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Which is the best postoperative chemotherapy regimen in patients with rectal cancer after neoadjuvant therapy?

  • Peng Gao1,
  • Yong-xi Song1,
  • Jing-xu Sun1,
  • Xiao-wan Chen1,
  • Ying-ying Xu1,
  • Jun-hua Zhao1,
  • Xuan-zhang Huang1,
  • Hui-mian Xu1 and
  • Zhen-ning Wang1Email author
Contributed equally
BMC Cancer201414:888

https://doi.org/10.1186/1471-2407-14-888

Received: 10 May 2014

Accepted: 11 November 2014

Published: 27 November 2014

Abstract

Background

There is no general agreement about whether patients who have already received neoadjuvant chemoradiotherapy need further postoperative chemotherapy based on 5-fluorouracil(5-FU) or 5-FU plus oxaliplatin.

Methods

Medicare beneficiaries from 1992 to 2008 with Union for International Cancer Control ypStages I to III primary carcinoma of the rectum who underwent 5-FU-based neoadjuvant chemoradiotherapy and surgery for curative intent were identified through the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. A Cox proportional hazards model and propensity score-matched techniques were used to evaluate the effect of treatment on survival.

Results

For patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy, postoperative 5-FU-based chemotherapy did not prolong cancer-specific survival (CSS) in ypStage I (P = 0.960) and ypStage II (P = 0.134); however, it significantly improved the CSS in ypStage III (hazard ratio = 1.547, 95% CI = 1.101-2.173, P = 0.012). No significant differences in survival between the 5-FU group and oxaliplatin group were observed.

Conclusions

For patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy, postoperative 5-FU-based chemotherapy prolongs the CSS of groups in ypStage III. Adding oxaliplatin to fluoropyrimidines in the postoperative chemotherapy did not improve the CSS for patients who received neoadjuvant chemoradiotherapy.

Keywords

Rectal neoplasms SEER program Chemotherapy Neoadjuvant therapy

Background

Rectal cancer has been defined as a cancerous lesion located within 12 cm of the anal verge [1]. At present, the main treatment for locally advanced rectal cancer is chemoradiotherapy plus total mesorectal excision (TME). Although it is debatable whether preoperative chemoradiotherapy improves long-term survival [24], randomized clinical trials have shown better local control, lower toxicity, and higher compliance if preoperative chemoradiotherapy is administered rather than postoperative conventionally fractionated chemoradiotherapy [5, 6]. Thus, the current “gold standard” of treatment recommended by both the National Comprehensive Cancer Network (NCCN) [7] and the European Society for Medical Oncology (ESMO) [8] for locally advanced rectal cancers with invading through the muscularis propria into the pericolorectal tissues (cT3), penetrating to the surface of the visceral peritoneum (cT4a), invading or being adherent to other organs or structures (cT4b), or lymph nodal metastasis on imaging (cN1-2) is preoperative radiotherapy plus 5-fluorouracil (5-FU)-based chemotherapy.

Is adjuvant chemotherapy needed after curative surgery for rectal cancer patients who have received neoadjuvant chemoradiotherapy? The NCCN recommended postoperative chemotherapy for all patients undergoing preoperative chemoradiotherapy regardless of the pathological stage [7]. The ESMO guidelines state that “similar to the situation in colon cancer Stages III (and “high-risk” Stage II), adjuvant chemotherapy can be provided, even if the scientific support for sufficient effect is less” [8]. However, several studies questioned the use of adjuvant chemotherapy in patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and curative surgery, especially in patients without pathological lymph node metastasis (ypN0) [2, 914]. Results from all these studies showed that adding postoperative adjuvant chemotherapy did not significantly improve disease-free survival (DFS) or overall survival (OS) in patients who have already received neoadjuvant chemoradiotherapy. On the other hand, a unique randomized clinical trial suggested that good-prognosis patients (ypT0-2) benefit from postoperative chemotherapy [15]. Furthermore, it was not reported whether adding postoperative 5-FU-based chemotherapy could improve the survival of patients with pathological lymph node metastasis (ypN1-2). Hence, for patients who have received neoadjuvant therapy, the role of postoperative chemotherapy is still controversial.

Although lack of data from rigorous randomized clinical trials confirmed the effectiveness, oxaliplatin has been used in rectal cancer for several years based on the extrapolated data in colon cancer. Similarly, the role of postoperative oxaliplatin in patients with rectal cancer who have already received neoadjuvant chemoradiotherapy is still not yet defined. To the best of our knowledge, only two ongoing randomized clinical trials presented preliminary results, though contradictory, on this issue [16, 17].

The aim of the current study was to investigate whether postoperative 5-FU-based chemotherapy or 5-FU plus oxaliplatin provides a benefit for patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy.

Methods

Data source

The data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare-linked database were examined. The approval and subsequent access to the data for this study were granted by the National Cancer Institute (NCI) and Information Management Services (IMS), Inc. following submission of a formal data request outlining the research objectives. Also, this study was approved by the Institutional Review Board of the first hospital of China Medical University.

The SEER cancer registries include information on patient demographics, tumor characteristics, first course of treatment, and survival of patients who were newly diagnosed with cancer. SEER regions included approximately 26% of the US population [18]. Medicare is the primary health insurer for 97% of the US population aged ≥65 years [19]. The details of the database were presented elsewhere [20].

Patient selection

All Medicare-enrolled patients aged ≥66 years that were diagnosed with primary adenocarcinoma of the rectum from 1992 to 2008 were included in the study (SEER cancer site codes: 19.9 and 20.9; SEER histology codes: 8000–8152, 8154–8231, 8243–8245, 8250–8576, 8940–8950, and 8980–8981). Those who underwent primary tumor resection with likely curative intent within 180 days of diagnosis were selected, excluding presumably palliative operations. Data of all patients who received preoperative (from diagnosis of rectal cancer to operation) radiotherapy plus 5-FU or capecitabine, which was the regimen recommended by the NCCN, were included. Regarding the postoperative chemotherapy, the no-chemo group included patients with no record for chemotherapy within 120 days of surgery. The oxaliplatin group included patients with any record of oxaliplatin within 30 days of their first chemotherapy dose. The 5-FU group comprised all other patients, including those who received 5-FU or capecitabine. The Health Care Financing Administration Common Procedure Coding System or National Drug Code for drugs were presented in Additional file 1.

Patients were excluded from this study if they (1) received other chemotherapy regimen preoperatively or postoperatively; (2) had prior non-rectal cancer; (3) had incomplete pathological stage entries or diagnostic data; (4) died during the immediate postoperative period (within 30 days); (5) were diagnosed with another malignancy 1 year after the date of rectal cancer diagnosis; (6) had membership in a Medicare-sponsored health maintenance organization or lack of enrollment in Medicare Parts A and B from 12 months preceding diagnosis through 9 months after diagnosis; (7) had complete pathologic response because it was unable to identify accurately in the SEER-Medicare database; and (8) had ypStage 0 (Tis N0 M0), because of too small sample size.

Variables

Age at diagnosis, year of diagnosis, sex, race, marital status, rural/urban county of residence, census tract-level median household income, and level of education (percentage of people aged >25 years and <12 years of education) were obtained from the SEER patient entitlement and diagnosis summary file. For risk adjustment, Centers for Medicare and Medicaid Services Hierarchical Condition Categories (HCC) based on outpatient and inpatient diagnoses from the 12 months before rectal cancer diagnosis were used. The resulting score can be interpreted as a patient’s predicted level of “future health care need” relative to the average Medicare beneficiary (HCC = 1.0) [21].

Patients were staged according to the seventh edition of the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) staging system [22]. Postoperative pathological stage (ypTNM) was used. The preoperative clinical stage was not available in the SEER-Medicare. Other covariates included were tumor grade, histological type, preoperative intestinal obstruction, preoperative intestinal perforation, postoperative radiotherapy, and the number of lymph nodes examined.

Statistical analysis

In the univariable analysis, the cancer-specific (CSS) was analyzed by Kaplan-Meier survival curves, and comparisons were made by the log-rank test stratified by the ypTNM stage.

In clinical practice, significant differences exist between patients who are and are not treated with chemotherapy, particularly with regard to age and comorbidities. Because treatment effect estimates are likely confounded by factors related to treatment selection, a propensity score (PS)-matched analysis was performed to compare the effect of treatment on survival among patients of similar risk profiles as assessed by measured known confounders [23, 24]. For this analysis, logistic regression models were built for each stage to estimate each patient’s probability of receiving 5-FU or oxaliplatin, conditional on covariates. Later two PSs were generated: one estimated the likelihood of 5-FU receipt and the other estimated the likelihood of oxaliplatin receipt in chemotherapy-treated patients. For each comparison, patients exposed to treatment (5-FU and oxaliplatin) were matched with patients with the same PS from the unexposed treatment group. Patients for whom there was no match were excluded. In this manner, a PS-matched cohort balanced across treatment groups for measured confounders was generated. The CSS was then compared in these PS-matched cohorts using the log-rank test stratified by the ypTNM stage.

As the sample size was moderate, a Cox proportional hazards model was also used in the adjusted analysis. The covariates included all variables that were identified to be significantly related to survival in the univariable analysis and the tests were made stratified by the ypTNM stage.

All statistical analyses and graphics were performed by the lead author using SAS 9.3 (SAS Institute, Cary, NC, USA), STATA 12.0 software (STATA, College Station, TX, USA), and PASW Statistics 18.0 software (SPSS, Inc., Somers, NY, USA). For all analyses, P < 0.05 was considered to indicate a significant result.

Results

Patient demographics

A total of 1535 patients with resected rectal cancer who received neoadjuvant chemoradiotherapy regimen recommended by the NCCN were included (Table 1). Details of race, marital status, median household income, level of education, histologic type, and intestinal perforation were not presented in Table 1, because the number of patients in some subgroups was too small and the SEER-Medicare rules require that cell sizes less than eleven in a table must be suppressed.
Table 1

Clinicopathologic features of patients with different chemotherapy regimens

 

No-chemo

5-FU

Oxaliplatin

Gender

   

  Male

448

321

131

  Female

324

219

92

Age at diagnosis, years

   

  66-70

201

184

105

  71-75

234

175

70

  >75

337

181

48

Residence location

   

  Big Metro

383

261

127

  Metro or Urban

303

199

77

  Less Urban or Rural

86

80

19

Year of diagnosis

   

  1992-1996

17

10

0

  1997-2000

132

115

0

  2001-2004

296

251

26

  2005-2008

327

164

197

Histologic grade

   

  Well

59

35

14

  Moderate

519

360

146

  Poor/Undifferentiated

116

87

37

  Unknown

78

58

26

ypT category

   

  ypT1-2

261

146

50

  ypT3

446

367

160

  ypT4

65

27

13

ypN category

   

  ypN0

609

339

134

  ypN1a

79

85

34

  ypN1b

42

59

26

  ypN2a

20

36

16

  ypN2b

22

21

13

ypTNM stage

   

  ypTNM I

233

113

36

  ypTNM II

376

226

98

  ypTNM III

163

201

89

Intestinal obstruction

   

  No

677

484

201

  Yes

95

56

22

HCC risk score

   

  1st quartile

210

143

56

  2nd quartile

157

131

45

  3rd quartile

189

152

67

  4th quartile

216

114

55

Number of examined lymph node

   

  ≥12

265

200

106

  <12

507

340

117

Postoperative radiotherapy

   

  No

676

455

208

  Yes

96

85

15

Abbreviations: HCC Hierarchical Condition Categories, No-chemo without postoperative chemotherapy, 5-FU 5-fluorouracil.

CSS without chemotherapy or with 5-FU

The unmatched 5-year CSS rates for the patients in the no-chemo group were 90.6%, 78.8%, and 49.5% as compared with 90.9%, 84.0%, and 59.0% for the 5-FU group in ypStage I (T1-2 N0 M0), II (T3-4 N0 M0), and III (Any T N1-2 M0), respectively (Figure 1). There was no significant difference in survival between two groups in ypStage I (P = 0.961) and ypStage II (P = 0.109). The prognosis of patients in the no-chemo group was significantly worse than the 5-FU group in ypStage III (P = 0.024).
Figure 1

Kaplan-Meier comparison of cancer-specific survival among patients who received different postoperative treatment stratified by pathologic stage. A. ypStage I; B. ypStage II; C. ypStage III.

The variables that were significantly related to the patients’ probability of receiving 5-FU were presented in Additional file 2. The PS-matched cohorts were generated using these variables. The CSS was then compared in these PS-matched cohorts. There were still no significant differences in survival between the two groups in ypStage I (P = 0.884) and ypStage II (P = 0.345), but for patients in ypStage III the prognosis of the no-chemo group was significantly worse than the 5-FU group (P = 0.009; Figure 2).
Figure 2

After PS-matched, Kaplan-Meier comparison of cancer-specific survival between patients in the no-chemo group and in the 5-FU group stratified by pathologic stage. A. ypStage I; B. ypStage II; C. ypStage III.

A Cox proportional hazards model was also used for comparison of survival between the two groups. The covariates included all variables that were identified to be significantly related to survival (Additional file 3). The results were consistent with that of the PS-matched analysis, and in ypStage III, the patients in the no-chemo group was significantly worse than the 5-FU group (hazard ratio = 1.547, 95% CI = 1.101-2.173, P = 0.012; Table 2).
Table 2

Cox proportional hazards model stratified by ypTNM stage

 

HR

95%CI

P

Stage I

   

  Chemotherapy regimens

   

   5-FU

1

  

   No-chemo

1.021

0.459-2.273

0.960

   Oxaliplatin

1.002

0.215-4.670

0.998

Stage II

   

  ypT category

   

   ypT3

1

  

   ypT4a

1.187

0.291-4.841

0.811

   ypT4b

1.878

1.058-3.334

0.031

  Postoperative radiotherapy

   

   No

1

  

   Yes

1.870

1.159-3.018

0.010

  Histologic type

   

   Adenocarcinoma

1

  

   Mucinous carcinoma

1.877

1.138-3.094

0.014

   Signet-ring cell carcinoma

8.078

2.351-27.748

0.001

  Chemotherapy regimens

   

   5-FU

1

  

   No-chemo

1.393

0.903-2.148

0.134

   Oxaliplatin

0.926

0.438-1.956

0.840

Stage III

   

  ypT category

   

   ypT1

1.150

0.491-2.692

0.747

   ypT2

0.759

0.436-1.321

0.329

   ypT3

1

  

   ypT4a

0.691

0.244-1.959

0.487

   ypT4b

1.592

0.934-2.713

0.088

  ypN category

   

   ypN1a

1

  

   ypN1b

1.233

0.825-1.844

0.306

   ypN2a

1.468

0.905-2.381

0.119

   ypN2b

2.098

1.310-3.357

0.002

  Residence location

   

   Big Metro

1

  

   Metro or Urban

1.147

0.822-1.600

0.419

   Less Urban or Rural

0.487

0.257-0.923

0.027

  Histologic type

   

   Adenocarcinoma

1

  

   Mucinous carcinoma

1.466

0.993-2.163

0.054

   Signet-ring cell carcinoma

1.220

0.459-3.239

0.690

  Histologic grade

   

   Well

0.716

0.229-2.239

0.565

   Moderate

1

  

   Poor

1.650

0.753-3.619

0.211

   Undifferentiated

2.817

0.891-8.910

0.078

   Unknown

1.037

0.496-2.171

0.922

  Chemotherapy regimens

   

   5-FU

1

  

   No-chemo

1.547

1.101-2.173

0.012

   Oxaliplatin

0.626

0.372-1.054

0.078

Abbreviations: No-chemo without postoperative chemotherapy, 5-FU 5-fluorouracil, CI Confidential intervals.

CSS with or without oxaliplatin

The unmatched 5-year CSS rates for the patients in the oxaliplatin group were 91.1%, 87.9%, and 73.7% as compared with 90.9%, 84.0%, and 59.0% for the 5-FU group in ypStage I, II, and III, respectively (Figure 1). There were no significant differences in survival between the two groups in all stages (P ≥; 0.05).

The variables that significantly related to the patients’ probability of receiving 5-FU plus oxaliplatin compared with 5-FU alone were presented in Additional file 2. The PS-matched cohorts were generated using these variables. The CSS was then compared in these PS-matched cohorts. There were still no significant differences in survival between the two groups in all stages (P > 0.05; Figure 3).
Figure 3

After PS-matched, Kaplan-Meier comparison of cancer-specific survival between patients in the 5-FU group and in the oxaliplatin group stratified by pathologic stage. A. ypStage I; B. ypStage II; C. ypStage III.

A Cox proportional hazards model was also used for comparison of survival between the two groups. The covariates included all variables which were identified to be significantly related to survival (Additional file 3). The results showed that there were still no significant differences in survival between the two groups in all stages (Table 2).

Discussion

Preoperative chemoradiotherapy is the standard treatment for locally advanced rectal cancer. However, there is no general agreement about whether patients who have already received neoadjuvant chemoradiotherapy need further postoperative chemotherapy based on 5-FU. Janjan [25] proposed that there was significant improvement in CSS in response to preoperative chemoradiotherapy and the administration of adjuvant chemotherapy. Collette [15] analyzed a subset of data from the European Organization for Research and Treatment of Cancer (EORTC) Trial 22921, which revealed that the postoperative 5-FU-based chemotherapy prolonged survival in ypT0-2, but not in ypT3-4, patients. Hypothetically, distal micrometastasis may be cleared by chemotherapeutic drugs more effectively in patients who were good in response (in low ypStage) to preoperative chemoradiotherapy.

However, Das [26] proposed that postoperative chemotherapy may be of greater benefit for patients in a higher ypStage such as ypStage III (ypN1-2), and lower ypStage subgroups should receive a relatively conservative therapeutic regimen. Subsequently, a study by Huh [11] revealed that postoperative adjuvant chemotherapy for patients in ypT0-2 N0 classification after preoperative chemoradiation and curative surgery did not significantly improve the survival, which was consistent with the suggestion of Das [26], but these results contradictory to that of Collette [15]. Later the results of the study by Govindarajan [9] confirmed that there was no significant difference in the 5-year DFS between patients, in ypT0-2 N0 and ypT3-4 N0 classifications, who did and did not receive adjuvant treatment. In addition, both Fietkau [10] and Kiran [12] proposed that adding postoperative chemotherapy did not significantly improve the survival of patients in ypN0 classification. More recently, Bosset [14] completed the EORTC Trial 22921 and proposed that postoperative 5-FU-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) did not affect DFS or OS. The result was confirmed in both ypT0-2 and ypT3-4 classifications; however, this analysis was not stratified on the basis of ypN classification.

Although the conclusions of the aforementioned studies were different, a consensus may be arrived at based on the postoperative pathologic stage of the patient in determining the need for adjuvant chemotherapy. Simultaneously, several studies proposed that the risk of distant metastases is directly proportional to the postoperative pathologic stage [9, 2729], and Quah [28] found that the outcome was most accurately estimated by the postoperative pathologic stage. Nevertheless, the NCCN recommended postoperative chemotherapy for all patients undergoing preoperative chemoradiotherapy regardless of the results of the surgical pathology tests [7].

Considering the importance of ypTNM stage in determining the need for adjuvant chemotherapy, all tests were made stratified by ypTNM stage. We compared the prognosis among patients in no-chemo, 5-FU, and oxaliplatin group in the unmatched univariable survival analysis. We found that postoperative 5-FU-based chemotherapy did not prolong the CSS in ypStage I (ypT1-2 N0) (Figure 1A) and ypStage II (ypT3-4 N0) (Figure 1B), which was similar to the study by Govindarajan [9]. On the contrary, adding postoperative 5-FU-based chemotherapy significantly improved survival of patients in ypStage III (ypN1-2) (Figure 1C). To the best of our knowledge, the outcome of postoperative 5-FU-based chemotherapy in ypStage III patients was never reported previously, although researchers stressed the need for a randomized clinical trial [30, 31]. To confirm our results, both the PS-matched analysis and the Cox proportional hazards model were used to make adjusted analysis, and the results were in accordance with the univariable survival analysis (Figure 2, Table 2).

Adding oxaliplatin to fluoropyrimidines in the adjuvant setting improved the OS in colon cancer compared with FU and leucovorin regimens [32]. According to the NCCN guidelines, for patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy, 5-FU/leucovorin/oxaliplatin (FOLFOX) was an optional regimen for postoperative chemotherapy. Several ongoing randomized clinical trials in rectal cancer focused on improving 5-FU-based chemotherapy through the addition of oxaliplatin preoperatively, postoperatively, or both [16, 17, 3335]. Two study groups presented preliminary results. Hong [17] proposed that postoperative FOLFOX significantly improved the 2-year DFS relative to postoperative 5-FU-based chemotherapy for rectal cancer patients in ypStage II or III after 5-FU-based neoadjuvant chemoradiotherapy followed by TME. On the contrary, Nimeiri [16] discovered that there was no difference in the OS between patients who received 5-FU alone or FOLFOX as postoperative chemotherapy. In the current study, no significant differences were found in the survival between the two groups (5-FU vs. oxaliplatin) of patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy (Figures 1 and 3; Table 2). Although this result need to be confirmed by further clinical trials, we argue that, for patients who received neoadjuvant chemoradiotherapy, adding oxaliplatin to fluoropyrimidines in the postoperative chemotherapy require serious consideration at present.

The current study has some limitations. First, as it was a retrospective exploratory study, the potential for confounding based on patient selection could not be eliminated. Both traditional Cox proportional hazards model and PS-matched techniques were used to account for known relevant confounders. Second, only patients aged ≥66 years at the time of diagnosis were included in this study, which may limit the applicability of the findings to younger patients with rectal cancer. Third, the role of several known prognostic features such as tumor regression grade, preoperative carcinoembryonic antigen, microsatellite instability, perineural invasion, and lymphovascular invasion could not be investigated, as these characteristics were not available within the SEER-Medicare database. Patients with pCR were excluded from analysis because the pCR status was not well supported by the SEER-medicare database. Fourth, this study retrospectively examined the use of chemotherapy as identified through the Medicare claims data using a “one-claim” algorithm [36, 37]. This created a heterogeneous population in which some patients received a substandard duration of therapy. However, O'Connor [38] proposed that the “none versus any” approach used to assign treatment status provided a window into the effectiveness of chemotherapy in real-world practice, in which an individual’s likelihood of completing the treatment course is not known at the outset of the study. Finally, the preoperative clinical stage as well as pathologic response to neoadjuvant therapy was not supported by the SEER-Medicare database. Both the preoperative clinical stage and pathologic response were related to outcome; however, Quah [28] found that the outcome was most accurately estimated by the postoperative pathologic stage and the clinical stage adds no predictive value to the prognosis. In addition, the 100% accuracy of clinical staging was untenable even in the best of centers [39]. Based on this, the decision of postoperative chemotherapy could be regarded mainly as based on postoperative pathologic stage.

Conclusions

It is concluded that, for patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy, postoperative 5-FU-based chemotherapy prolongs the CSS of groups in ypStage III. Adding oxaliplatin to fluoropyrimidines in the postoperative chemotherapy did not improve the CSS for patients who received neoadjuvant chemoradiotherapy.

Consent

The manuscript was approved by SEER-Medicare for anonymity prior to submission for publication. Because the SEER-Medicare data are de-identified and are based on registry data, no prior informed consent was required.

Notes

Abbreviations

TME: 

Total mesorectal excision

NCCN: 

National Comprehensive Cancer Network

ESMO: 

European Society for Medical Oncology

5-FU: 

5-fluorouracil

DFS: 

Disease-free survival

OS: 

Overall survival

CSS: 

Cancer-specific survival

SEER: 

Surveillance, Epidemiology, and End Results

HCC: 

Hierarchical Condition Categories

UICC: 

Union for International Cancer Control

TNM: 

Tumor-node-metastasis

PS: 

Propensity score

EORTC: 

European Organization for Research and Treatment of Cancer

FOLFOX: 

5-FU/leucovorin/oxaliplatin.

Declarations

Acknowledgements

This work was supported by National Science Foundation of China (No.81201888, 81372549 and No. 81172370), Specialized Research Fund for the Doctoral Program of Higher Education (No.20122104110009) and Natural Science Foundation of Liaoning Province (No. 2014029201).

Authors’ Affiliations

(1)
Department of Surgical Oncology and General Surgery, the First Hospital of China Medical University

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