Research

JAMA Surgery | Original Investigation

Combined Surgery and Extensive Intraoperative

Peritoneal Lavage vs Surgery Alone for Treatment
of Locally Advanced Gastric Cancer
The SEIPLUS Randomized Clinical Trial
Jing Guo, MD; Aman Xu, MD; Xiaowei Sun, MD; Xuhui Zhao, MD; Yabin Xia, MD; Huamin Rao, MD;
Yaming Zhang, MD; Rupeng Zhang, MD; Li Chen, MD; Tao Zhang, MD; Gang Li, MD;
Hongtao Xu, MD; Dazhi Xu, PhD, MD

Invited Commentary page 616

IMPORTANCE Peritoneal metastasis is the most frequent pattern of postoperative recurrence Supplemental content
in patients with gastric cancer. Extensive intraoperative peritoneal lavage (EIPL) is a new
prophylactic strategy for treatment of peritoneal metastasis of locally advanced gastric
cancer; however, the safety and efficacy of EIPL is currently unknown.

OBJECTIVE To evaluate short-term outcomes of patients with advanced gastric cancer who
received combined surgery and EIPL or surgery alone.

DESIGN, SETTING, AND PARTICIPANTS From March 2016 to November 2017, 662 patients with
advanced gastric cancer receiving D2 gastrectomy were enrolled in a large, multicenter,
randomized clinical trial from 11 centers across China. In total, 329 patients were randomly
assigned to receive surgery alone, and 333 patients were randomly assigned to receive
surgery plus EIPL. Clinical characteristics, operative findings, and postoperative short-term
outcomes were compared between the 2 groups in the intent-to-treat population.

MAIN OUTCOMES AND MEASURES Short-term postoperative complications and mortality.

RESULTS The present analysis included data from 550 patients, 390 men and 160 women,
with a mean (SD) age of 60.8 (10.7) years in the surgery alone group and 60.6 (10.8) in the
surgery plus EIPL group. Patients assigned to the surgery plus EIPL group exhibited reduced
mortality (0 of 279 patients) compared with those assigned to surgery alone (5 of 271
patients [1.9%]) (difference, 1.9%; 95% CI, 0.3%-3.4%; P = .02). A significant difference in
the overall postoperative complication rate was observed between patients receiving surgery
alone (46 patients [17.0%]) and those receiving surgery plus EIPL (31 patients [11.1%])
(difference, 5.9%; 95% CI, 0.1%-11.6%; P = .04). Postoperative pain occurred more often
following surgery alone (48 patients [17.7%]) than following surgery plus EIPL (30 patients
[10.8%]) (difference, 7.0%; 95% CI, 0.8%-13.1%; P = .02).

CONCLUSIONS AND RELEVANCE Inclusion of EIPL can increase the safety of D2 gastrectomy
and decrease postoperative short-term complications and wound pain. As a new, safe,
and simple procedure, EIPL therapy is easily performed anywhere and does not require any
special devices or techniques. Our study suggests that patients with advanced gastric cancer
appear to be candidates for the EIPL approach.

TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02745509

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Dazhi Xu,
PhD, MD, Department of Gastric
Surgery, Sun Yat-sen University
Cancer Center, 651 East Dongfeng Rd,
JAMA Surg. 2019;154(7):610-616. doi:10.1001/jamasurg.2019.0153 Guangzhou 510060, China (xudzh
Published online March 27, 2019. @sysucc.org.cn).

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Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery for Locally Advanced Gastric Cancer
G
astric cancer, the fourth most commonly diagnosed
malignant neoplasm and the second leading cause of
cancer death, constitutes a major international health
problem.1,2 The standard treatment of gastric cancer after resec-
tion is chemotherapy. Peritoneal metastasis is the most frequent
pattern of postoperative recurrence in patients with gastric
cancer.3 The prognosis of patients with peritoneal metastasis re-
mains extremely poor. The median survival time of such patients
is 3 to 6 months.4
Peritoneal metastasis is caused by direct cancer cell dissemi-
nation from serosa-invasive tumors.2 Consequently, it is impor-
tant to prevent peritoneal metastasis before the fixation of free
cancer cells on the peritoneum.3 Two therapies are available to
prevent this condition: intraperitoneal chemotherapy (IPC) and
extensive intraoperative peritoneal lavage (EIPL).
Intraperitoneal chemotherapy was first described in 1980.4
It was used to treat peritoneal metastasis through locore-
gional chemotherapy and cytoreduction of numerous malig-
nant neoplasms.5-8 However, the value of IPC is still debated.6,8
Some studies have shown that IPC does not benefit the
progress of patients with advanced gastric cancer (AGC).
Moreover, the procedure is costly and associated with an in-
creased rate of postoperative complications.7,8
Recently, the use of EIPL, a new lavage method that is simi-
lar to the so-called limiting dilution approach, has been of con-
siderable interest in AGC.9,10 In 2009, Kuramoto et al11 re-
ported that EIPL plus IPC reduces the number of intraperitoneal
free cancer cells to potentially zero in patients with AGC. There-
fore, these researchers advocate EIPL therapy as an optimal
treatment protocol for AGC.4 However, the safety and effi-
cacy of EIPL for treatment of AGC has not been defined to date.
Currently, 3 multicenter randomized clinical trials (RCTs)
are ongoing to assess the value of EIPL as standard prophy-
lactic treatment of peritoneal recurrence of local AGC. These
studies are being conducted in Japan ([CCOG1102 RCT]12; a ran-
domized trial exploring the prognostic value of extensive in-
traoperative peritoneal lavage for resectable AGC), Singapore
([EXPEL RCT]13; extensive peritoneal lavage after curative gas-
trectomy for gastric cancer), and China ([SEIPLUS RCT]; EIPL
after curative gastrectomy for locally AGC).
In the present study, we aim to demonstrate the safety and
efficacy of EIPL. The overall survival of these patients is still
being assessed in the follow-up phase. We are scheduled to ana-
lyze the primary end point of 3-year overall survival in 2020.
Methods
Study Design and Participants
This was a multicenter parallel-group randomized trial. All
patients with local AGC from 11 participating hospitals in China
were screened for inclusion in the trial from March 2016 to No-
vember 2017. Eligibility criteria are given in the Box. The preop-
erative staging modalities included multidetector computed to-
mographic scans and ultrasonographic gastroscopy. The ethics
committees of every participating center provided ethical ap-
proval for the trial. All candidates provided written informed con-
sent. The study protocol is available in Supplement 1.
jamasurgery.com
© 2019 American Medical Association. All rights reserved.
Original Investigation Research
Key Points
Question How do the short-term outcomes following combined
surgery and extensive intraoperative peritoneal lavage compare
with those of open surgery alone for treatment of locally advanced
gastric cancer?
Findings In this multicenter randomized clinical trial that included
550 adults, the overall postoperative complication rate following
surgery alone (17%) was significantly higher than that following
combined surgery and lavage (11.1%). Patients receiving surgery
plus lavage also exhibited reduced mortality and postoperative
pain compared with those receiving surgery alone.
Meaning Patients may benefit from the addition of extensive
intraoperative peritoneal lavage with surgery for treatment of
locally advanced gastric cancer.
Box. Eligibility Criteria for Enrolling Patients
Preoperative Inclusion Criteria
Aged between 18 and 80 y
Eastern Cooperative Oncology Group performance status 0 or 1
Written informed consent
Open surgery
Preoperative evaluation of cT3/4NanyM0 according to the Ameri-
can Joint Committee on Cancer Staging Manual, seventh edition
Intraoperative Inclusion Criteria
Macroscopic appearance in exploratory laparotomy of cT3/
4NanyM0
R0 surgery
Exclusion Criteria
Previous neoadjuvant chemotherapy or radiotherapy
Peritoneal dissemination, distant lymph nodes, ovary, liver, lung,
brain, or bone metastases
Massive ascites or cachexia
Current participation in any other clinical trial
Severe cardiovascular, respiratory tract, kidney, liver, or psychiatric
disease or diabetes
Poor compliance
Randomization and Masking
Patients were randomized by the trial coordinator (D. Xu) at Sun
Yat-sen University Cancer Center, Guangzhou, China. Patients
were randomized to the EIPL plus surgery or the surgery alone
group in a 1:1 ratio (with a block size of 4). Randomization was
stratified by participating center. Allocation was performed using
sealed opaque envelopes that contained computer-generated ran-
dom numbers and the procedure to which patients were allocated.
Theenvelopeswereopenedafterexploratorylaparotomy.Patients
were blinded to their procedure. Intent-to-treat analysis was used
for all participants who met the inclusion criteria.
Patients were excluded after randomization only if stage T1,
T2, or M1 disease was detected as a histopathologic result. Data
from 550 patients with a pathologic depth of invasion confined
to the subserosal or serosal layer (pT3/4NanyM0) were analyzed.
(Reprinted) JAMA Surgery July 2019 Volume 154, Number 7 611
 Research Original Investigation Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery for Locally Advanced Gastric Cancer
Figure. CONSORT Diagram of Patient Flow
662 Patients randomized
329 Randomized to receive 333 Randomized to receive
surgery surgery plus EIPL
58 Ineligible 54 Ineligible
49 T1/T2 disease 44 T1/T2 disease
9 M1 disease 10 M1 disease
271 Eligible 279 Eligible
550 Completed surgery with
curative intent
550 Included in modified
intention-to-treat analysis
EIPL indicates extensive intraoperative peritoneal lavage.
The American Joint Committee on Cancer Staging Manual, sev-
enth edition, criteria for gastric cancer staging was used for TNM
classification.14 The Borrmann classification was provided as a
baseline characteristic of the intention-to-treat population.15
Procedures
All patients had open curative D2 gastrectomy and achieved
margin-negative (R0) resection. Depending on the location of
the primary tumor, surgeons (A.X., X.S., X.Z., Y.X., H.R., Y.Z.,
R.Z., L.C., T.Z., G.L., H.X., and D.X.) performed either total,
proximal subtotal, or distal subtotal gastrectomy. The D2 gas-
trectomy was defined by the guidelines of the Japanese Re-
search Society for the Study of Gastric Cancer.16 Before the start
of the study, standard operating procedures were predefined
and given to all surgeons to ensure the quality of the surgical
procedure. All surgeons had sufficient experience for D2 gas-
trectomy (>100 procedures per year at each institute).
After the potentially curative operation, EIPL was per-
formed. Patients assigned to the surgery alone group re-
ceived conventional peritoneal lavage using less than 3 L of
physiological saline (<3 times). Patients assigned to the EIPL
group received EIPL using 10 L of physiological saline (1 L for
10 times). Every time, the peritoneal cavity was stirred and
washed, and the fluid was completely aspirated.
All patients were recommended to undergo eight 3-week
cycles of oral S-1 (40 mg/m2 twice daily on days 1-14 of each
cycle) plus intravenous oxaliplatin (100 mg/m2 on day 1 of each
cycle) postoperatively. Patients received chemotherapy for 2
weeks (days 1-14), followed by 1 week of no chemotherapy (days
15-21). Dose reductions or interruptions were used to manage
potentially serious or life-threatening adverse events.
Outcomes
The end points reported herein are short-term postoperative
complications and mortality. During the preoperative, intraop-
erative, and postoperative periods, all patients were observed
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and the observations recorded. Mortality (death within 30 days
of the operation or during a hospital stay), complications (eg, il-
eus, abscess, hemorrhage, and leakage), laboratory and patho-
logic findings, abdominal pain, time to first flatus, and length of
hospital stay were evaluated. Major bleeding was defined as an
amount of hemorrhage exceeding 300 mL. Ileus, abscess, and
leakage were diagnosed by clinical suspicion and postopera-
tive radiologic examination. The Clavien-Dindo classification was
used to assess the severity of postoperative complications.17 Pain
intensity was assessed postoperatively using a numerical rat-
ing scale that ranged from 0 to 10 (0, no pain; 1-3, mild pain
[nagging, annoying, interfering little with daily living activi-
ties]; 4-6, moderate pain [substantially interfering with daily liv-
ing activities]; 7-10, severe pain [disabling; unable to perform
daily living activities]). In this trial, pain was defined as greater
than 3 on the scale, which was considered to potentially affect
emotional or physical functioning.18
Statistical Analysis
This study was designed to assess the superiority in terms of
overall survival of combining surgery and EIPL compared with
surgery alone. We calculated using the log-rank test with a
2-sided α level of .05 and a power of 80% that 254 patients were
needed in each group to detect a difference in 3-year overall
survival of 60% for the surgery alone group and 71% for the
EIPL plus surgery group.
The differences between groups were compared using χ2
tests and t tests. All P values calculated in the analysis were
2-sided, and P < .05 was considered statistically significant. Sta-
tistical analyses were performed using SPSS software, ver-
sion 17.0 (IBM Corporation).
Results
From March 2016 to November 2017, we enrolled and ran-
domly assigned 662 patients from 11 centers in China, with 329
patients assigned to the surgery alone group and 333 as-
signed to the surgery plus EIPL group. The reasons for exclu-
sion after randomization were stage IV cancer (including 11 pa-
tients with peritoneal metastasis, 6 patients with distance
lymphatic metastasis, and 2 patients with liver metastasis) and
T1/T2 cancers (93 patients) (Figure).
The present analysis included 550 patients (390 men and
160 women) who underwent surgery alone (n = 271) or sur-
gery plus EIPL (n = 279), with a mean (SD) age of 60.8 (10.7)
years in the surgery alone group and 60.6 (10.8) in the sur-
gery plus EIPL group. Table 1 indicates that the baseline clini-
cal characteristics of the 550 patients were well balanced be-
tween the intervention groups.
The surgical outcomes are presented in Table 2. Total and
distal gastrectomy procedures were performed in a large pro-
portion of patients (95.6%): 138 total, 122 distal, and 11 proxi-
mal gastrectomy procedures were performed in the surgery alone
group, and 139 total, 127 distal, and 13 proximal gastrectomy pro-
cedures were performed in the surgery plus EIPL group. No sig-
nificant differences were observed between the 2 groups with
respect to time to first flatus and postoperative hospital stay.
jamasurgery.com
 Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery for Locally Advanced Gastric Cancer Original Investigation Research

Whereas 5 deaths occurred in the surgery alone group

Table 1. Baseline Characteristics of the Intention-to-Treat Population
(1 patient died of intra-abdominal bleeding, 3 patients died of
respiratory failure, and 1 patient died of heart failure), zero Patients, No.
deaths occurred during the study period in the surgery plus Surgery Alone Surgery Plus EIPL
Characteristic (n = 271) (n = 279) P Value
EIPL group across the various centers (difference, 1.9%; 95% Age, mean (SD), y 60.8 (10.7) 60.6 (10.8) .87
CI, 0.3%-3.4%; P = .02) (Table 3).
Sex
Postoperative abdominal pain occurred more frequently
Male 196 194
in the surgery alone group (48 of 271 patients [17.7%]) com- .47
Female 75 85
pared with the surgery plus EIPL group (30 of 279 patients
Smoking status
[10.8%]) (difference, 7.0%; 95% CI, 0.8%-13.1%; P = .02).
Yes 81 91
Among 550 patients undergoing gastrectomy, 77 (14%) expe- .49
No 190 188
rienced at least 1 postoperative complication. A significant dif-
BMI, mean (SD) 21.97 (3.01) 22.16 (3.42) .47
ference in the postoperative complication rate was observed
Tumor location
between the surgery alone group (46 of 271 patients [17.0%])
and the surgery plus EIPL group (31 of 279 patients [11.1%]) (dif- Upper third 85 81

ference, 5.9%; 95% CI, 0.1%-11.6%; P = .04). Compared with Middle third 75 72
.78
the group of 271 patients receiving surgery alone, the group Lower third 101 116
of 279 patients receiving surgery plus EIPL showed de- Total 10 10
creased morbidity due to ileus (17 patients [6.3%] vs 14 pa- Tumor size, mean (SD), cm 5.27 (3.02) 5.25 (2.49) .91
tients [5.0%]), intra-abdominal abscess (5 patients [1.9%] vs Pathologic T category
2 patients [0.7%]), intra-abdominal bleeding (7 patients T3 72 71
.77
[2.6%]% vs 3 patients [1.1%]), wound problems (7 patients T4 199 208
[2.6%] vs 5 patients [1.8%]), deep vein thrombosis 2 patients Pathologic N category
[0.7%] vs 0 patients), and cardiac (2 patients [0.7%] vs 0 pa- N0 50 47
tients) and pulmonary (9 patients [3.3%] vs 7 patients [2.5%]) N1 49 61
disease postoperatively (Table 3). .73
N2 72 70
N3 100 101
Borrmann classificationa

Discussion
Previously, Kuramoto et al11 showed that EIPL plus IPC could
improve the survival of patients with AGC. However, given that
the role of IPC in AGC is debated, our intervention group in-
volved only an EIPL component, without IPC. Another differ-
ence between their study and the present study is that they
only recruited 88 patients with cytology-positive peritoneal
lavage fluid.
The findings in the present study indicated that EIPL de-
creased the incidence of postoperative complications. For ex-
ample, there were more cases of intra-abdominal abscess in
the surgery alone group (5 patients [1.9%]) compared with the
surgery plus EIPL group (2 patients [0.7%]). On the basis of pre-
vious clinical trial reports, the rate of intra-abdominal ab-
scess is 1.3% to 17% after stomach surgery, which is higher than
that observed for the surgery plus EIPL group in the present
study.19-21
Indeed, EIPL appears to be a new and useful technique to
minimize the risk of surgical infection. In contrast to the con-
ventional lavage method, EIPL is performed 10 times using
1 L of physiological saline.22,23 The technique can largely re-
duce the amount of intraperitoneal damaged tissue and wound
exudate and clean the peritoneal cavity, similar to the so-
called limiting dilution method.23
We also found that EIPL significantly decreased postop-
erative pain. The reason for the decrease in pain might be re-
lated to a reduction in the inflammatory response. Pain per-
ception is often triggered by local release of cytokines from
inflammatory cells and is a clinical reflection of tissue dam-
I 14 13
II 86 85
.53
III 141 159
IV 30 22
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided
by height in meters squared); EIPL, extensive intraoperative peritoneal lavage.
a
The Borrmann classification scheme is explained in Kim et al.15
age and the inflammatory response.23,24 Schwarz et al25 and
Kalff et al26 also found a postoperative inflammatory field-
effect phenomenon within the manipulated gastrointestinal
tract. Peritoneal lavage can remove bacterial materials, pro-
moting proinflammatory cytokines.23,24 Notably, the use of
EIPL with 1 L of saline for 10 rounds of washing and stirring of
the abdominal cavity would be likely to remove metabolic
waste and tissue debris that may enhance local inflammation.4
In addition, the rate of ileus in the EIPL group appeared
lower than that in the surgery alone group. This finding is con-
sistent with published results that indicate that a reduction in
the postoperative inflammatory reaction could avoid adhe-
sion formation that results in ileus.27,28
Whereas no deaths occurred in the surgery plus EIPL group,
5 deaths occurred in the surgery alone group during the study
period. Three patients died of respiratory failure, and 1 pa-
tient died of heart failure. We considered these deaths to be
associated with upregulation of the inflammatory reaction and
postoperative pain.29 Tsui et al30 also found that controlled pain
could decrease pulmonary and cardiovascular complications
along with postoperative mortality.

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 Research Original Investigation Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery for Locally Advanced Gastric Cancer

Table 2. Surgical Outcomes Following Surgery Alone or Surgery With EIPL

Mean (SD) Values

Surgery Alone Surgery Plus EIPL Between-Group Difference
Outcome (n = 271) (n = 279) (95% CI) P Value
Gastrectomy, No. (%)
Total 138 (50.9) 139 (49.8)
Distal 122 (45.0) 127 (45.5)
Proximal 11 (4.1) 13 (4.7)
Additional organ resection, No. 10 (3.7) 15 (5.4)
Time to first flatus, d 4.32 (1.41) 4.19 (1.20) 0.13 (−0.09 to 0.35) .26
Postoperative hospital stay, d 18.47 (5.86) 18.54 (5.89) −0.07 (−1.06 to 0.92) .89
Postoperative laboratory results
White blood cell count, /μL 11 880 (3580) 12 130 (4290) −250 (−910 to 410) .46 Abbreviation: EIPL, extensive
Neutrophil count, /μL 12 570 (14 630) 11 600 (11 210) 960 (−1230 to 3150) .39 intraoperative peritoneal lavage.
Neutrophil lymphocyte ratio 20.1 (31.2) 21.3 (50.1) −1.2 (−8.3 to 5.8) .73 SI conversion factors: To convert
white blood cell and neutrophil
Hemoglobin, g/dL 11.1 (1.9) 11.1 (2.4) 0.04 (−0.3 to 0.4) .82
counts to ×109 per liter, multiply by
Platelet, ×103/μL 196 (84) 197 (75) −1.6 (−14.8 to 12.0) .84 0.001; hemoglobin level to grams per
Albumin, g/dL 3.3 (8.7) 3.2 (5.1) 0.06 (−0.06 to 0.17) .37 liter, by 10; platelet count to ×109 per
liter, by 1; and albumin level to grams
Albumin globulin ratio 1.4 (0.5) 1.4 (0.3) 0.04 (−0.03 to 0.11) .25
per liter, by 10.

Table 3. Postoperative Complications and Mortality

Patients, No. (%)

Surgery Alone Surgery and Between-Group
Complication (n = 271) EIPL (n = 279) Difference, % (95% CI) P Value
Mortality 5 (1.9) 0 1.9 (0.3 to 3.4) .02
Abdominal pain 48 (17.7) 30 (10.8) 7.0 (0.8 to 13.1) .02
Patients with at least 1 postoperative complication 46 (17.0) 31 (11.1) 5.9 (0.1 to 11.6) .04
Ileus 17 (6.3) 14 (5.0)
Intra-abdominal abscess 5 (1.9) 2 (0.7)
Intra-abdominal bleeding 7 (2.6) 3 (1.1)
Wound problem 7 (2.6) 5 (1.8)
Anastomotic leakage 1 (0.4) 2 (0.7)
Pancreatic leakage 1 (0.4) 1 (0.4)
Anastomotic stenosis 1 (0.4) 0
Cardiac disease 2 (0.7) 0
Deep vein thrombosis 2 (0.7) 0
Pulmonary disease 9 (3.3) 7 (2.5)
Clavien-Dindo classificationa
I/II 43 (15.9) 30 (10.8) 5.1 (−0.5 to 10.7) .08 Abbreviation: EIPL, extensive
intraoperative peritoneal lavage.
III/IV 3 (1.1) 1 (0.4) 0.7 (−0.7 to 2.1) .30
a
The Clavien-Dindo classification
V 5 (1.9) 0 1.9 (0.3 to 3.4) .02
scheme is explained in Dindo et al.17

In the present study, 1 patient died of intra-abdominal bleed-
ing in the surgery alone group. We also observed more intra-
abdominal bleeding cases (7 patients [2.58%]) in the surgery alone
group compared with the EIPL group (3 patients [1.08%]). The
use of EIPL may identify potential bleeding more easily via suf-
ficient stirring and washing of the abdominal cavity.
Limitations
The present study has several limitations. First, the quality of
the study may be decreased because 112 (16.9%) patients were
excluded owing to T1, T2 or M1 disease. However, the balance
was essentially unchanged in the 2 groups. Second, no objec-
tive inflammatory reaction measure was collected. Future stud-
ies could be designed to include in vitro and in vivo measures
that would elucidate changes in inflammatory mechanisms as-
sociated with this new technique.
Conclusions
To our knowledge, this study is the first to show that EIPL sig-
nificantly reduced short-term postoperative complications,
wound pain, and mortality associated with D2 gastrectomy. In-
cluding EIPL can increase safety and result in early recovery
postoperatively. As a new, safe, and simple procedure, EIPL
therapy is easily performed anywhere and does not require any
special devices or techniques. Thus, EIPL is a promising and
exciting therapeutic strategy for patients with AGC.

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 Research Invited Commentary Extensive Intraoperative Peritoneal Lavage to Prevent Metastases

postoperative C-reactive protein concentrations:
a RCT. Gynecol Surg. 2015;12(4):271-274. doi:10.
1007/s10397-015-0897-1
25. Schwarz NT, Kalff JC, Türler A, et al. Selective
jejunal manipulation causes postoperative
pan-enteric inflammation and dysmotility.
Gastroenterology. 2004;126(1):159-169. doi:10.1053/
j.gastro.2003.10.060
26. Kalff JC, Carlos TM, Schraut WH, Billiar TR,
Simmons RL, Bauer AJ. Surgically induced
leukocytic infiltrates within the rat intestinal
muscularis mediate postoperative ileus.
Gastroenterology. 1999;117(2):378-387. doi:10.
1053/gast.1999.0029900378
27. Corona R, Verguts J, Schonman R, Binda MM,
Mailova K, Koninckx PR. Postoperative
inflammation in the abdominal cavity increases
adhesion formation in a laparoscopic mouse model.
Fertil Steril. 2011;95(4):1224-1228. doi:10.1016/j.
fertnstert.2011.01.004
28. Sortini D, Feo CV, Maravegias K, et al. Role of
peritoneal lavage in adhesion formation and
survival rate in rats: an experimental study. J Invest
Surg. 2006;19(5):291-297. doi:10.1080/
08941930600889409
29. Kalff JC, Schraut WH, Billiar TR, Simmons RL,
Bauer AJ. Role of inducible nitric oxide synthase in
postoperative intestinal smooth muscle
dysfunction in rodents. Gastroenterology. 2000;118
(2):316-327. doi:10.1016/S0016-5085(00)70214-9
30. Tsui SL, Law S, Fok M, et al. Postoperative
analgesia reduces mortality and morbidity after
esophagectomy. Am J Surg. 1997;173(6):472-478.
doi:10.1016/S0002-9610(97)00014-7

Invited Commentary

Extensive Intraoperative Peritoneal Lavage to Prevent

Metastases From Gastric Cancer
The Elegance of Simplicity
Edward A. Levine, MD

Gastric cancer is the second leading cause of death from can-
cer worldwide.1 Consequently, prevention of peritoneal me-
tastases after resection2 remains a substantial clinical need.
Gastric cancer is more likely than other gastrointestinal ma-
lignant neoplasms to metas-
Related article page 610
tasize to peritoneal sites, and
survival with peritoneal me-
tastases is less than a year. Although systemic therapy for
gastric cancer has improved, it has not prevented peritoneal
dissemination. There has been interest in intraperitoneal ap-
proaches to preventing peritoneal dissemination since the
1980s.3 Hyperthermic intraperitoneal chemotherapy follow-
ing radical gastrectomy initially found promising results in ran-
domized trials.3,4 However, methodologic flaws and long-
term follow-up did not bring this into common practice. An
elegantly simple approach of extensive intraoperative perito-
neal lavage (EIPL) was suggested to decrease gastric cancer cells
shed into the operative field.5 That study found substantially
improved outcomes with EIPL and intraperitoneal cisplatin vs
intraperitoneal therapy and surgery alone.
In this issue of JAMA Surgery, initial findings for the
SEIPLUS study are reported.6 The study randomized 662 pa-
tients (550 evaluable) to EIPL (ten 1-L lavages with saline) vs
conventional lavage (<3 L total) after D2 radical gastrectomy
for (T3/4NanyM0) gastric cancers. All patients were recom-
mended to receive postoperative systemic chemotherapy with
8 cycles of S-1 and oxaliplatin.
This accrual occurred over a remarkably short period of 14
months at 11 high-volume centers with experienced surgeons
in China. Outcome measures are 3-year overall survival, dis-
ease-free survival, and short-term outcomes. The article de-
scribes the short-term outcomes, as we must wait at least un-
til 2020 for survival outcomes. Overall, less than 1% mortality,
even with more than half of the patients having total gastrec-
tomy, and leak rates of less than 1% speak to the high quality
of the surgical procedures performed in this trial.
Compared with the group receiving surgery alone, those
who also received EIPL had significantly less abdominal pain
(6.9%), fewer postoperative complications (5.9%), and 0% mor-
tality (vs 1.9% with surgery alone). The authors attributed these
results to less inflammation. Although using EIPL will “re-
duce the amount of intraperitoneal damaged tissue and wound
exudate and clean the peritoneal cavity,” the effect on out-
come may be more modest than hoped.6 The complications
were nearly all minor (about 95% Clavien-Dindo class I/II), and
4 of the 5 mortalities were from cardiorespiratory failure, not
intra-abdominal causes.
The decrease in abdominal pain assessed with a numeri-
cal scale is impressive. Furthermore, the improvements in
short-term outcomes were achieved with a total cost of ap-
proximately $20, making it the least expensive parenteral an-
algesic I know of. The key to this trial will be the forthcoming
long-term oncologic outcomes. However, EIPL is elegant in its
simplicity, safety, and low cost, and it has the potential to de-
crease the incidence of dreaded peritoneal metastases in the
long-term. Congratulations to the authors for this ambitious
randomized trial. We should eagerly look forward to the long-
term outcomes.

ARTICLE INFORMATION Corresponding Author: Edward A. Levine, MD, Published Online: March 27, 2019.
Author Affiliation: Surgical Oncology, Wake Forest Surgical Oncology, Wake Forest University, Medical doi:10.1001/jamasurg.2019.0154
University, Winston-Salem, North Carolina. Center Blvd, Winston-Salem, NC 27157 (elevine@ Conflict of Interest Disclosures: None reported.
wakehealth.edu).

616 JAMA Surgery July 2019 Volume 154, Number 7 (Reprinted) jamasurgery.com

© 2019 American Medical Association. All rights reserved.

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