Hindawi
Gastroenterology Research and Practice
Volume 2017, Article ID 8928353, 6 pages
https://doi.org/10.1155/2017/8928353
Clinical Study
Multicenter Phase 2 Study about the Safety of No Antimicrobial
Prophylaxis Use in Low-Risk Patients Undergoing Laparoscopic
Distal Gastrectomy for Gastric Carcinoma (KSWEET-01 Study)
Oh Jeong,1 Mi Ran Jung,1 Seong Yeob Ryu,1 Young-Kyu Park,1 Min Chan Kim,2
Ki Han Kim,2 Seung Wan Ryu,3 In Gyu Kwon,3 and Young Gil Son3
1
Department of Surgery, Chonnam National University School of Medicine, Gwangju, Republic of Korea
Department of Surgery, Dong-A University School of Medicine, Busan, Republic of Korea
3
Department of Surgery, Keimyung University School of Medicine, Daegu, Republic of Korea
2
Correspondence should be addressed to Young-Kyu Park; parkyk@jnu.ac.kr
Received 5 January 2017; Revised 13 April 2017; Accepted 9 May 2017; Published 5 June 2017
Academic Editor: martin hubner
Copyright © 2017 Oh Jeong et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Recent studies have shown a lower risk of surgical site infections (SSI) after laparoscopic distal gastrectomy compared
to open surgery. This is a phase 2 study aiming to determine the incidence of SSI after laparoscopic distal gastrectomy without using
antimicrobial prophylaxis (AMP). Methods. cT1N0 gastric cancers that were subject to laparoscopic distal gastrectomy were
enrolled. Based on the unacceptable SSI incidence of ≥12.5% and the target SSI incidence of ≤5%, 105 patients were enrolled
with an α of 0.05 and a power of 80% (ClinicalTrials.gov, NCT02200315). Results. In intention-to-treat analysis, patients did not
reach the target SSI rate (12.4%, 95% conf idence interval = 6 8%–19 8%). Of patients, 44 patients had a protocol violation, such
as extended lymph node dissection (LND) or inappropriate nonpharmacological SSI prevention measures. Per-protocol analysis
excluding these patients (n = 61) showed a SSI rate of 4.9%, which was within the target SSI range. Multivariate analysis revealed
that extracorporeal anastomosis and extended LND were independent risk factors for SSI. Conclusions. This study failed to
reach the target SSI rate without using AMP. However, per-protocol analysis suggests that no AMP might be feasible when
limited LND and adequate SSI prevention measures were performed.
1. Introduction
Since laparoscopic distal gastrectomy was first reported in
1994 [1], it has been widely adopted for the treatment of
early-stage gastric cancer in Korea, China, and Japan [2].
Since laparoscopic surgery is associated with smaller surgical wounds and minimal tissue damage, it could reduce
the risk of postoperative complications in patients undergoing laparoscopic distal gastrectomy. For example, a
comprehensive meta-analysis of six randomized controlled
trials and 19 nonrandomized studies comparing open and
laparoscopic distal gastrectomy showed that the laparoscopic surgery group had lower overall complications,
medical complications, and minor surgical complications
than the open surgery group [3]. A recent large multicenter randomized controlled trial in Korea (KLASS-01) has
also demonstrated that complication rates were significantly lower after laparoscopic distal gastrectomy than
those after open distal gastrectomy, particularly in the
incidences of wound complications [4].
Antimicrobial prophylaxis (AMP) for various clean or
clean-contaminated surgical procedures has long been the
standard to prevent postoperative surgical site infections
(SSI). Compared to open gastrectomy, recent studies on
laparoscopic gastrectomy have shown significantly lower
incidences of SSI ranging from 2% to 4% [4–6]. Current
guidelines recommend the single intraoperative use of
cefazoline for gastric cancer surgery [7]. However,
2
previous studies on the use of AMP for gastric cancer surgery have mostly focused on patients undergoing open
gastrectomy [8, 9].
Reducing the use of antibiotics could help reduce the
medical costs, prevent the antibiotics-related complications and emergence of resistant strains. Recently, several
randomized controlled trials have demonstrated that
AMP can be safely omitted for low-risk patients undergoing laparoscopic cholecystectomy [10]. With advances
in surgical techniques and instruments, the risk of SSI
after laparoscopic distal gastrectomy is considered as
low as that after laparoscopic cholecystectomy. Therefore,
in this preliminary phase 2 trial, we investigated the
incidence of SSI without AMP in low-risk patients
undergoing laparoscopic distal gastrectomy for gastric
carcinoma.
2. Methods
2.1. Study Design. This was a multicenter single-arm phase 2
study to investigate the incidence of SSI after laparoscopic
distal gastrectomy without AMP. Inclusion criteria were histologically proven gastric adenocarcinoma (cT1N0) that
were treated with laparoscopic distal gastrectomy and limited
(D1+) lymph node dissection (LND), age of patients between
18 and 65 years, European Cooperative Oncology Group
(ECOG) performance status of 0 to 1, and adequate bone
marrow, hepatic, renal, pulmonary, and cardiac function.
Patients were excluded if they had active infections, other
major organ resection, preoperative chemotherapy or radiotherapy, poorly controlled diabetes mellitus or hypertension,
or malnutrition (preoperative weight loss ≥10% or body mass
index of ≤18 kg/m2).
The primary endpoint was the incidence of SSI within 30
days postsurgery. SSI was defined based on the diagnostic
criteria of the National Nosocomial Infections Surveillance
(NNIS) system by Centers for Disease Control and Prevention (CDC) [11]. Secondary outcomes were the incidences
of infection at remote sites and postoperative hospital
courses including postoperative fever (≥38°C), length of
hospital stay, and other complications.
Three institutions that operate more than 200 gastric
cancer surgeries per year participated in this study. This
study was approved by the institutional review board at each
institution. All patients provided written informed consent
before entering the study. This study was registered at
ClinicalTrials.gov (NCT02200315).
2.2. Operative Techniques and Perioperative Care. During
surgery, four to five abdominal trocars were used as appropriate. The choice of operative approach (extra- or intracorporeal anastomosis) and reconstruction technique (Billroth
I, Billroth II, or Roux-en-Y gastrojejunostomy) were decided
as per the surgeon’s preference. If extracorporeal anastomosis was performed, a 5 to 6 cm long minilaparotomy was
performed at the upper abdomen. In principle, D1+ LND
with partial omentectomy was the choice of procedure in
the protocol. However, D2 LND and total omentectomy were
allowed in cases with more than T2 or N1 disease observed in
Gastroenterology Research and Practice
the operative findings. Abdominal drain and nasogastric tube
were selectively used at the surgeon’s discretion.
Based on existing evidence [12], we developed the following nonpharmacological SSI prevention measures to reduce
the risk of infection in patients without AMP: (1) preoperative body shower or bath using bacteriostatic soap, (2) maintaining intraoperative normothermia, (3) intra-abdominal
irrigation with more than 1 L of fluid, and (4) high oxygen
supply on the operation day. Other postoperative cares
including oral nutrition, pain management, and intravenous fluid administration were followed as per each
institution’s practice.
2.3. Statistics. Prior to this study, we analyzed the data of
1075 patients (not published) and found that three participating institutions showed similar SSI incidences of around
5% after laparoscopic distal gastrectomy. Based on this, we
determined a target SSI rate of ≤5% and an unacceptable
SSI rate of ≥12.5% (relative risk = 2 5) in patients without
using AMP. Based on Simon’s two-stage design, 105 patients
were needed to test this hypothesis (H0; SSI rate ≥ 12.5%, H1:
SSI rate ≤ 5%) with an α of 0.05 and a power of 80%. We performed analyses in two groups, namely, intention-to-treat
group and per-protocol group. The intention-to-treat group
included all patients who were enrolled in the study, whereas
the per-protocol group included patients who did not have
violations in the operative techniques or SSI prevention
measures as outlined in the protocol. All statistical analyses
were performed using SPSS version 22.0 (IBM Corp., NY,
USA), and two-sided p values of <0.05 were considered
statistically significant.
3. Results
3.1. Patient Characteristics. Between June 2014 and July
2015, 114 patients were screened and 105 patients were
finally enrolled (Figure 1). Demographic and clinicopathological characteristics of patients are summarized in
Table 1. Study groups consisted of 60 men and 35
women with a mean age (years) of 51.6. Within these,
41 (39.0%) patients had comorbidities, among which diabetes mellitus and hypertension were the most common.
Most patients (n = 102) underwent total laparoscopic distal gastrectomy with intracorporeal anastomosis. With
respect to reconstruction techniques, Billroth I, Billroth
II, and Roux-en-Y gastrojejunostomy were performed in
5, 50, and 50 patients, respectively. In the final pathological examination, there were 99 patients with stage I, nine
patients with stage II, and two patients with stage III carcinomas according to the UICC/AJCC TNM classification
(7th edition).
3.2. Postoperative Outcomes and SSI. In overall patients, the
postoperative complication rate was 24.8% (n = 26) and there
was no hospital mortality (Table 2). The mean hospital stay
was 8.7 ± 5.3 days. Thirteen patients (12.4%) developed SSI
(95% CI = 6 8%–19 8%) including wound (n = 7) and
abdominal infections (n = 6). These outcomes did not
achieve the target SSI rate of ≤5% in this study (Table 2).
Gastroenterology Research and Practice
3
Screened (n = 114)
Ineligible patients (n = 6)
Consent withdrawal (n = 3)
Underwent LDG without prophylactic antibiotics (n = 105)
Protocol violation (n = 44)
D2 lymph node dissection (n = 38)
Total omentectomy (n = 8)
No SSI preventive measure (n = 13)
Analyzed with ITT (n = 105)/PP (n = 61)
Figure 1: Consort flow diagram. ITT—intention-to-treat group; PP—per-protocol group; SSI—surgical site infection.
Among the patients with SSI, two patients with an abdominal
infection required radiologic intervention, and others recovered with conservative management.
A total of 38 patients had a protocol violation in the
operative techniques (D2 LND or total omentectomy). Furthermore, thirteen patients did not receive adequate SSI
prevention measures as outlined in the protocol. Overall, 41
(39.0%) patients experienced a violated protocol in either
the operative techniques or SSI prevention measures
(Figure 1). However, as shown in Table 3, the incidence of
SSI in the per-protocol group (n = 61) was 4.9% (95%
CI = 0 0%–10 34%), which was within the target SSI rate of
this study (H0: SSI rate ≥ 12.5%, H1: SSI rate ≤ 5%,
p = 0 049). There were 3 cases of wound infections but no
abdominal infections occurred in this group.
3.3. Risk Factor Analysis for SSI. Table 4 shows univariate and
multivariate analyses of risk factors for developing SSI. In the
univariate analysis, higher body mass index, lower preoperative albumin levels, extracorporeal anastomosis, D2 LND,
and inappropriate SSI preventative measures were associated
with an increase in the frequency of SSI (all p values ≤ 0 1).
Multivariate analysis of these factors revealed that operative
factors including extracorporeal anastomosis (odds ratio
OR = 78 70, 95% confidence interval CI = 3 15–1948 98)
and D2 LND (OR = 7 45, 95% CI = 1 15–48 06) were independent risk factors for developing SSI.
4. Discussion
With the introduction of laparoscopic surgery, the operative
quality and surgical outcomes of gastric cancer surgery have
significantly improved over the past few decades. Accordingly, the incidences of SSI after laparoscopic gastrectomy
have become significantly lower compared to that in the era
of open surgery [5, 6]. Given this low risk, this phase 2 trial
examined the incidence of SSI without using AMP in lowrisk patients undergoing laparoscopic distal gastrectomy. In
this study, the intention-to-treat group did not reach the target SSI, which was thought to be attributed to relatively many
cases with a protocol violation, such as extended lymph node
dissection or inappropriate nonpharmacological SSI prevention measures. However, the per-protocol group that underwent limited LND and adequate SSI prevention measures
showed an acceptable SSI without AMP after laparoscopic
distal gastrectomy. Our analysis showed that operative techniques, such as extended LND and extracorporeal anastomosis, are important factors increasing the risk of SSI after
laparoscopic distal gastrectomy. Unfortunately, our study
failed to show the feasibility of no AMP use in patients
undergoing laparoscopic distal gastrectomy. However, our
study suggests the possibility that nonpharmacological SSI
prevention measures may be sufficient to prevent SSI in
patients undergoing intracorporeal anastomosis and limited
LND during laparoscopic distal gastrectomy. Therefore, we
believe that more studies will be warranted to investigate
the feasibility of no AMP use in totally laparoscopic distal
gastrectomy with limited LND for early gastric cancer in
the future.
The overuse of prophylactic antibiotics in gastrointestinal
surgery is relatively common. For example, according to a
large nationwide survey in Japan, more than 50% of surgeons
reported administering of AMP until 3 to 4 days postsurgery
in clean-contaminated operations including abdominal surgery [13]. Another study showed that as many as 11 out of
14 high-volume centers in Korea and Japan administered
AMP for longer than 24 hours after gastric cancer surgery
[14]. Current guidelines recommend a single dose of AMP
for gastric cancer surgery and emphasize that appropriate
administration within 60 minutes before incision is more
efficient than the postoperative extended use of AMP [7].
Some may argue that reducing a single dose of AMP to no
4
Gastroenterology Research and Practice
Table 1: Patient characteristics.
Age (years)
Gender
Male
Female
BMI (kg/m2)
ASA status
1
2-3
Comorbidity
Abdominal operation history
Preoperative hemoglobin
Mean
<12 g/dl
≥12 g/dl
Preoperative albumin
Mean
<3.1 g/dl
≥3.1 g/dl
Operative approach
Totally laparoscopic
Laparoscopy assisted
Reconstruction
Billroth I
Billroth II
Roux-en-Y
Lymphadenectomy
D1+
D2
Omentectomy
Partial
Complete
Operating time (min)
Operative blood loss (ml)
Harvested lymph nodes
Tumor location
Lower
Middle
Tumor depth
T1a
T1b
T2
T3
T4a
Nodal metastasis
N0
N1
N3a
Table 2: Postoperative outcomes in the overall group.
Patients (n = 105)
51.6 ± 8.3
70 (66.7)
35 (33.3)
24.7 ± 3.6
90 (85.7)
15 (12.4)
41 (39.0)
19 (18.1)
14.4 ± 1.4
5
100
4.7 ± 0.4
0
105
Diet start (POD)
Gas passage (POD)
Postoperative fever
Transfusion
Hospital stay (POD)
Overall complication
Wound complication
Abdominal infection
Gastric stasis
Paralytic ileus
Anastomosis leak
Atelectasis
Omental infarction
Mortality
Surgical site infection
Superficial incisional (grade I/II/III/IV)
Deep incisional (grade I/II/III/IV)
Organ/space (grade I/II/III/IV)
Patients (n = 105)
2.2 ± 2.7
2.6 ± 0.8
38 (36.2)
1 (1.0)
8.7 ± 5.3
26 (24.8)
7
6
5
4
1
1
1
0
13 (12.4)
6 (5/1/0/0)
1 (0/1/0/0)
6 (0/4/2/0)
Data are expressed as mean ± SD or n (%); POD: postoperative day.
102 (97.1)
3 (2.9)
Table 3: Postoperative outcomes in the per-protocol group.
5 (4.8)
50 (47.6)
50 (47.6)
67 (63.9)
38 (36.2)
97 (92.4)
8 (7.6)
213 ± 62
43 ± 34
52 ± 18
69 (65.7)
36 (34.3)
61 (58.1)
36 (34.3)
3 (2.9)
4 (3.8)
1 (1.0)
98 (93.3)
6 (5.7)
1 (1.0)
BMI: body mass index; ASA: American Society of Anesthesiologists score.
Overall complication
Surgical site infection
Superficial incisional (grade I/II/III/IV)
Deep incisional
Organ/space
Diet start (POD)
Gas passage (POD)
Postoperative fever
Hospital stay (POD)
Patients (n = 61)
13 (21.3)
3 (4.9)
3 (3/0/0/0)
0
0
2.0 ± 3.4
2.3 ± 0.8
22 (36.1)
8.3 ± 5.0
Data are expressed as mean ± SD or n (%); POD: postoperative day.
use in laparoscopic distal gastrectomy may be trivial for individual patients. However, developing resistance to antibiotics
is an alarming level [15]. For instance, in the U.S., more
than two million people get infections that are resistant
to antibiotics and at least 23,000 people die as a result
according to the report issued by Centers for Disease Control and Prevention [16]. Considering this alarming level
of increasing resistance of bacteria and associated medical
cost, efforts to reduce unnecessary antibiotic use will be
essential to improve the quality of surgical care and to prevent emergence of resistant strains.
Studies on the use of AMP for gastric cancer surgery are
limited. Recently, two randomized controlled trials have
demonstrated that a single use of intraoperative AMP is as
effective as extended postoperative use to prevent SSI after
gastric cancer surgery [8, 9]. However, these studies are
Gastroenterology Research and Practice
5
Table 4: Multivariate analysis of risk factors for SSI.
Age (years)
Male
BMI
Comorbidity
Preoperative albumin
Extracorporeal anastomosis
D2 LND
RYGJ
Omentectomy
Operating time
Operative blood loss
SSI preventive measures
Univariate
OR (95% CI)
1.04 (0.97–1.13)
1.29 (0.39–4.29)
1.16 (0.99–1.35)
0.66 (0.19–2.30)
0.14 (0.03–0.79)
16.55 (1.39–197.70)
7.62 (1.95–29.82)
0.17 (0.03–0.81)
1.01 (0.11–8.96)
0.99 (0.98–1.00)
1.01 (0.99–1.02)
0.24 (0.06–0.95)
p
0.281
0.676
0.073
0.516
0.025
0.027
0.004
0.026
0.992
0.166
0.151
0.043
Multivariate
Adjusted OR (95% CI)
p
1.19 (0.99–1.45)
0.058
0.45 (0.03–7.39)
78.70 (3.18–1948.98)
7.45 (1.15–48.06)
0.17 (0.02–1.48)
0.574
0.008
0.035
0.108
0.63 (0.11–3.79)
0.613
BMI: body mass index; LND: lymph node dissection; RYGJ: Roux-en-Y gastrojejunostomy; SSI: surgical site infection; OR: odds ratio; CI: confidence interval.
mostly limited to open surgery, and no previous studies have
appraised the true efficacy of AMP in laparoscopic gastrectomy. In this preliminary phase 2 trial, the incidence of SSI
after laparoscopic distal gastrectomy without AMP was
4.9% in the per-protocol group, which is comparable to previous studies and our historical data. Given that nearly half of
all gastric cancer patients are being treated with laparoscopic
approaches in our regions, we expect that the use of antibiotics could be significantly reduced if we can omit AMP for
laparoscopic gastrectomy.
AMP has long been the standard for preventing SSI.
However, preventing SSI does not entirely rely on antibiotics.
Preoperative bathing or showering with antiseptic soap is
considered a good clinical practice to ensure that the skin is
as clean as possible before surgery and reduces the bacterial
load, particularly at the site of incision [17]. Recent studies
suggest that attention to intraoperative temperature control
and supplemental oxygen administration may also decrease
the risk of SSI [12]. Theoretically, hypothermia and subsequent tissue hypoxia reduce oxidative killing by neutrophils
via reducing the availability of tissue oxygen and impairing
the production of reactive oxygen intermediates [18]. Hypothermia also increases the risk of infections by increasing
blood loss, thus, requiring blood transfusion [19]. Based on
these notions, we applied nonpharmacological prevention
measures to reduce SSI in patients without using AMP. As
a result, we found that these SSI prevention measures are
helpful for reducing the risk of SSI (OR = 0 24, 95%
CI = 0 06–0 95). The importance of nonpharmacological
measures to prevent SSI should be emphasized in the practice
of surgical care.
The incidence of infectious complications after laparoscopic cholecystectomy is extremely low and is significantly
lower compared to that after open surgery. A meta-analysis
of 15 randomized controlled trials evaluating AMP in elective
laparoscopic cholecystectomy showed no significance of
AMP in preventing SSI in low-risk patients undergoing
laparoscopic cholecystectomy [10]. Given this low risk of
SSI, current guidelines do not support routine use of AMP
in elective laparoscopic cholecystectomy [7]. Meanwhile,
advantages of laparoscopic gastrectomy, such as small incision, minimal tissue damage, and no exposure of abdominal
cavity, have also led to significantly lower incidences of SSI
(2% to 4%) compared to that in open gastrectomy [4–6]. Theoretically, gastrectomy and cholecystectomy are both classified as a clean-contaminated surgery, which means they
have a similar risk of SSI. However, we should be careful to
extrapolate the data from laparoscopic cholecystectomy to
gastrectomy because of the longer operating time and much
blood loss. Optimal AMP use should be guided based on the
clinical evidence considering different aspects of each type
of surgery. Therefore, we performed this study on the premise
that nonpharmacologic prevention measures would be
sufficient for preventing SSI in low-risk patients undergoing
laparoscopic distal gastrectomy.
There are a few limitations in this study. As we noted
earlier, the number of patients with protocol violations was
too high due to the lack of experience in early phases of the
study. As a result, per-protocol analysis may be underpowered due to a small sample size. Second, this study only
included low-risk patients in terms of age, comorbidity, and
nutrition status. Besides, participating institutions were
highly specialized centers that operate more than 200 cases
of gastric cancer per year. Finally, this is a preliminary phase
2 study that examined SSI incidence with historic controls. A
randomized controlled trial will be warranted to further
investigate the role of AMP in laparoscopic distal gastrectomy.
In conclusion, this study failed to show the target SSI rate
in patients undergoing laparoscopic distal gastrectomy for
gastric carcinoma. However, per-protocol analysis and risk
factor analysis showed the possibility that nonpharmacological SSI prevention measures might be sufficient to prevent
SSI when limited lymph node dissection and intracorporeal anastomosis are performed during laparoscopic distal
gastrectomy. Therefore, we believe more studies will be
warranted to test the feasibility of no AMP use in selected
patients undergoing laparoscopic distal gastrectomy for
gastric carcinoma.
6
Additional Points
Key Points. This phase 2 trial did not reach the target surgical
site infection rate without using antimicrobial prophylaxis
after laparoscopic distal gastrectomy. However, per-protocol
analysis showed that the surgical site infection rate was
acceptable without antimicrobial prophylaxis when intracorporeal anastomosis and limited lymph node dissection
were performed.
Conflicts of Interest
All authors (Oh Jeong, Mi Ran Jung, Seong Yeob Ryu,
Young-Kyu Park, Min Chan Kim, Ki Han Kim, Seung Wan
Ryu, Young Gil Son, and In Gyu Kwon) declare no conflicts
of interest.
Acknowledgments
This is a multicenter study performed by the Korean
Southwest East study group (K-SWEET). This study was supported by a grant (HCRI15009-1) at Chonnam National
University Hwasun Hospital Institute for Biomedical Science.
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Oncology
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Parkinson’s
Disease
Computational and
Mathematical Methods
in Medicine
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
AIDS
Behavioural
Neurology
Hindawi Publishing Corporation
http://www.hindawi.com
Research and Treatment
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Oxidative Medicine and
Cellular Longevity
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014