Introduction
According to the World Health Organization (WHO)
data, there were an estimated 1,089,103 new cases of
gastric cancer worldwide in 2020. Gastric cancer was
the sixth in the incidence ranking, accounting for 5.6%
of all cancer cases. There were an estimated 768,793
deaths (7.7% of all cancer-related deaths) due to gastric
cancer in 2020.[] There are significant differences in
the incidence of the disease due to dietary habits, ethnic
differences, geographical conditions, socio-economic
conditions, lifestyle, prevalence of Helicobacter pylori,
and most importantly, improved outcomes due to early
diagnosis of the disease.[-] In Asian countries such
as Japan and Korea, treatment results have improved,
primarily due to early diagnosis of the disease. However,
in western countries, 80% of gastric cancer patients
are diagnosed in advanced stages and the prognosis of
these patients is generally poor.[]
It is known that the only curative treatment of
gastric cancer is complete resection of the tumor
and involved lymph nodes.[,] More than half of
radically resected gastric cancer cases recur locally
and/or with distant metastases. Therefore, median
survival is rarely more than 12 months and 5-year
survival in patients with metastatic gastric cancer is
<10%.[] Today, the diagnosis of recurrence remains
difficult, and the standard treatment is not fully established.
If the clinicopathological factors that play
a role in recurrence are known, treatment modalities
which can prevent or delay the development of recurrence
can be developed.
In the previous studies, T-stage was reported to be a
significant independent predictor of tumor recurrence
and metastases in patients with node-negative gastric
cancer. However, there is no consensus on the prognostic
significance of other clinicopathological factors
such as age, tumor size, number of lymph nodes taken,
and lymphovascular invasion.[]
The purpose of this study was to determine the
clinicopathological and prognostic factors and their effects
on overall survival (OS) and disease-free survival
(DFS) in patients who underwent curative resection for
gastric cancer and did not have lymph node metastasis.
Methods
This study was performed in the Department of Medical
Oncology of Ankara Numune Training and Research
Hospital. A total of 138 patients followed-up for
node-negative gastric cancer between 2001 and 2016 were included in the study. The Local Ethics Committee
approved the study with the approval dated 27.04.2016
and numbered 2016-1139. All subjects were informed
about our study in detail and signed an informed consent
form before enrollment.
Inclusion criteria were determined as: (i) To have
undergone curative surgery and (ii) to have followed
up for node-negative gastric cancer. The exclusion criteria
were defined as presence of one of the following
conditions: (i) Lymph node metastasis, (ii) distant metastasis,
and (iii) neoadjuvant chemotherapy.
Data such as age, sex, tumor localization, tumor
differentiation, tumor TNM stage, type of surgery,
lymphovascular invasion, perineural invasion, presence
of H. pylori, tumor size, histopathologic subtype
of the tumor, complete blood count, tumor markers,
and adjuvant treatments were recorded. Post-operative
performance status of the patients according to Eastern
Cooperative Oncology Group (ECOG) performance
scale was recorded. Patients included in the study were
followed every 3 months for the first 2 years, every 6
months for the next 2 years and then annually. Ultrasonography,
abdominal computed tomography (CT),
esophagogastroscopy, and measurement of serum tumor
marker levels were performed to determine postoperative
recurrence.
Statistical Analysis
Statistical analyses were performed using the Statistical
Package for the Social Sciences (SPSS) for Windows 20
(IBM SPSS Inc., Chicago, IL) program. Kolmogorov-
Smirnov test was used to determine whether the data
were normally distributed or not. Continuous variables
were given as mean±standard deviation if the distribution
was normal, and as median (minimum-maximum)
if the distribution was not normal. In the comparison
of independent group differences, the significance test
of the difference between the two means (Independent
samples t-test) was used when the parametric test assumptions
are provided; The Mann-Whitney U-test
was used to compare the independent group differences
when the parametric test assumptions were not
provided. Chi-square and Fisher's exact Chi-square
test were used to compare categorical data. DFS was
determined as the time from operation to recurrence.
In the patients who died before the recurrence assessment,
the date of death was accepted as the date of recurrence.
The final date of the disease assessment was
taken into account for the patients who had no recurrence
until the end of the study. OS was calculated as
the time from diagnosis to death. In the patients who were still alive at the end of the study, the last date on
which the patient was evaluated was taken into consideration.
Multivariable stepwise Cox regression analysis
was used to determine the independent risk factors for
recurrence and mortality. Cutoff value of numerical
independent predictors was evaluated with receiver
operating characteristic curve analysis Youden index
method and Kaplan-Meier analysis were used to show
the effect on recurrence and mortality according to
cutoff value. A probability p<0.05 was defined as statistically
significant.
Results
The study population consisted of 138 patients (39.1%
female and 60.9% male) and the mean age at diagnosis
was 61.6±12.0 years. The median follow-up period
was 130 months (min: 1 month, max: 175 months).
During the follow-up, 29% of the patients died. When
the pathological stages were examined, most of the
patients (39.9%) were in stage T3, 28.3% were in stage
T2, 23.2% were in stage T1, and 8.7% were in stage T4.
Surgical treatment and pathological data of the patients
are shown in Table 1.
Table 1 Surgical treatment and pathological data
Of the 138 patients included in the study, 66 (47.8%)
received adjuvant chemotherapy. When it comes to the
details of adjuvant treatment, 25 (18.1%) of the patients
received 5- Fluorouracil (5-FU) +Folinic acid, 11
(8.0%) patients received Cisplatin+Folinic acid+5- FU,
and 30 (21.7%) patients received the MAYO regimen
(5-FU+leukovorin). Five (3.6%) of the patients received
adjuvant radiotherapy. A total of 49 (35.5%) patients
received adjuvant chemoradiotherapy, of which
8 (5.8%) received radiotherapy+Bolus 5-FU, and 41
(29.7%) received radiotherapy+5-FU.
Recurrence occurred in 31.2% of the patients and
the median DFS was 128 months (min: 3 months and
max: 175 months). The effects of possible risk factors
on DFS are shown in Table 2. Accordingly, ECOG level
before adjuvant treatment (hazard ratio [HR]=2.320;
p<0.001), the largest tumor diameter (HR=1.198;
p=0.029), carbohydrate antigen 19-9 (CA19-9) level
(HR=1.104; p=0.047), and post-operative carcinoembryonic
antigen (CEA) level (HR=1.183; p=0.043)
were the independent predictors of the risk of recurrence.
A 1 ng/mL increase in the post-operative CEA
level increased the risk of recurrence by 1.183-fold
and a 1 U/mL increase in post-operative CA 19-9
level was found to increase the risk of recurrence by
1.104 fold (Table 2). The largest tumor diameter above
3.5 cm predicted the risk of recurrence with 86.7% sensitivity and 45.1% specificity (area under curve
[AUC]±standard error [SE]=0.674±0.054; p=0.001)
(Fig. 1). The largest tumor diameter above 3.5 cm was
found to have a risk of recurrence of 3.667 times more
than the largest tumor diameter of 3.5 cm and below
(HR=3.667; Median DFS: ≤3.5 cm=107 months vs.
>3.5 cm=91 months; log rank p=0.009) (Fig. 2). Postoperative
CEA level above 1.7 ng/mL predicted recurrence
risk with 72.7% sensitivity and 58.7% specificity
(AUC±SE=0.840±0.058; p<0.001) (Fig. 3). Post-operative
CEA levels above 1.7 ng/mL were found to have
a risk of recurrence of 2.865 times more than postoperative
CEA levels of 1.7 ng/mL or less (HR=2.865;
Median DFS: ≤1.7 ng/mL = 111 months vs. >1.7 ng/
mL =90 months; Log Rank p=0.023) (Fig. 4).
Table 2 Independent predictors of recurrence (DFS)
Fig. 1. The predictive value of the largest tumor diameter
in predicting the risk of recurrence.
Fig. 2. Recurrence risk according to the determined
largest tumor diameter cutoff value (DFS:
months).
Fig. 3. The predictive value of the post-operative carcinoembryonic
antigen level in predicting the risk
of recurrence.
Fig. 4. Recurrence risk according to the determined
post-operative carcinoembryonic antigen cutoff
value (DFS: months).
The effects of possible risk factors on OS are
shown in Table 3. ECOG level before adjuvant treatment
(HR=2.585; p<0.001), post-operative CEA level
(HR=1.128; p=0.005), and post-operative CA 19-9
level (HR=1.080; p=0.006) were independent predictors
of mortality.
Table 3 Independent predictors of mortality risk (OS)
A 1 ng/mL increase in the post-operative CEA level
increased the mortality risk by 1.128-fold and a 1 U/
mL increase in post-operative CA 19-9 level was found to increase the mortality risk by 1.080 fold. Post-operative
CEA level above 1.58 ng/mL predicted mortality
risk with sensitivity of 84.2% and specificity of 53.8%
(AUC±SE=0.711±0.074; p=0.004) (Fig. 5). Post-operative
CEA level above 1.58 ng/mL was found to have a
mortality risk of 4.936 times higher than post-operative
CEA levels of 1.58 ng/mL or less (HR=4.936; Median
OS: ≤1.58 ng/mL=117 months vs. > 1.58 ng/mL =
94 months; Log Rank p=0.005) (Fig. 6).
Fig. 5. Predictive value of post-operative carcinoembryonic
antigen level in predicting mortality risk.
Fig. 6. Mortality risk according to the determined postoperative
carcinoembryonic antigen cutoff value
(OS: months).
Discussion
In gastric cancer, which has a high risk of mortality, a
satisfactory decrease in the mortality rate has not yet
been achieved, and studies on the factors affecting survival
and the development of effective treatments are
still current issues.[,] Patients with node- negative
gastric cancer have better OS rates compared to those
with lymph node metastases, but it is a known fact
that some patients with node-negative gastric cancer
are at an increased risk of recurrence.[] Therefore, many studies have been conducted to determine the
prognostic factors associated with OS and DFS in patients
with node-negative gastric cancer. In curatively
resected gastric cancer cases, the most important prognostic
factors are the gastric wall invasion depth and
lymph node metastasis status.[-] Although the
relationship between the gastric wall invasion depth
and OS has been sufficiently clarified, the role of many
important prognostic factors such as tumor size, tumor
markers, presence of lymphovascular invasion, tumor
localization, and ECOG performance status of the patient
is still unclear.[,]
Zhao et al.[] in their study with 646 patients
with lymph node negative advanced stage gastric cancer
showed that lymphovascular invasion, advanced T
stage (T3-T4), and an inadequate number of retrieved
lymph nodes were independent predictive factors of
tumor recurrence in node-negative advanced gastric
cancer. Older age, localization in the upper third of the
stomach, lymphovascular invasion and the depth of tumor
invasion (T4 stage) were independently associated
with long-term survival. With regard to node-negative
patients with ≥15 retrieved lymph nodes and advanced
T stage (T3-T4) were independent risk factors for both
tumor recurrence and long-term survival. Pacelli et
al.[] have compared distal gastric cancer with proximal
gastric cancer in 707 patients and the prognosis of
proximal gastric cancer was found to be worse due to
advanced tumor stage and higher postoperative mortality.
In our study, tumor localization was not found
to be an independent predictor, but univariable overall
OS analysis showed better prognosis of gastric cancer
with distal (antrum- pylor) localization.
Kim et al.[] compared node-negative and nodepositive
gastric cancer in 2848 gastric cancer patients
and tumor size, serosa invasion and recurrence were
found as independent predictors of OS. In a study of
277 patients with node-negative gastric cancer, Saito et
al.[] reported that tumor diameter was a prognostic
predictor, and patients with a tumor diameter >7 cm
had worse survival than those with a tumor diameter
<7 cm. In our study, tumor diameter was not found to
be associated with OS, but was found to be an independent
predictor of recurrence. In addition, we found the
cutoff value of tumor diameter, which is an independent
predictor for recurrence, as 3.5 cm. The sensitivity
of this cutoff value was 86.7%, the specificity was
45.1%, and it was found to be insufficient in terms of
diagnostic evaluation. Kaplan-Meier analysis showed
that patients with a tumor diameter >3.5 cm had a risk
of recurrence of 3.667 times more than patients with a tumor diameter of 3.5 cm or less. However, this predictive
value was not effective in terms of mortality.
Studies comparing the total gastrectomy and subtotal
gastrectomy in the treatment of gastric cancer have shown
that life expectancy is the same but the morbidity and
mortality rates are higher in total gastrectomy.[] Bozzetti
et al.[] have compared 315 patients who were underwent
subtotal gastrectomy with 303 patients who were
underwent total gastrectomy in terms of survival and
there was no difference between total gastrectomy and
surgical margin negative subtotal gastrectomy. According
to the study conducted by Hartgrink et al.[] with a total
of 1078 patients, total gastrectomy is recommended only
if the tumor localization requires total gastrectomy. In the
study of Deng et al.[] with 112 node-negative gastric
cancer patients, the operation type was found to be an
independent predictor of OS, and subtotal gastrectomy
was associated with longer post-operative survival. In our
study, subtotal gastrectomy showed longer DFS and OS
compared to total gastrectomy, and it was determined by
univariable analysis that it may be a possible prognostic
predictor, although it is not an independent predictor.
In a study of 774 patients with gastric cancer, Harrison
et al.[] found that D2 lymph node dissection
affected survival in patients with node-negative gastric
cancer. In the study of Bilici et al.[] 113 node-negative
gastric cancer patients were included in the study and
the prognostic significance of D1 and D2 dissection
could not be determined. In our study, longer DFS and
OS were observed in D2 dissection than D1 dissection
but it was not found as a prognostic factor. In fact, this
may be explained by inadequate lymph node dissection
in patients who underwent D1 lymph node dissection.
Sura et al.[] reported that 20 or more lymph node
dissections were associated with better survival in a
study of 17,851 gastric cancer patients. In the study performed
by Liu et al.,[] 147 patients with stage 3 gastric
cancer, the cutoff value for the number of dissected
lymph nodes was found to be 15. The mean number of
dissected lymph nodes was 15.88 in the study of Sura et
al., and 18.3 in the study of Liu et al.[,]
Gu et al.[] found that lymph node count was positively
correlated with OS and was an independent predictor
of OS in patients with node-negative gastric cancer. In
a study of 2373 patients with stage III gastric cancer, Liu
et al.[] investigated the prognostic impact of negative
lymph node counts and reported that patients with negative
lymph node count >14 had better 5-year OS than
those with negative lymph node count ≤14. In another
study, Zhang et al.[] suggested that lymph node count
should be >31 for an accurate prognostic assessment in patients with node-negative Stage III gastric cancer. In
our study, the median number of dissected lymph nodes
was 16. The fact that the number of dissected lymph
nodes in our study was not related to survival and recurrence
may be due to the fact that we did not undergo a
stage-based examination as in other studies.
Baba et al.[] in their study with 123 patients with
stage 4 gastric cancer, found a poor prognosis in patients
with an ECOG score of 2 or higher compared to
those with ECOG scores 0 and 1. In our study, the increase
in ECOG score was found to be an independent
predictor of both recurrence and mortality risk.
There are reports in the literature that CEA and CA
19-9 may have prognostic significance in gastric cancer.
Marrelli et al.[] showed that CA 19-9 level positively
correlated with stage in 153 gastric cancer patients. Kwon
et al.[] showed that normalization of Ca 19-9 levels
after curative gastric resection in gastric cancer was
associated with curative surgical treatment. In a study
of 36 patients with gastric cancer, Mihmanlı et al.[]
showed that patients with normal CEA levels had better
survival than those with high CEA levels. In their study,
Sun et al.[] aimed to identify factors associated with
early and late recurrence in patients with node-negative
gastric cancer, and they found that high CA19-9 level
was an independent predictor of late recurrence (>24
months). In our study, post-operative CEA and CA 19-9
levels were found to be independent prognostic factors
in terms of both recurrence and mortality.
In a study conducted by Jeong et al.[] with 1874
gastric cancer patients, 967 of whom were lyph node
negative, CEA level was associated with survival and
the cut-off value for CEA was determined as 5 ng/
mL. In our study, it was found that having a CEA level
above 1.7 ng/mL was associated with a higher risk of
relapse and a value above 1.58 ng/mL was associated
with a higher risk of mortality.
Our study has some limitations such as retrospective
design and small sample size.
Conclusion
ECOG score, CEA, and CA 19-9 levels were found to
be predictors of both recurrence and mortality risk
in gastric cancer patients who underwent curative
surgery and had no lymph node metastasis. Tumor
diameter was determined as an independent predictor
for recurrence only. These parameters may have a role
in making a more accurate treatment timing decision
and prognosis evaluation. Prospective studies with
larger sample sizes are needed on this subject.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Ankara Numune Training and Research Hospital Scientific
Research Ethics Committee (no: 2016-1139, date:
27/04/2016).
Financial Support: None declared.
Authorship contributions: Concept - M.K., S.K.; Design -
M.K., S.K., N.Ö.; Supervision - M.K., M.C.; Funding - M.K.,
M.C.; Materials - M.K., S.K., N.Ö.; Data collection and/or
processing - M.K., S.K.; Data analysis and/or interpretation
- M.K., S.K., M.C.; Literature search - M.K., M.C.; Writing -
M.K., M.C.; Critical review - S.K., N.Ö.
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