non-infectious IACs were related to poor prognosis.
The reason why IACs are related to poor prognosis remains unclear. With regard to infectious complications,immune suppression might be a factor in poor survival. We have previously reported that number of total
lymphocytes significantly decreased after gastrectomy
for GC although some inflammation markers, such as
numbers of white blood cells and neutrophils and serum
CRP levels, significantly increased.18 The lymphocyte
count reached a minimum on postoperative day (POD)
1 and then increased to preoperative level on day 30.
Prolonged inflammation could have induced prolonged
suppression of cell-mediated immunity in patients with
infectious IACs, which would put those patients at highrisk of recurrence.
Non-infectious IACs are also associated with poor
survival. In this regard, delayed initiation of AC mightworsen survival of patients with non-infectious IAC. In
the current study, time before starting AC after surgery
differed significantly in the IAC group (55.3 ± 34.7 days)

and the NC group (26.6 ± 11.9 days). As the aim of AC
is to eradicate micrometastatic tumor cells, delaying
AC allows such cells to grow after operation. Someclinicians often believe that chemotherapy may therefore have little or no adjuvant benefit after a 3-monthdelay19, 20 Time before initiating AC has been associatedwith survival in breast and colorectal cancers,20, 21 andrecently, in prognosis for advanced GC patients whostarted S-1 AC within or after 6 weeks post-surgery.11
As postoperative complications are a common reason for
delaying AC, the poorer prognosis in our IAC group is
likely due to delayed AC.
The present retrospective study has limitations.
First, clinicopathological factors differed between the
IAC and NC groups. As pathological stage is considered
to be the strongest prognostic clinicopathological factor
for GC after curative gastrectomy,22, 23 we conducted
multivariate analysis and found IACs to be an independent prognostic factor. Second, the degree of immune
suppression was not assessed in this study, but should be
examined in a future trial to verify our hypothesis thatpatients with intra-abdominal infectious complications
have severe immune suppression that leads to high recurrence rates and poor overall and relapse-free survival
rates. Third, the two anti-cancer drugs that were used for
AC in the current study, UFT and S-1, were mainly used
before 2003 and after 2004, respectively. Those two
drugs may have differently affected the patients’ prognoses. In this regard, patients who took UFT and those
who took S-1 did no significantly differ in prognosis,
which indicates that the differences of the two drugs’ effects on outcomes was small for patients included in thecurrent study.
In conclusion, our study clearly shows that postoperative IACs—both infectious and non-infectious—are related to poor survival of patients with stage II–III gastriccancer. Therefore, every effort should be made to avoid
the development of these complications.
The authors declare no conflict of interest.

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