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Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases
Accepted Manuscript Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases Xiao-Mei Fan, Jun Zhang, Shu-Huai Niu, Kui-Xiu Li, Cang-Zhu Song PII:
S1743-9191(16)31196-7
DOI:
10.1016/j.ijsu.2016.12.031
Reference:
IJSU 3329
To appear in:
International Journal of Surgery
Received Date: 22 October 2016 Revised Date:
17 December 2016
Accepted Date: 20 December 2016
Please cite this article as: Fan X-M, Zhang J, Niu S-H, Li K-X, Song C-Z, Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases, International Journal of Surgery (2017), doi: 10.1016/j.ijsu.2016.12.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases Xiao-Mei Fan1, Jun Zhang2, Shu-Huai Niu1, Kui-Xiu Li1, Cang-Zhu Song1
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Author Institution:
Gynecology and Oncology Department, Fourth Hospital of Hebei Medical University,
Shijiazhuang, 050011, China
Gynecology Department, Fourth Hospital of Hebei Medical University, Shijiazhuang,
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050011, China
Corresponding author: Jun Zhang, Gynecology Department, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
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Email: [email protected]
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Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases Abstract
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Background: Due to satisfactory cytoreductive surgery combined with platinum-based chemotherapy in epithelial ovarian cancer has improved greatly, however, the relapse rate also high. In current study, we analyzed prognostic factors related to secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer.
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Methods: Clinical and follow-up data from 103 patients with recurrent epithelial ovarian cancer who received secondary cytoreductive surgery and were admitted to our hospital between January
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2000 and December 2008 were analyzed.
Results: Median survival after recurrence (RS) after the first relapse for the 103 patients was 36 months, and median overall survival (OS) was 60 months. Patients without visible residual tumors after secondary cytoreductive surgery had longer RS and OS compared to those with residual tumors ≥ 1 cm. The RS and OS of patients without visible residual tumors after secondary cytoreductive surgery were not significantly different compared to those with residual tumors between 0.1–1 cm. Patients with disease free interval (DFI) ≥ 12 months at secondary
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cytoreductive surgery had longer RS and OS compared to those with DFI < 12 months. Patients
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with one recurrent lesion had longer RS and OS compared to those with more than one lesion. Conclusions: Residual tumor at secondary cytoreductive surgery, DFI and number of lesions were independent prognostic factors for secondary cytoreductive surgery in patients with
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epithelial ovarian cancer. Patients with DFI ≥ 12 months and a single lesion had better prognosis
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for achieving satisfactory cytoreduction, especially the absence of visible residual tumors. Keywords: Recurrent Epithelial Ovarian Cancer; Survival After Recurrence; Secondary Cytoreductive Surgery
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INTRODUCTION Epithelial ovarian cancer is one of the common gynecological malignancies. The five-year survival rate in epithelial ovarian cancer has improved greatly due to satisfactory cytoreductive surgery combined with platinum-based chemotherapy. However, even after systemic treatment
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involving surgery with chemotherapy, the relapse rate at the early stages of epithelial ovarian cancer is still 20%–25%, while that at the advanced stages can be as high as 70% [1]. The treatment procedure after relapse is mainly chemotherapy, although surgery can also be performed on a proportion of patients. Reports on the prognosis of patients with recurrent
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epithelial ovarian cancer who underwent secondary cytoreductive surgery are inconsistent. In this study, a total of 103 patients from our hospital with recurrent epithelial ovarian cancer who underwent secondary cytoreductive surgery were included. Their surgical conditions were
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analyzed retrospectively, including clinical and pathological data, recurrence condition, and conditions of secondary surgery, in order to explore the factors related to the prognosis of patients with recurrent epithelial ovarian cancer who underwent secondary cytoreductive surgery. METHODS Basic information
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A total of 103 patients with recurrent epithelial ovarian cancer, who received secondary
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cytoreductive surgery and were admitted to the Department of Gynecology at the Fourth Hospital of Hebei Medical University between January 2000 and December 2008, were selected as subjects for this study. Detailed records were kept, which included the age of onset, condition of
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residual tumor after the first surgery, tumor pathology, pathological staging, recurrence conditions, and conditions of secondary surgery. All patients underwent surgery and 6–8 courses
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of platinum-based adjuvant chemotherapy for their first treatment, as well as secondary cytoreductive surgery after relapse followed by systemic adjuvant chemotherapy. Responders (platinum-sensitive) were defined as an ovarian cancer patient who had a treatment-free interval greater than 6 months from the last date of the initial six cycles of platinum-based combination chemotherapy. A nonresponder (platinum-resistance) was defined as an ovarian cancer patient who had a treatment-free interval less than 6 months from the last date of the initial six cycles of platinum-based combination chemotherapy, including disease that had progressed during chemotherapy. All patients were followed-up until October 2012. Conditions of secondary surgery
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All 103 patients underwent surgery for their first treatment and after recurrence, which was followed by adjuvant chemotherapy. Selection of patients with recurrent epithelial ovarian cancer, DFI ≥ 12 months and a single lesion, as well as achieving satisfactory cytoreduction or even removing all visible residual tumors as much as possible. Based on the condition of residual
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tumor during surgery, patients were divided into groups: no visible residual tumor, residual tumor with diameter < 1 cm and residual tumor with diameter ≥ 1 cm, whereby residual tumor < 1 cm was classified as satisfactory cytoreduction.
Disease free interval, survival after recurrence and overall survival
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DFI refers to the interval between the day of the last chemotherapy treatment and disease relapse. Based on the treatment-free interval before secondary cytoreductive surgery, patients were
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divided into two groups: treatment-free interval ≥ 12 months and treatment-free interval < 12 months. RS refers to the interval between the day of recurrence diagnosis and death or the last follow-up. OS refers to the interval between the day of diagnosis and death or the last follow-up. Statistical analysis
Measurement data were described using median, mean and standard deviation. Count data were described using ratio and percentage. SPSS 19.0 (SPSS, Chicago, IL, USA) was used for
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statistical analysis. Survival times were analyzed using Kaplan-Meier estimator and Cox
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regression model; differences were tested using the Log-rank test. P < 0.05 indicated statistical significance.
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RESULTS
Basic patient information at first treatment
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As shown in Table 1, the median age of the 103 patients at disease onset was 49 years old, of which the youngest was 29 years old and the oldest was 74 years old. At the end of follow-up, 68.9% (71/103) had died and 31.1% (32/103) survived; OS was 20–114 months, and the median OS was 60 months.
Conditions at secondary cytoreductive surgery after relapse As shown in Table 2, the median RS of the 103 patients after the first relapse was 36 months. During secondary cytoreductive surgery, nine patients underwent splenectomy, eight underwent partial hepatectomy, four underwent Dixon’s operation, 24 underwent small intestine or colon
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resection, seven underwent intestinal fistula, 13 underwent pelvic and/or para-aortic lymph node biopsy or dissection, and the remaining cases underwent abdominal cytoreductive surgery. Univariate analysis of factors influencing RS and OS
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Using RS and OS as the dependent variables, univariate analyses were conducted to examine various factors that might have influenced the patients’ RS and OS (Table 3). Univariate analysis of age, pathology type, differentiation degree, residual tumor at first surgery, chemotherapy before cytoreductive surgery, CA-125 before secondary cytoreductive surgery, ascites before secondary cytoreductive surgery and maximum size of lesion at relapse did not reveal clear
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correlations with RS and OS. FIGO stage, DFI at secondary cytoreductive surgery, number of lesions at relapse and residual tumor at secondary cytoreductive surgery were correlated with the
Multivariate Cox regression analysis
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patients’ RS and OS.
Univariate analysis revealed that FIGO stage was correlated with patients’ RS and OS. However, multivariate analysis did not show statistical significance, which may due to a small number of stage Ⅰand Ⅱ patients. Results from multivariate Cox regression analysis suggested that DFI for secondary cytoreductive surgery, number of lesions at recurrence and residual tumor at secondary
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cytoreductive surgery were all correlated with patients’ RS and OS (Table 4). Hence, these are
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independent factors influencing the prognosis of patients with epithelial ovarian cancer who underwent secondary cytoreductive surgery.
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DISCUSSION
The treatment for recurrent epithelial ovarian cancer is mainly chemotherapy, but surgery can
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also be performed on a proportion of patients. By reviewing the results of previous studies on the analysis of factors influencing the prognosis of patients who underwent secondary cytoreductive surgery, we found that aside from the conditions of residual tumor at secondary cytoreductive surgery, there still remains much controversy amongst the effects on prognosis of factors such as DFI, number of tumor recurrence, ascites, histology type, tumor recurrence site, maximum diameter of recurrent tumors, and the presence of chemotherapy after secondary cytoreductive surgery [2]. In patients with epithelial ovarian cancer who received first surgical treatment, satisfactory cytoreductive surgery, especially those without visible residual tumors, significantly correlated
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with OS [3]. Similar situation has also been observed in patients with recurrent epithelial ovarian cancer who underwent surgical treatment. The DESKTOP Ⅰexperiment [4] retrospectively analyzed the data from 267 cases of recurrent epithelial ovarian cancer found that the difference in the OS of patients with tumors between 0.1–1 cm and those greater than 1 cm was not
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statistically significant, and complete tumor resection was an independent contributing factor for RS [5]. Zang et al. [6] once again demonstrate that satisfactory cytoreduction, especially those without visible residual tumors, ensured a good prognosis. Various local and international researchers [7-9] have also expressed a similar viewpoint. Our study indicates that satisfactory cytoreduction (< 1 cm) was achieved when the size of the residual tumor was between 0.1–1 cm
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with relatively good prognosis. Similar to primary cytoreductive surgery, the efficacy of chemotherapy after secondary cytoreductive surgery was related to the number of residual tumor
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cells.
Previously researchers reported that DFI was one of predict the OS of patients with recurrent epithelial ovarian cancer [10]. The authors posited that the longer the DFI, the longer the patient’s OS. In regard to the prognosis after secondary cytoreductive surgery in recurrent ovarian cancer, Tian et al. [11] found that patients with disease free interval(DFI) < 16 months accounted for 39.3% , amongst which 27.7% had complete tumor resection, while patients with DFI ≥ 16
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months accounted for 60.7%, amongst which 48.6% had complete tumor resection; there was a statistically significant difference between the two groups, suggesting that the longer the DFI, the
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higher the rate of complete tumor resection. Zang et al. [6] reported that after secondary cytoreductive surgery, patient prognosis was related to four factors, of which the median OS of
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patients with DFI 6–23.1 months and < 23.1 months were 45.0 months and 21.0 months, suggesting that the longer the treatment-free interval, the longer the OS and the better the prognosis. Other local and international researchers [7, 9, 12, 13] have also agreed with this
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viewpoint. However, nearly half of the reports [2] indicated that DFI was not correlated with the OS of patients who had undergone secondary cytoreductive surgery. For example, the DESKTOP Ⅰ [4] experiment discovered that using multivariate analysis, the length of the DFI was not an independent contributing factor for the prognosis of secondary cytoreductive surgery. Zang et al. [14] also reported that DFI length affected prognosis in univariate analysis, but this was not confirmed in multivariate analysis. There are other researchers who also believe that DFI is not significantly correlated with the postoperative survival time of patients after secondary cytoreductive surgery [15, 16]. It was found in this study that DFI before secondary cytoreductive surgery ≥ 12 months accounted for 66.0% (68/103), while DFI < 12 months accounted for 34%
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(35/103). The median RS and OS for the group with DFI ≥ 12 months were 40 and 72 months, respectively, while that for the group with DFI < 12 months were 28 and 53 months, respectively. Multivariate Cox regression analysis revealed statistically significant differences between the two groups (HR = 1.893, 95% CI = 0.455–2.630; P = 0.028, HR = 2.446, 95% CI = 1.239–4.828, P =
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0.011). We can therefore conclude that DFI was significantly correlated with patient prognosis: the longer the DFI of the recurrent patient, the longer the post-operative RS and OS.
Chi et al. [12] found that the median survival times for secondary cytoreduction patients who had single-site lesion, multi-site lesion and carcinomatosis were 60, 42 and 28 months, respectively.
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Multivariate analysis revealed that the number of lesions was an independent prognostic factor for recurrent epithelial cancer. Zang et al. [6] found that the OS of patients with ≤ 3 lesions and > 3 lesions were 43.9 and 20 months, respectively. Patients with ≤ 3 recurrent lesions had longer
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post-operative OS. However, some [7, 15] also believe that the number of recurrent lesions does not affect surgical outcome and patient prognosis. In this study, statistical results revealed that the number of patients with one recurrent lesion accounted for 27.2% (28/103), for which the median RS and OS were 48 and 71 months, respectively. Patients with two or more recurrent lesions accounted for 72.8% (75/103), for which the median RS and OS were 30 and 52 months, respectively. Univariate and multivariate analyses showed significant differences between these
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two groups (P < 0.05); the median RS and OS of the patients with one lesion were longer than that of the patients with two or more lesions. Taken together with previous reports, we can
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conclude that the fewer the recurrent lesions, the better the patient’s prognosis. In 1983, Berek et al. [17] first proposed the concept of secondary cytoreductive surgery for
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recurrent ovarian cancer, in hopes of reducing tumor load, improving quality of life and alleviating tumor-related symptoms, thereby elevating survival rate. In recent years, numerous domestic and international studies have reported that surgical treatment of recurrent epithelial
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ovarian cancer can significantly prolong survival. An increasing number of researchers believe that surgical treatment should be performed where possible in patients with recurrent epithelial ovarian cancer that is platinum-sensitive and where complete resection is possible. The NCCN [18] guidelines have also suggested that surgical treatment is an option for patients with chemotherapy-free intervals > 6 months if the tumor is localized and satisfactory cytoreduction is possible. NCCN guideline has indications for secondary cytoreductive surgery: DFI>12 month, no ascite, one lesion of recurrence. However, occurrence rate of perioperative complications and mortality rate of secondary surgical procedures for epithelial ovarian cancer are relatively high [19], and hence the careful selection of suitable patients is extremely important. A few scholars 6
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have outlined a set of selection criteria for secondary surgery in recurrent epithelial ovarian cancer: (1) an interval greater than 12 months between the end of the first treatment and recurrence, (2) good response to previous chemotherapy, (3) possibility of complete tumor resection, (4) in good general condition, (5) and younger patients [20, 21].
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In the past few years, great emphasis has been placed on the importance of a series of DESKTOP OVAR trials investigating pre-operative prediction of whether secondary cytoreductive surgery in recurrent epithelial ovarian cancer can achieve complete tumor resection. The experiments proposed a scoring system to evaluate whether surgical treatment would be able to achieve a lack
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of visible residual tumors in epithelial ovarian cancer, in order provide important reference for the selection of patients for secondary cytoreductive surgery. Results of the DESKTOP Ⅰ retrospective clinical study pointed out that amongst patients with Eastern Cooperative Oncology
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Group (ECOG) score of 0 points, absence of residual tumor at first surgery or at clinical stage Ⅰ/Ⅱ, and ascites < 500 ml at supplementary examination after recurrence, 79% achieved complete resection during the secondary surgery. The DESKTOP Ⅱ [22] trial verified the abovementioned scoring system in a prospective study, showing that amongst patients with good survival status (ECOG score = 0), absence of visible residual tumors at the first surgery, and ascites < 500 ml at supplementary examination after recurrence, 76% achieved complete tumor
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resection; these patients were ideal candidates for secondary cytoreductive surgery. DESKTOP Ⅲ is a prospective, multi-center, randomized trial for the continued evaluation of this scoring system.
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Tian et al. [11] analyzed cases from multi-center surgical treatments of recurrent epithelial ovarian cancer; 1075 cases were included in the study, of which 40.4% (434/1075) achieved
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complete tumor resection. This study discovered that there were six factors which predicted whether complete tumor resection could be achieved: FIGO stage, residual tumor at primary surgery, DFI, ECOG score, CA-125 level and presence of ascites at recurrence. The DESKTOP
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trial series and the report by Tian predicted whether secondary cytoreductive surgery could achieve complete tumor resection using unique scoring systems, thus providing reference criteria for the selection of patients for secondary surgery. In this study, we found that residual tumor condition at secondary cytoreductive surgery, PFI and number of recurrent lesions were correlated with the RS and OS of patients with epithelial ovarian cancer who underwent secondary cytoreductive surgery. Selection of patients with recurrent epithelial ovarian cancer, DFI ≥ 12 months and a single lesion, as well as achieving satisfactory cytoreduction or even removing all visible residual tumors as much as possible will increase patient survival. Evidently, this study is similar to most other studies on secondary 7
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cytoreductive surgery in that it is retrospective. Therefore, further prospective studies are still required for verification. Acknowledgements
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This work was supported by Gynecology Department, Fourth Hospital of Hebei Medical University.
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will benefit? A systematic analysis of 240 consecutive patients. J Surg Oncol, 2010. 102(6): 656-62. [9] Zhang Jiajia, Evidence-baced medicine and Meta-Analysis of secondary surgery in recurrent
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[13] Yuan Guangwen, Wu Lingying, Yao Hongwen., et al. Analysis of treatment and prognosis of recurrent epithelial ovarian carcinoma. 2009. 31(9): 710-713.
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ovarian carcinoma: who benefits? Cancer, 2004. 100(6): 1152-61.
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[15] Gungor, M., et al., The role of secondary cytoreductive surgery for recurrent ovarian cancer. Gynecol Oncol, 2005. 97(1): 74-9.
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[16] Bristow, R.E., et al., Recurrent micropapillary serous ovarian carcinoma. Cancer, 2002. 95(4): 791-800.
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[17] Berek, J.S., et al., Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol, 1983. 61(2): 189-93.
[18] Jennifer Burns, et al., NCCN Clinical Practice Guidelines in Oncology: epithelial ovarian cancer. 2015
[19] Morris, M., et al., Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol, 1989. 34(3): 334-8. [20] Ivanov, S., [Results of cytoreductive surgery for advanced and recurrent ovarian neoplasms and papillary serous carcinomas of the peritoneum]. Akush Ginekol (Sofiia), 2004. 43(5): 9
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36-8. [21] Pfisterer, J., et al., The role of surgery in recurrent ovarian cancer. Int J Gynecol Cancer, 2005. 15 Suppl 3: p. 195-8.
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[22] Harter, P., et al., Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J
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Gynecol Cancer, 2011. 21(2):289-95.
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Table 1 Basic patient information at first treatment Cases
Percentage (%)
35
34.0
≤ 1 cm
40
38.8
> 1 cm
28
No residual tumor
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Residual tumor at first surgery
27.2
Pathological stage 5
Ⅱ
29
Ⅲ
61
Ⅳ
8
4.90 28.1 59.2
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Ⅰ
7.80
Pathological type 16
Serous adenocarcinoma Other epithelial cancers* Degree of differentiation High differentiation Moderate differentiation Low differentiation
75
72.8
12
11.7
3
2.9
16
15.6
71
68.9
13
12.6
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Differentiation not recorded
15.5
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Mucinous adenocarcinoma
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FIGO: International Federation of Gynecology and Obstetrics. *Including one case of mucinous adenocarcinoma, two cases of clear-cell carcinoma, four cases
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of endometrial adenocarcinoma, one case of transitional cell carcinoma and four cases of mixed
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epithelial carcinoma.
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Table 2 Conditions at secondary cytoreductive surgery after relapse Cases
Percentage (%)
≥ 12 months
68
< 12 months
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DFI 66.0 34.0
Number of relapses
Two or more relapses
39
Chemotherapy before secondary cytoreductive surgery Present
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CA-125 before secondary
37.9
51
49.5
52
50.5
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Absent
62.1
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64
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First relapse
cytoreductive surgery ≥ 100u/ml
34.0
68
66.0
Present
14
13.6
Absent
89
86.4
< 100u/ml
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35
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Ascites before secondary cytoreductive surgery
No. of lesions found during Secondary cytoreductive surgery
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One
28
27.2
Two or more
75
72.8
≥ 10 cm
12
11.7
< 10 cm
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Maximum size of lesion at relapse
88.3
Residual tumor at secondary
56
54.3
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No residual tumor
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cytoreductive surgery
0.1–1 cm ≥ 1cm
25
24.3
22
21.4
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FIGO: International Federation of Gynecology and Obstetrics.Including 19 cases in the pelvis,
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spleen.
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while the relapse sites of the remaining cases were mainly in the liver, pelvic lymph nodes, and
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Table 3 Univariate analysis of factors influencing RS and OS RS after first relapse (month)
OS (month)
Median
P value
Median
0.2625
≤ 49
56
37
> 49
47
35
Ⅰ& Ⅱ stage
14
40
Ⅲ & IV stage
89
34
75
34
28
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Age of disease onset
adenocarcinoma
Degree of
Grade 1 & 2
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Grade 3
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differentiation
No differentiation
0.1385
0.7456
37
78
0.0013
53
59
0.6429
62
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Other types
0.0051
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Serous
65 56
FIGO stage
Pathology type
P value
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Cases
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Variables
19
47
0.0934
75
71
35
62
13
29
47
35
40
0.0627
degree recorded
Residual tumor at first surgery No residual tumor
0.3656
14
74
0.6311
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0.1–1 cm
40
37
64
≥ 1 cm
28
30
59
≥ 12 months
68
40
< 12 months
35
28
Present
51
35
Absent
52
38
DFI
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before secondary
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cytoreductive surgery
CA-125 before
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cytoreductive
35
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< 100u/ml
0.5896
61
0.3452
59
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secondary
≥ 100u/ml
0.0097
53
Chemotherapy
surgery
72
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0.0123
34
68
39
Present
14
35
Absent
89
38
0.0734
57
0.0478
71
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Ascites before secondary
cytoreductive surgery
0.8948
58 61
15
0.4984
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No. of lesions found during secondary
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cytoreductive surgery One
28
48
Two or more
75
30
≥ 10 cm
12
32
< 10 cm
91
38
0.0219
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lesion at relapse
Residual tumor at
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56
51
0.0035
58
0.4096
63
73
25
45
63
22
30
49
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≥ 1 cm
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Cytoreductive
0.1–1 cm
0.1555
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Secondary
No tumor
0.0308
52
Maximum size of
surgery
71
FIGO: International Federation of Gynecology and Obstetrics.
16
0.0016
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Table 4 Multivariate Cox regression analysis OS
HR
P value
95%CI
HR
FIGO stage
2.221
0.094
0.886-5.397
2.672
DFI
1.893
0.028
0.455-2.630
2.446
No. of lesions found
1.409
0.027
1.028-2.545
1.514
during secondary
surgery Residual tumor at Secondary
0.065
1.197-7.123
0.011
1.239-4.828
0.032
1.122-2.773
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Cytoreductive
No residual tumor
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surgery 1.0
1.678
0.245
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≥ 1 cm
95%CI
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cytoreductive
0.1–1 cm
P value
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RS after first relapse
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Factor
2.689
0.035
1.0 0.526-5.933
2.048
0.286
0.598-6.008
0.645-8.097
3.098
0.026
1.460-8.549
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FIGO: International Federation of Gynecology and Obstetrics.
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Highlights: 1. The relapse rate of epithelial ovarian cancer is high. 2. DFI and lesions number were independent prognostic factors for secondary cytoreductive surgery. 3. DFI ≥ 12 months and a single lesion had better prognosis for achieving satisfactory cytoreduction.
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Conceived and designed the experiments: Xiao-Mei Fan and Jun Zhang Performed the experiments: Xiao-Mei Fan and Jun Zhang Analyzed the data: Shu-Huai Niu and Kui-Xiu Li Contributed reagents/materials/analysis tools: Cang-Zhu Song
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Shu-Huai Liu accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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S1743-9191(16)31196-7
DOI:
10.1016/j.ijsu.2016.12.031
Reference:
IJSU 3329
To appear in:
International Journal of Surgery
Received Date: 22 October 2016 Revised Date:
17 December 2016
Accepted Date: 20 December 2016
Please cite this article as: Fan X-M, Zhang J, Niu S-H, Li K-X, Song C-Z, Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases, International Journal of Surgery (2017), doi: 10.1016/j.ijsu.2016.12.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases Xiao-Mei Fan1, Jun Zhang2, Shu-Huai Niu1, Kui-Xiu Li1, Cang-Zhu Song1
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Author Institution:
Gynecology and Oncology Department, Fourth Hospital of Hebei Medical University,
Shijiazhuang, 050011, China
Gynecology Department, Fourth Hospital of Hebei Medical University, Shijiazhuang,
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050011, China
Corresponding author: Jun Zhang, Gynecology Department, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
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Email: [email protected]
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Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases Abstract
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Background: Due to satisfactory cytoreductive surgery combined with platinum-based chemotherapy in epithelial ovarian cancer has improved greatly, however, the relapse rate also high. In current study, we analyzed prognostic factors related to secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer.
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Methods: Clinical and follow-up data from 103 patients with recurrent epithelial ovarian cancer who received secondary cytoreductive surgery and were admitted to our hospital between January
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2000 and December 2008 were analyzed.
Results: Median survival after recurrence (RS) after the first relapse for the 103 patients was 36 months, and median overall survival (OS) was 60 months. Patients without visible residual tumors after secondary cytoreductive surgery had longer RS and OS compared to those with residual tumors ≥ 1 cm. The RS and OS of patients without visible residual tumors after secondary cytoreductive surgery were not significantly different compared to those with residual tumors between 0.1–1 cm. Patients with disease free interval (DFI) ≥ 12 months at secondary
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cytoreductive surgery had longer RS and OS compared to those with DFI < 12 months. Patients
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with one recurrent lesion had longer RS and OS compared to those with more than one lesion. Conclusions: Residual tumor at secondary cytoreductive surgery, DFI and number of lesions were independent prognostic factors for secondary cytoreductive surgery in patients with
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epithelial ovarian cancer. Patients with DFI ≥ 12 months and a single lesion had better prognosis
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for achieving satisfactory cytoreduction, especially the absence of visible residual tumors. Keywords: Recurrent Epithelial Ovarian Cancer; Survival After Recurrence; Secondary Cytoreductive Surgery
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INTRODUCTION Epithelial ovarian cancer is one of the common gynecological malignancies. The five-year survival rate in epithelial ovarian cancer has improved greatly due to satisfactory cytoreductive surgery combined with platinum-based chemotherapy. However, even after systemic treatment
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involving surgery with chemotherapy, the relapse rate at the early stages of epithelial ovarian cancer is still 20%–25%, while that at the advanced stages can be as high as 70% [1]. The treatment procedure after relapse is mainly chemotherapy, although surgery can also be performed on a proportion of patients. Reports on the prognosis of patients with recurrent
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epithelial ovarian cancer who underwent secondary cytoreductive surgery are inconsistent. In this study, a total of 103 patients from our hospital with recurrent epithelial ovarian cancer who underwent secondary cytoreductive surgery were included. Their surgical conditions were
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analyzed retrospectively, including clinical and pathological data, recurrence condition, and conditions of secondary surgery, in order to explore the factors related to the prognosis of patients with recurrent epithelial ovarian cancer who underwent secondary cytoreductive surgery. METHODS Basic information
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A total of 103 patients with recurrent epithelial ovarian cancer, who received secondary
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cytoreductive surgery and were admitted to the Department of Gynecology at the Fourth Hospital of Hebei Medical University between January 2000 and December 2008, were selected as subjects for this study. Detailed records were kept, which included the age of onset, condition of
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residual tumor after the first surgery, tumor pathology, pathological staging, recurrence conditions, and conditions of secondary surgery. All patients underwent surgery and 6–8 courses
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of platinum-based adjuvant chemotherapy for their first treatment, as well as secondary cytoreductive surgery after relapse followed by systemic adjuvant chemotherapy. Responders (platinum-sensitive) were defined as an ovarian cancer patient who had a treatment-free interval greater than 6 months from the last date of the initial six cycles of platinum-based combination chemotherapy. A nonresponder (platinum-resistance) was defined as an ovarian cancer patient who had a treatment-free interval less than 6 months from the last date of the initial six cycles of platinum-based combination chemotherapy, including disease that had progressed during chemotherapy. All patients were followed-up until October 2012. Conditions of secondary surgery
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All 103 patients underwent surgery for their first treatment and after recurrence, which was followed by adjuvant chemotherapy. Selection of patients with recurrent epithelial ovarian cancer, DFI ≥ 12 months and a single lesion, as well as achieving satisfactory cytoreduction or even removing all visible residual tumors as much as possible. Based on the condition of residual
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tumor during surgery, patients were divided into groups: no visible residual tumor, residual tumor with diameter < 1 cm and residual tumor with diameter ≥ 1 cm, whereby residual tumor < 1 cm was classified as satisfactory cytoreduction.
Disease free interval, survival after recurrence and overall survival
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DFI refers to the interval between the day of the last chemotherapy treatment and disease relapse. Based on the treatment-free interval before secondary cytoreductive surgery, patients were
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divided into two groups: treatment-free interval ≥ 12 months and treatment-free interval < 12 months. RS refers to the interval between the day of recurrence diagnosis and death or the last follow-up. OS refers to the interval between the day of diagnosis and death or the last follow-up. Statistical analysis
Measurement data were described using median, mean and standard deviation. Count data were described using ratio and percentage. SPSS 19.0 (SPSS, Chicago, IL, USA) was used for
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statistical analysis. Survival times were analyzed using Kaplan-Meier estimator and Cox
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regression model; differences were tested using the Log-rank test. P < 0.05 indicated statistical significance.
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RESULTS
Basic patient information at first treatment
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As shown in Table 1, the median age of the 103 patients at disease onset was 49 years old, of which the youngest was 29 years old and the oldest was 74 years old. At the end of follow-up, 68.9% (71/103) had died and 31.1% (32/103) survived; OS was 20–114 months, and the median OS was 60 months.
Conditions at secondary cytoreductive surgery after relapse As shown in Table 2, the median RS of the 103 patients after the first relapse was 36 months. During secondary cytoreductive surgery, nine patients underwent splenectomy, eight underwent partial hepatectomy, four underwent Dixon’s operation, 24 underwent small intestine or colon
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resection, seven underwent intestinal fistula, 13 underwent pelvic and/or para-aortic lymph node biopsy or dissection, and the remaining cases underwent abdominal cytoreductive surgery. Univariate analysis of factors influencing RS and OS
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Using RS and OS as the dependent variables, univariate analyses were conducted to examine various factors that might have influenced the patients’ RS and OS (Table 3). Univariate analysis of age, pathology type, differentiation degree, residual tumor at first surgery, chemotherapy before cytoreductive surgery, CA-125 before secondary cytoreductive surgery, ascites before secondary cytoreductive surgery and maximum size of lesion at relapse did not reveal clear
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correlations with RS and OS. FIGO stage, DFI at secondary cytoreductive surgery, number of lesions at relapse and residual tumor at secondary cytoreductive surgery were correlated with the
Multivariate Cox regression analysis
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patients’ RS and OS.
Univariate analysis revealed that FIGO stage was correlated with patients’ RS and OS. However, multivariate analysis did not show statistical significance, which may due to a small number of stage Ⅰand Ⅱ patients. Results from multivariate Cox regression analysis suggested that DFI for secondary cytoreductive surgery, number of lesions at recurrence and residual tumor at secondary
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cytoreductive surgery were all correlated with patients’ RS and OS (Table 4). Hence, these are
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independent factors influencing the prognosis of patients with epithelial ovarian cancer who underwent secondary cytoreductive surgery.
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DISCUSSION
The treatment for recurrent epithelial ovarian cancer is mainly chemotherapy, but surgery can
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also be performed on a proportion of patients. By reviewing the results of previous studies on the analysis of factors influencing the prognosis of patients who underwent secondary cytoreductive surgery, we found that aside from the conditions of residual tumor at secondary cytoreductive surgery, there still remains much controversy amongst the effects on prognosis of factors such as DFI, number of tumor recurrence, ascites, histology type, tumor recurrence site, maximum diameter of recurrent tumors, and the presence of chemotherapy after secondary cytoreductive surgery [2]. In patients with epithelial ovarian cancer who received first surgical treatment, satisfactory cytoreductive surgery, especially those without visible residual tumors, significantly correlated
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with OS [3]. Similar situation has also been observed in patients with recurrent epithelial ovarian cancer who underwent surgical treatment. The DESKTOP Ⅰexperiment [4] retrospectively analyzed the data from 267 cases of recurrent epithelial ovarian cancer found that the difference in the OS of patients with tumors between 0.1–1 cm and those greater than 1 cm was not
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statistically significant, and complete tumor resection was an independent contributing factor for RS [5]. Zang et al. [6] once again demonstrate that satisfactory cytoreduction, especially those without visible residual tumors, ensured a good prognosis. Various local and international researchers [7-9] have also expressed a similar viewpoint. Our study indicates that satisfactory cytoreduction (< 1 cm) was achieved when the size of the residual tumor was between 0.1–1 cm
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with relatively good prognosis. Similar to primary cytoreductive surgery, the efficacy of chemotherapy after secondary cytoreductive surgery was related to the number of residual tumor
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cells.
Previously researchers reported that DFI was one of predict the OS of patients with recurrent epithelial ovarian cancer [10]. The authors posited that the longer the DFI, the longer the patient’s OS. In regard to the prognosis after secondary cytoreductive surgery in recurrent ovarian cancer, Tian et al. [11] found that patients with disease free interval(DFI) < 16 months accounted for 39.3% , amongst which 27.7% had complete tumor resection, while patients with DFI ≥ 16
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months accounted for 60.7%, amongst which 48.6% had complete tumor resection; there was a statistically significant difference between the two groups, suggesting that the longer the DFI, the
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higher the rate of complete tumor resection. Zang et al. [6] reported that after secondary cytoreductive surgery, patient prognosis was related to four factors, of which the median OS of
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patients with DFI 6–23.1 months and < 23.1 months were 45.0 months and 21.0 months, suggesting that the longer the treatment-free interval, the longer the OS and the better the prognosis. Other local and international researchers [7, 9, 12, 13] have also agreed with this
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viewpoint. However, nearly half of the reports [2] indicated that DFI was not correlated with the OS of patients who had undergone secondary cytoreductive surgery. For example, the DESKTOP Ⅰ [4] experiment discovered that using multivariate analysis, the length of the DFI was not an independent contributing factor for the prognosis of secondary cytoreductive surgery. Zang et al. [14] also reported that DFI length affected prognosis in univariate analysis, but this was not confirmed in multivariate analysis. There are other researchers who also believe that DFI is not significantly correlated with the postoperative survival time of patients after secondary cytoreductive surgery [15, 16]. It was found in this study that DFI before secondary cytoreductive surgery ≥ 12 months accounted for 66.0% (68/103), while DFI < 12 months accounted for 34%
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(35/103). The median RS and OS for the group with DFI ≥ 12 months were 40 and 72 months, respectively, while that for the group with DFI < 12 months were 28 and 53 months, respectively. Multivariate Cox regression analysis revealed statistically significant differences between the two groups (HR = 1.893, 95% CI = 0.455–2.630; P = 0.028, HR = 2.446, 95% CI = 1.239–4.828, P =
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0.011). We can therefore conclude that DFI was significantly correlated with patient prognosis: the longer the DFI of the recurrent patient, the longer the post-operative RS and OS.
Chi et al. [12] found that the median survival times for secondary cytoreduction patients who had single-site lesion, multi-site lesion and carcinomatosis were 60, 42 and 28 months, respectively.
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Multivariate analysis revealed that the number of lesions was an independent prognostic factor for recurrent epithelial cancer. Zang et al. [6] found that the OS of patients with ≤ 3 lesions and > 3 lesions were 43.9 and 20 months, respectively. Patients with ≤ 3 recurrent lesions had longer
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post-operative OS. However, some [7, 15] also believe that the number of recurrent lesions does not affect surgical outcome and patient prognosis. In this study, statistical results revealed that the number of patients with one recurrent lesion accounted for 27.2% (28/103), for which the median RS and OS were 48 and 71 months, respectively. Patients with two or more recurrent lesions accounted for 72.8% (75/103), for which the median RS and OS were 30 and 52 months, respectively. Univariate and multivariate analyses showed significant differences between these
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two groups (P < 0.05); the median RS and OS of the patients with one lesion were longer than that of the patients with two or more lesions. Taken together with previous reports, we can
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conclude that the fewer the recurrent lesions, the better the patient’s prognosis. In 1983, Berek et al. [17] first proposed the concept of secondary cytoreductive surgery for
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recurrent ovarian cancer, in hopes of reducing tumor load, improving quality of life and alleviating tumor-related symptoms, thereby elevating survival rate. In recent years, numerous domestic and international studies have reported that surgical treatment of recurrent epithelial
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ovarian cancer can significantly prolong survival. An increasing number of researchers believe that surgical treatment should be performed where possible in patients with recurrent epithelial ovarian cancer that is platinum-sensitive and where complete resection is possible. The NCCN [18] guidelines have also suggested that surgical treatment is an option for patients with chemotherapy-free intervals > 6 months if the tumor is localized and satisfactory cytoreduction is possible. NCCN guideline has indications for secondary cytoreductive surgery: DFI>12 month, no ascite, one lesion of recurrence. However, occurrence rate of perioperative complications and mortality rate of secondary surgical procedures for epithelial ovarian cancer are relatively high [19], and hence the careful selection of suitable patients is extremely important. A few scholars 6
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have outlined a set of selection criteria for secondary surgery in recurrent epithelial ovarian cancer: (1) an interval greater than 12 months between the end of the first treatment and recurrence, (2) good response to previous chemotherapy, (3) possibility of complete tumor resection, (4) in good general condition, (5) and younger patients [20, 21].
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In the past few years, great emphasis has been placed on the importance of a series of DESKTOP OVAR trials investigating pre-operative prediction of whether secondary cytoreductive surgery in recurrent epithelial ovarian cancer can achieve complete tumor resection. The experiments proposed a scoring system to evaluate whether surgical treatment would be able to achieve a lack
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of visible residual tumors in epithelial ovarian cancer, in order provide important reference for the selection of patients for secondary cytoreductive surgery. Results of the DESKTOP Ⅰ retrospective clinical study pointed out that amongst patients with Eastern Cooperative Oncology
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Group (ECOG) score of 0 points, absence of residual tumor at first surgery or at clinical stage Ⅰ/Ⅱ, and ascites < 500 ml at supplementary examination after recurrence, 79% achieved complete resection during the secondary surgery. The DESKTOP Ⅱ [22] trial verified the abovementioned scoring system in a prospective study, showing that amongst patients with good survival status (ECOG score = 0), absence of visible residual tumors at the first surgery, and ascites < 500 ml at supplementary examination after recurrence, 76% achieved complete tumor
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resection; these patients were ideal candidates for secondary cytoreductive surgery. DESKTOP Ⅲ is a prospective, multi-center, randomized trial for the continued evaluation of this scoring system.
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Tian et al. [11] analyzed cases from multi-center surgical treatments of recurrent epithelial ovarian cancer; 1075 cases were included in the study, of which 40.4% (434/1075) achieved
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complete tumor resection. This study discovered that there were six factors which predicted whether complete tumor resection could be achieved: FIGO stage, residual tumor at primary surgery, DFI, ECOG score, CA-125 level and presence of ascites at recurrence. The DESKTOP
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trial series and the report by Tian predicted whether secondary cytoreductive surgery could achieve complete tumor resection using unique scoring systems, thus providing reference criteria for the selection of patients for secondary surgery. In this study, we found that residual tumor condition at secondary cytoreductive surgery, PFI and number of recurrent lesions were correlated with the RS and OS of patients with epithelial ovarian cancer who underwent secondary cytoreductive surgery. Selection of patients with recurrent epithelial ovarian cancer, DFI ≥ 12 months and a single lesion, as well as achieving satisfactory cytoreduction or even removing all visible residual tumors as much as possible will increase patient survival. Evidently, this study is similar to most other studies on secondary 7
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cytoreductive surgery in that it is retrospective. Therefore, further prospective studies are still required for verification. Acknowledgements
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This work was supported by Gynecology Department, Fourth Hospital of Hebei Medical University.
REFERENCES
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[2] Lorusso D; Mancini M; Di Rocco R., et al. The role of secondary surgery in recurrent ovarian cancer. Int J Surg Oncol, 2012V2012N:613980.
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will benefit? A systematic analysis of 240 consecutive patients. J Surg Oncol, 2010. 102(6): 656-62. [9] Zhang Jiajia, Evidence-baced medicine and Meta-Analysis of secondary surgery in recurrent
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[12] Chi, D.S., et al., Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer, 2006. 106(9): 1933-9.
[13] Yuan Guangwen, Wu Lingying, Yao Hongwen., et al. Analysis of treatment and prognosis of recurrent epithelial ovarian carcinoma. 2009. 31(9): 710-713.
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ovarian carcinoma: who benefits? Cancer, 2004. 100(6): 1152-61.
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[15] Gungor, M., et al., The role of secondary cytoreductive surgery for recurrent ovarian cancer. Gynecol Oncol, 2005. 97(1): 74-9.
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[16] Bristow, R.E., et al., Recurrent micropapillary serous ovarian carcinoma. Cancer, 2002. 95(4): 791-800.
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[17] Berek, J.S., et al., Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol, 1983. 61(2): 189-93.
[18] Jennifer Burns, et al., NCCN Clinical Practice Guidelines in Oncology: epithelial ovarian cancer. 2015
[19] Morris, M., et al., Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol, 1989. 34(3): 334-8. [20] Ivanov, S., [Results of cytoreductive surgery for advanced and recurrent ovarian neoplasms and papillary serous carcinomas of the peritoneum]. Akush Ginekol (Sofiia), 2004. 43(5): 9
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36-8. [21] Pfisterer, J., et al., The role of surgery in recurrent ovarian cancer. Int J Gynecol Cancer, 2005. 15 Suppl 3: p. 195-8.
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[22] Harter, P., et al., Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J
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Gynecol Cancer, 2011. 21(2):289-95.
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Table 1 Basic patient information at first treatment Cases
Percentage (%)
35
34.0
≤ 1 cm
40
38.8
> 1 cm
28
No residual tumor
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Residual tumor at first surgery
27.2
Pathological stage 5
Ⅱ
29
Ⅲ
61
Ⅳ
8
4.90 28.1 59.2
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Ⅰ
7.80
Pathological type 16
Serous adenocarcinoma Other epithelial cancers* Degree of differentiation High differentiation Moderate differentiation Low differentiation
75
72.8
12
11.7
3
2.9
16
15.6
71
68.9
13
12.6
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Differentiation not recorded
15.5
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Mucinous adenocarcinoma
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FIGO: International Federation of Gynecology and Obstetrics. *Including one case of mucinous adenocarcinoma, two cases of clear-cell carcinoma, four cases
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of endometrial adenocarcinoma, one case of transitional cell carcinoma and four cases of mixed
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epithelial carcinoma.
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Table 2 Conditions at secondary cytoreductive surgery after relapse Cases
Percentage (%)
≥ 12 months
68
< 12 months
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DFI 66.0 34.0
Number of relapses
Two or more relapses
39
Chemotherapy before secondary cytoreductive surgery Present
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CA-125 before secondary
37.9
51
49.5
52
50.5
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Absent
62.1
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64
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First relapse
cytoreductive surgery ≥ 100u/ml
34.0
68
66.0
Present
14
13.6
Absent
89
86.4
< 100u/ml
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35
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Ascites before secondary cytoreductive surgery
No. of lesions found during Secondary cytoreductive surgery
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One
28
27.2
Two or more
75
72.8
≥ 10 cm
12
11.7
< 10 cm
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Maximum size of lesion at relapse
88.3
Residual tumor at secondary
56
54.3
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No residual tumor
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cytoreductive surgery
0.1–1 cm ≥ 1cm
25
24.3
22
21.4
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FIGO: International Federation of Gynecology and Obstetrics.Including 19 cases in the pelvis,
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spleen.
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while the relapse sites of the remaining cases were mainly in the liver, pelvic lymph nodes, and
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Table 3 Univariate analysis of factors influencing RS and OS RS after first relapse (month)
OS (month)
Median
P value
Median
0.2625
≤ 49
56
37
> 49
47
35
Ⅰ& Ⅱ stage
14
40
Ⅲ & IV stage
89
34
75
34
28
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Age of disease onset
adenocarcinoma
Degree of
Grade 1 & 2
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Grade 3
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differentiation
No differentiation
0.1385
0.7456
37
78
0.0013
53
59
0.6429
62
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Other types
0.0051
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Serous
65 56
FIGO stage
Pathology type
P value
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Cases
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Variables
19
47
0.0934
75
71
35
62
13
29
47
35
40
0.0627
degree recorded
Residual tumor at first surgery No residual tumor
0.3656
14
74
0.6311
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0.1–1 cm
40
37
64
≥ 1 cm
28
30
59
≥ 12 months
68
40
< 12 months
35
28
Present
51
35
Absent
52
38
DFI
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before secondary
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cytoreductive surgery
CA-125 before
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cytoreductive
35
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< 100u/ml
0.5896
61
0.3452
59
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secondary
≥ 100u/ml
0.0097
53
Chemotherapy
surgery
72
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0.0123
34
68
39
Present
14
35
Absent
89
38
0.0734
57
0.0478
71
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Ascites before secondary
cytoreductive surgery
0.8948
58 61
15
0.4984
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No. of lesions found during secondary
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cytoreductive surgery One
28
48
Two or more
75
30
≥ 10 cm
12
32
< 10 cm
91
38
0.0219
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lesion at relapse
Residual tumor at
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56
51
0.0035
58
0.4096
63
73
25
45
63
22
30
49
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≥ 1 cm
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Cytoreductive
0.1–1 cm
0.1555
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Secondary
No tumor
0.0308
52
Maximum size of
surgery
71
FIGO: International Federation of Gynecology and Obstetrics.
16
0.0016
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Table 4 Multivariate Cox regression analysis OS
HR
P value
95%CI
HR
FIGO stage
2.221
0.094
0.886-5.397
2.672
DFI
1.893
0.028
0.455-2.630
2.446
No. of lesions found
1.409
0.027
1.028-2.545
1.514
during secondary
surgery Residual tumor at Secondary
0.065
1.197-7.123
0.011
1.239-4.828
0.032
1.122-2.773
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Cytoreductive
No residual tumor
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surgery 1.0
1.678
0.245
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≥ 1 cm
95%CI
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cytoreductive
0.1–1 cm
P value
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RS after first relapse
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Factor
2.689
0.035
1.0 0.526-5.933
2.048
0.286
0.598-6.008
0.645-8.097
3.098
0.026
1.460-8.549
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FIGO: International Federation of Gynecology and Obstetrics.
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Highlights: 1. The relapse rate of epithelial ovarian cancer is high. 2. DFI and lesions number were independent prognostic factors for secondary cytoreductive surgery. 3. DFI ≥ 12 months and a single lesion had better prognosis for achieving satisfactory cytoreduction.
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Conceived and designed the experiments: Xiao-Mei Fan and Jun Zhang Performed the experiments: Xiao-Mei Fan and Jun Zhang Analyzed the data: Shu-Huai Niu and Kui-Xiu Li Contributed reagents/materials/analysis tools: Cang-Zhu Song
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Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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Shu-Huai Liu accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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