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Benefits of intraoperative systemic chemotherapy during curative surgery for patients with locally advanced gastric
cancer
MENG Qing-bin, MD, YU Jian-chun, MD*, MA Zhi-qiang, MD, KANG Wei-ming, MD, ZhOU Li, MD, and YE Xin, MD
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking
Union Medical College, Beijing 100730, PR China
*Correspondence to: Dr. YU Jian-chun, Department of General Surgery, Peking Union Medical College Hospital, Chinese
Academy of Medical Science and Peking Union Medical College, No. 1 Shuai Fu Yuan, Dongcheng District, 100730 Beijing,
PR China
Tel: +86-10-69156038; Fax: +86-10-69156038; E-mail: [email protected]
Financial support: This study was supported by the Innovation Fund from the Chinese Academy of Medical Science and
Peking Union Medical College (Grant No. X2010028).
The authors have no conflicts of interest to declare.
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Key Words: stomach neoplasms; chemotherapy; R0 resection; D2 lymphadenectomy; survival
Abstract
Background: There is little information on the impact of intraoperative systemic chemotherapy on gastric cancer. The aim of
this study was to identify prognostic factors in patients with locally advanced gastric cancer undergoing curative resection,
with a focus on evaluating the survival benefit and tolerance of intraoperative systemic chemotherapy.
Methods: We retrospectively analyzed clinicopathological data for 264 consecutive patients who underwent curative resection
for gastric cancer at Peking Union Medical College Hospital from January 2002 to January 2007. Survival curves were plotted
using the Kaplan-Meier method and compared using log-rank tests. Univariate and multivariate analyses were performed with
the Cox proportional hazard model.
Results: Patients who received intraoperative systemic chemotherapy had higher 5-year overall survival and 5-year
disease-free survival rates (P = 0.019 and 0.010, respectively) than those of patients who did not receive intraoperative
systemic chemotherapy. In the subgroup analysis, systemic intraoperative chemotherapy benefited the 5-year overall survival
and disease-free survival rates of patients with stage pTNM IB-IIIB, but not stage pTNM IIIC, cancer. Patients who received
intraoperative systemic chemotherapy in combination with postoperative chemotherapy had higher 5-year overall survival and
5-year disease-free survival rates (P = 0.046 and 0.021, respectively) than those of patients who only received postoperative
chemotherapy. However, the difference in these rates between patients who received only intraoperative systemic
chemotherapy and patients who only received curative surgery was not statistically significant (P = 0.150 and 0.170,
respectively). Multivariate analyses showed that intraoperative systemic chemotherapy was a favorable prognostic factor for
the overall survival and disease-free survival rates (P = 0.048 and 0.023, respectively). No grade 4 toxicities related to
intraoperative systemic chemotherapy were recorded within 4 weeks after surgery.
Conclusions: Intraoperative systemic chemotherapy during curative surgery may benefit patients with stage pTNM IB-IIIB
gastric cancer in terms of both overall survival and disease-free survival.
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Introduction
The overall age-standardized incidence rate of gastric cancer in China is more than 29.9 per 100,000 per year.1 Radical
gastrectomy (R0 resection) with D2 lymphadenectomy is the standard treatment for curable gastric cancer in eastern Asia, but
patients undergoing curative surgery are still at risk of recurrence originating from minimal residual disease. 2,3 In addition,
surgical maneuvers can result in hematogenous metastasis.4 In these circumstances, multimodal treatment may improve
survival compared with surgery alone.5,6
Fisher et al. investigated the influence of the interval between primary tumor removal and chemotherapy on the kinetics and
growth of metastases and found that chemotherapy administered at the time of or before primary tumor removal was most
effective in controlling metastases.7 However, the role of intraoperative systemic chemotherapy for gastric cancer has rarely
been reported in the English literature, with the exception of the study of Lelcuk et al., who used intravenous 5-fluorouracil
(5-FU) during surgery when advanced cancer was detected.8 Since January 2002, many patients with locally advanced gastric
cancer have received intraoperative systemic chemotherapy in the Department of General Surgery, Peking Union Medical
College Hospital (PUMCH). However, the outcomes have not been analyzed statistically.
This study therefore aimed to identify the prognostic factors in patients with local advanced gastric cancer undergoing curative
resection, with a focus on evaluating the safety and efficacy of intraoperative systemic chemotherapy during curative surgery
in patients with gastric cancer.
METHODS
Patients
A total of 619 patients underwent surgery for gastric cancer in PUMCH from January 2002 to January 2007. The medical
records of these patients were reviewed to determine if they met the following inclusion criteria: (1) locally advanced gastric
cancer confirmed by postoperative histopathology, including AJCC pT2, pT3, and pT4a; (2) radical gastrectomy (R0 resection)
with D2 lymphadenectomy, with R0 resection being defined as no gross or microscopic residual tumor 9; and (3) no severe
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uncontrolled co-morbidities. Exclusion criteria were defined as follows: (1) gastric stump cancer, (2) histopathology-proven
neuroendocrine carcinoma or squamous-cell carcinoma, (3) fewer than 15 lymph nodes harvested, (4) neoadjuvant
chemotherapy or radiotherapy, (5) postoperative radiotherapy, and (6) unavailable or inaccurate medical records. A total of 264
patients were finally included in the study (Figure 1).
Variables
The following clinicopathological features of the patients were reviewed: sex, age, WHO performance status, anemia, tumor
location, tumor size, histological type, lymphovascular invasion, American Joint Committee on Cancer (AJCC) pT stage of the
primary tumor, and AJCC pN stage. A pathologist reassessed all primary slides and primary diagnostic reports of 264 patients
to confirm the previous diagnosis. The tumor location was classified according to the Japanese classification of gastric
carcinoma, 3rd English edition.9 The tumor (T) status and node (N) status were reclassified according to the 7th edition of the
AJCC tumor-node-metastasis (TNM) classification for carcinoma of the stomach. 10
Treatments
All patients underwent curative (R0) resection and D2 lymphadenectomy as a primary treatment. The criteria utilized for
selecting patients to receive intraoperative systemic chemotherapy were as follows: (1) patients with locally resectable
advanced gastric cancer, (2) histopathology-proven adenocarcinoma and/or signet ring cell carcinoma, (3) no severe
uncontrolled co-morbidities, and (4) agreement to undergo the treatment and sign an informed consent form.
Intraoperative systemic chemotherapy was administered with intravenous 5-FU 600 mg/m2 (maximum, ≤1000 mg), leucovorin
200 mg, mitomycin 5 mg/m2, and epirubicin 20 mg/m2.
Three main postoperative chemotherapy regimens were used in this study: the XELOX, FOLFOX4, and FOLFOX6 regimens.
Toxicity associated with intraoperative systemic chemotherapy was graded according to the National Cancer Institute
Common Toxicity Criteria, Version 2.0.11
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End points
The primary end point was overall survival (OS), which was defined as the period from the completion of curative
gastrectomy to death from any cause. The secondary end point was disease-free survival (DFS), defined as the period from the
completion of curative gastrectomy to first recurrence of gastric cancer or death from any cause. Patients lost to follow-up or
still alive at the end of the study were censored at the date they were last known to be alive.
Follow-up
All patients were followed up from the date of surgery to death, emigration, or October 10, 2011, whichever came first.
Patients were seen every 3 to 6 months for the first 3 years, then every 6 to 12 months thereafter. The survival data were
obtained based on both the patients’ records and telephone follow-up.
History, physical examination, whole blood count, and serum tumor markers (CEA and CA19-9) were routinely performed.
Computed tomography (CT) examinations were performed every 12 months during the first 3 years. CT, bone scintigraphy,
gastroscopy with biopsy, or positron emission tomography was performed if cancer recurrence was suggested by symptoms.
Statistical analysis
The chi-square test was used to compare differences between categorical variables. OS and DFS curves were constructed using
the Kaplan-Meier method,12 and differences between the curves were compared using the log-rank test. Univariate and
multivariate analyses were performed with the Cox proportional hazard model. Variables identified as potentially important by
univariate analysis were included in multivariate analysis. Proportional hazards assumption was roughly determined by
observing the log-minus-log curve. All analyses were performed using SPSS 12.0 (SPSS, Chicago, Illinois, USA). All P values
were two-sided, and P values of <0.05 were considered to be statistically significant.
The study was approved by the Ethics Committee of PUMCH, Chinese Academy of Medical Science and Peking Union
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Medical College, Beijing, China (No. 7-662).
RESULTS
Descriptive data
The median age of the 264 patients was 60 years (range, 27–83). There were 86 women and 178 men. The majority of patients
(84.1%) had poorly differentiated adenocarcinoma and/or signet ring cell carcinoma. All patients underwent gastrectomy and
D2 lymphadenectomy. A total of 149 patients received intraoperative systemic chemotherapy, and 196 patients received
postoperative chemotherapy. One hundred and eleven patients from the intraoperative systemic chemotherapy group received
postoperative chemotherapy, 90 (81.1%) of whom completed no more than 6 cycles. Eighty-five patients from the
non-intraoperative systemic chemotherapy group received postoperative chemotherapy, 70 (82.4%) of whom completed at
least 6 cycles.
The clinicopathological characteristics and treatments of patients are summarized in Table 1. There were no statistically
significant differences in the distribution of gender, age, WHO performance status, anemia, tumor size, tumor location,
histological type, lymphovascular invasion, AJCC pT stage, AJCC pN stage, postoperative chemotherapy, or cycles of
postoperative chemotherapy between the intraoperative systemic chemotherapy group and non-intraoperative systemic
chemotherapy group (Table 1).
After a median follow-up of 52 months (range, 1–114), there were 79 deaths in the systemic intraoperative chemotherapy
group and 75 deaths in the non-systemic intraoperative chemotherapy group. The estimated 5-year OS and 5-year DFS rates
for all patients were 46.1% and 42.8%, respectively. No treatment-related deaths or life-threatening events were reported
within 1 month after surgery with the exception of one patient in the intraoperative systemic chemotherapy group who died of
cardiac problems.
Intraoperative chemotherapy as a prognostic factor
Patients who received systemic intraoperative chemotherapy (n = 149) had a higher 5-year OS rate than that of patients who
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did not receive systemic intraoperative chemotherapy (n = 115) (53.0% vs. 37.3%, respectively; P = 0.019) (Figure 2), as well
as a higher 5-year DFS rate (48.3% vs. 35.8%, respectively; P = 0.010) (Figure 3). In the subgroup analysis, systemic
intraoperative chemotherapy benefited the 5-year OS of patients with stage pTNM Ib-II (80.2% vs. 51.0%, P = 0.012) and
pTNM IIIA-B (28.2% vs. 47.9%, P = 0.039) cancer, but not stage pTNM IIIC cancer (13.9% vs. 28.2% P = 0.388); systemic
intraoperative chemotherapy benefited the 5-year DFS of patients with stage pTNM Ib-II (73.6% vs. 48.9%, P = 0.009) and
pTNM IIIA-B (28.2% vs. 43.9%, P = 0.044) cancer, but not stage pTNM IIIC cancer (11.1% vs. 25.3% P = 0.626). Patients
who received both intraoperative systemic chemotherapy and postoperative chemotherapy (n = 110) had a higher 5-year OS
rate than that of patients who only received postoperative chemotherapy (n = 86) (53.4% vs, 42.5%, P = 0.046), as well as a
higher 5-year DFS rate (51.8% vs. 40.0%, P = 0.021). However, the difference in the 5-year OS rate between the patients who
received only intraoperative systemic chemotherapy (n = 39) and patients who only received curative surgery (n = 29) was not
statistically significant (51.3% vs. 21.6%, P = 0.150); neither was the 5-year DFS rate (38.5% vs. 21.6%, P = 0.170).
Univariate and multivariate analyses of factors affecting survival
Univariate analysis identified tumor location, lymphovascular invasion, AJCC pT stage, AJCC pN stage, intraoperative
systemic chemotherapy, and postoperative chemotherapy as being significantly associated with both OS and DFS (Table 2).
Tumor size was only associated OS (Table 2).
Multivariate analysis showed that tumor location (P = 0.019 and P = 0.027), pT stage (P = 0.023 and P = 0.042), pN stage (P
< 0.001 and P < 0.001), lymphovascular invasion (P = 0.028 and P = 0.026), intraoperative systemic chemotherapy (P =
0.048 and P = 0.023) and postoperative chemotherapy (P < 0.001 and P < 0.001) were independent factors for predicting OS
and DFS rate (Table 3). Tumor size lost independence in the prediction of survival rates by multivariate analysis.
Adverse events
No adverse events associated with intraoperative systemic chemotherapy occurred during surgery, and no grade 4 toxicities
related to intraoperative systemic chemotherapy were recorded. Grade 1–3 hematologic toxicities included anemia (24.2%)
and leukopenia (3.4%), and grade 1–3 gastrointestinal toxicities included nausea/vomiting (3.4%) and diarrhea (1.3%). Other
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adverse events and perioperative complications in the two groups are shown in Table 4.
DISCUSSION
Although several clinical trials have established multimodal treatments including perioperative chemotherapy, surgery, and
postoperative chemotherapy as relatively standard therapy for gastric adenocarcinoma or gastroesophageal junction
adenocarcinoma,5,13-17 the role of intraoperative systemic chemotherapy for locally advanced gastric cancer has rarely been
reported.
Many patients with locally advanced gastric cancer in the Department of General Surgery, Peking Union Medical College
Hospital have received intraoperative systemic chemotherapy since January 2002. The current study demonstrated a survival
benefit associated with the use of intraoperative systemic chemotherapy during curative surgery for locally advanced gastric
cancer, with an estimated 15.7% improvement in the 5-year OS rate and a 12.5% improvement in the 5-year DFS rate. In the
subgroup analysis, systemic intraoperative chemotherapy benefited the 5-year OS and DFS of patients with stage pTNM Ib-II
and pTNM IIIA-B cancer, but not stage pTNM IIIC cancer.
Patients who received both intraoperative systemic chemotherapy and postoperative chemotherapy had a higher 5-year OS rate
than that of patients who only received postoperative chemotherapy. However, the difference in the 5-year OS and 5-year DFS
rates between patients who received systemic chemotherapy during curative surgery and patients who only received curative
surgery was not statistically significant. The sample size must be expanded to verify this in future studies.
Multivariate analysis showed that intraoperative systemic chemotherapy is an independently favorable factor in patients who
can undergo curative surgery for locally advanced gastric cancer. Results showed that it does not significantly increase the
incidence of perioperative complications and is not associated with significant toxicity, in accordance with the results of
Lelcuk et al.8
Intraoperative systemic chemotherapy may result in less favorable growth kinetics of micrometastatic disease. Previous studies
found that surgical removal changed the growth and kinetics of residual tumors or metastases. 18,19 Gunduz et al. showed that
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surgical removal of the primary tumor resulted in an increase in the labeling index and growth rate of the residual tumor, with
minimal changes in the cell cycle.19 An animal study conducted by Fisher et al. suggested that chemotherapy was most
effective in controlling metastases when administered at the time of or before primary tumor removal.7 Overall, these findings
provide a biological rationale for the use of perioperative adjuvant chemotherapy, including intraoperative chemotherapy.
However, further studies are needed to determine whether the kinetic changes observed in animal models also occur following
tumor removal in humans.
The results of this study also show that tumor location, AJCC pT stage, AJCC pN stage, lymphovascular invasion, and
postoperative chemotherapy are independent factors for predicting survival in patients with locally advanced gastric cancer
undergoing R0 surgical resection and D2 lymphadenectomy. These results are consistent with the results of previous
studies.20-24
The main weakness of this study is the relatively small sample size. Another weakness is that the current study only evaluated
clinically overt hematogenous metastasis and peritoneal metastasis, which may have led to an overestimation of DFS.
In summary, this study shows that intraoperative systemic chemotherapy benefited patients with stage pTNM IB-IIIB gastric
cancer undergoing curative surgery. A randomized controlled clinical trial is required to confirm the survival benefit of
intraoperative systemic chemotherapy in patients with curable locally advanced gastric cancer.
Acknowledgments
This study was funded by the Innovation Fund (Grant No. X2010028). The authors thank PENG Jing-jing and ZHAO Lu for
help with the English in this manuscript. The authors also thank LI Ji for help with reclassification of the AJCC
tumor-node-metastasis.
Conflict of interest statement
None.
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Figure Legends
Fig. 1. Flowchart for this study
Fig. 2. Overall survival in patients with local advanced gastric cancer undergoing curative gastrectomy with or without
intraoperative systemic chemotherapy. The 5-year overall survival rates in patients with and without intraoperative systemic
chemotherapy were 53.0% and 37.3%, respectively (P = 0.019). NISC, no intraoperative systemic chemotherapy; ISC,
intraoperative systemic chemotherapy
Fig. 3. Disease-free survival in patients with local advanced gastric cancer undergoing curative gastrectomy with or
without intraoperative systemic chemotherapy. The 5-year disease-free survival rates in patients with and without
intraoperative systemic chemotherapy were 48.3% and 35.8%, respectively (P = 0.010).
NISC, no intraoperative systemic chemotherapy; ISC, intraoperative systemic chemotherapy
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