Surgery in platinum-resistant recurrent epithelial ovarian carcinoma

lNTRODUCTlON

Ovarian cancer is one of the three most common malignant tumors of the female reproductive tract and ranks first in terms of mortality among gynecological tumors[1]. Worldwide, there are more than 200000 new cases each year,

., approximately 6.6 per 100000 women[2]. In China, ovarian cancer incidence is 5.3 per 100000[3]. Epithelial ovarian carcinoma (EOC) is the most common ovarian malignancy,accounting for 90% of all primary ovarian tumors[4]. With advances in surgical treatments and the development of chemotherapeutic drugs and targeted therapies (

, PARP inhibitors), the prognosis of EOC patients has been greatly improved; however, five-year survival remains very low, predominantly due to cancer cell resistance to chemotherapy. The overall five-year survival rate of EOC patients in the United States is about 49%, but only 17% in cases with advanced disease[5-7]. The latest Chinese survey in 2014 showed an average five-year survival rate for ovarian cancer of 38.9%[3,8].

The response rate obtained after platinum-based chemotherapy is about 80% in the adjuvant setting but is reduced to approximately 20% in recurrent EOC[4,9,10]. In addition, newly available PARP inhibitors improve the prognosis of patients with platinum-sensitive EOC but show low efficacy in platinum-resistant EOC[11,12]. Thus, improving the management of platinum-resistant ovarian cancer is extremely important in improving patient prognosis. The main treatment goals in recurrent EOC include symptom relief, improved quality of life, and prolonged survival. According to the latest NCCN guidelines for recurrent EOC, alternative treatments for platinum-resistant recurrent EOC patients mainly include “participation in clinical trials, supportive care, chemotherapeutic regimens (nonplatinum monotherapy), or observation (category 2B)”[10]. For the treatment of cisplatin-resistant recurrent EOC, the traditional main approach is administering non-platinum chemotherapeutic drugs with or without bevacizumab, but its efficacy is poor, with an increase in progression-free survival of only about 3 mo[13,14]. Other chemotherapeutic drugs show objective response rates of 19%-27%[10]. In patients with platinum-resistant EOC, median overall survival (OS) is approximately 1 year[10,15].

每次測定至少重復3次，實驗數據以（平均值±標準差）表示，實驗數據處理使用Design Expert 10.0.7，采用Graphpad Prism 7.0等軟件進行處理及制圖。

Therefore, the objective of this study was to evaluate the feasibility of secondary cytoreductive surgery for the treatment of platinum-resistant recurrent EOC. The results could provide a promising option for improving the prognosis of such patients.

MATERlALS AND METHODS

Study design and patients

It was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Department of Gynecologic Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang, China) between September 2012 and June 2018. The present study was approved by the Medical Ethics Committee of Zhejiang Cancer Hospital. The study has obtained informed consent for all individual participants that appear in this manuscript.

Inclusion criteria were: (1) Pathologically confirmed recurrent EOC, defined as clinical relapse with objective radiological disease progression based on the modified RECIST version 1.1[26], with or without previous chemotherapy[10]; (2) Platinum-resistant recurrent EOC,

, failure to control condition after chemotherapy with platinum drugs or recurrence within 6 mo after discontinuation of chemotherapy (drug resistance after the initial administration of platinum drugs was defined as primary drug resistance; otherwise, secondary drug resistance was considered)[10,27]; (3) Cytoreductive surgery for recurrent EOC in our hospital; and (4) Complete medical records. Exclusion criteria were: (1)Concurrent malignant tumor; or (2) 5-year history of another primary malignant tumor, except for carcinoma

.

Cytoreductive surgery and other treatments

The patient underwent maximum cytoreductive surgery, and multiple organs were removed if necessary. Postoperative chemotherapy was administered. All surgeries were completed by the same team consisting of chief physicians with ＞ 20 years of experience. There is no standard surgical procedure for secondary surgery in recurrent ovarian cancer. Therefore, the operation depended on the involved organs. Recurrence locations (

, abdominopelvic cavity) were examined, with or without organ resection; most importantly, the presence or absence of residual lesions was recorded.

The chemotherapeutic regimen was platinum combined with liposomal doxorubicin, paclitaxel,gemcitabine, docetaxel, or etoposide, as suggested by the NCCN guidelines that were current at the time of patient treatment (

, the 2012-2018 NCCN guidelines).

間接減壓主要指傳統頸后路手術方式，包括全椎板切除術、椎管擴大椎板成形術及選擇性半椎板切除術等。一般認為，當發生廣泛OPLL（累及＞3個椎體）時，可優先選擇后路手術（技術簡便、并發癥發生率低），擴大脊髓活動空間為脊髓間接減壓。

Follow-up

The results of Cox univariable analysis are shown in Table 3. Macroscopic residual lesions (HR = 3.29;95%CI: 1.511-7.162;

= 0.003), intraoperative bleeding ＞ 800 mL (HR = 2.862; 95%CI: 1.048-7.813;

=0.04), and no postoperative chemotherapy (HR = 5.027; 95%CI: 1.061-23.828;

= 0.042) were associated with PFS. Pathological mixed type (HR = 11.285; 95%CI: 1.157-110.099;

= 0.037), macroscopic residual lesions (HR = 2.65; 95%CI: 1.115-6.298;

= 0.027), and no postoperative chemotherapy (HR = 57.66;95%CI: 5.099-651.995;

= 0.001) were associated with OS. Pathological type of endometrioid carcinoma(HR = 0.32; 95%CI: 0.107-0.956;

= 0.041) and macroscopic residual lesions (HR = 2.777; 95%CI: 1.108-4.679;

= 0.025) were associated with CFI.

Data collection

Patient baseline data were obtained from clinical records, including age, pathological type (high-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma, and mixed type),pathological classification (highly, moderately, and poorly differentiated), previous surgery (residual lesions of the first surgery, International federation of gynecology and obstetrics (FIGO) staging, and the number of previous surgeries), previous chemotherapy (neoadjuvant chemotherapy or not, the total number of previous chemotherapies, and remission time conferred by chemotherapy before drugresistance necessitating surgery), and type of drug resistance (primary or secondary platinum resistance). In addition, relevant surgical data were also documented, including the time from disease onset to this surgery, preoperative Eastern collaborative oncology group (ECOG) score, location of recurrent lesions, and surgical resection outcome (R0, no macroscopic residual lesion; R1, residual lesion≤ 1 cm; R2, ＞ 1 cm), intraoperative organ resection or not, intraoperative bleeding amount, perioperative complications, total number of postoperative chemotherapies, postoperative administration of targeted drugs or not, and postoperative hospital stay.

Outcomes

The primary outcome was PFS. Secondary outcomes included: (1) Postoperative OS; (2) chemotherapyfree interval (CFI) after surgery and first-line chemotherapy; and (3) perioperative complications,including their severity levels (severity classification of surgical complications of the MSKCC[28]) and treatment conditions.

The clinical value of cytoreductive surgery in patients with platinum-resistant recurrent EOC remains largely unclear.

Statistical analysis

All statistical analyses were carried out with SPSS 22.0 (IBM Corp., Armonk, NY, United States).Continuous data with normal distribution were presented as mean ± SD, and those with skewed distribution as median (range). Categorical data were presented as frequency (percentage). Univariable Cox regression analysis was performed for PFS, OS, and CFI. Kaplan-Meier curves were plotted and analyzed by the log-rank test. Multivariable models were unstable because of the small sample size, and such analyses could not be performed in a reliable manner. Two-sided

＜ 0.05 was considered statistically significant.

RESULTS

Patient characteristics

經常性團建聚餐、每周分享會、按員工意愿與特長分配工作、老父親般慈祥地對待員工失職借口。我還親手在公司搭健身角，鼓勵大家多鍛煉身體，保持良好狀態。

Characteristics of secondary cytoreductive surgeries

Table 2 presents the characteristics of cytoreductive surgeries. Most patients (33/38, 86.8%) had an ECOG of 0-1. The recurrent lesions were in the pelvic cavity in 7 (18.4%) patients, in the abdominopelvic cavity in 16 (42.1%), and in the abdominopelvic cavity and retroperitoneum in 15 (39.5%). R0 resection was achieved in 25 (65.8%) patients and R1/2 in 13 (34.2%). Twenty-five (65.8%) cases required organ resection. Nine (23.7%) patients showed operative complications, 36 (94.7%) underwent chemotherapy,and five (13.2%) received targeted therapy. Most patients (24/38, 63.2%) were hospitalized for ≤ 10 d.

PFS, OS, and CFI

Figure 1 displays PFS, OS, and CFI in the 38 patients. Median PFS and OS were 10 (95%CI: 8.27-11.73)months and 28 (95%CI: 12.75-43.25) months, respectively; median CFI was 9 (95%CI: 8.06-9.94) months.

Associations of various factors with treatment outcome

Follow-up ended on April 15, 2019, and was performed routinely at the outpatient clinic or by telephone. All data were extracted from medical charts. Routine follow-up of disease progression was performed as follows. CA125 assessment and physical examination were performed every 3 wk during treatment, including gynecological examination. Imaging assessment was carried out every 12 wk by Bmode ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). At the end of treatment, comprehensive reexamination, including CA125 detection, gynecological examination, and imaging, was performed. Imaging was performed to assess disease progression and recurrence,recurrence sites, lesion location, presence or absence of ascites,

Given that ovarian cancer recurrence may occur in the abdominopelvic cavity, chest, brain, and other locations, imaging examinations were performed for all these suspicious locations, mainly by B-mode ultrasound, but also by CT, MRI, and positron emission tomography. After treatment, follow-up was performed every 3 mo within 2 years and every 6 mo after that. CA125 detection, gynecological examination, and imaging were performed in post-treatment follow-ups. Progression-free survival (PFS) was determined as the time between the cytoreductive surgery and objective radiological disease progression based on the modified RECIST 1.1[26] or death. OS was determined as the time from the cytoreductive surgery to death.

以上闡述了PBL教學方法在實踐教學中具體應用方法和重要作用，該方法對.NET企業級應用開發系列課程都較為適用，所提出及設計的任務都是亟待解決的具體問題。學生自己解決問題，得到成就感與自信，促進了學習主動性。

Subgroup analyses

Subgroup analyses of important clinical indicators were performed based on the above univariate analysis (Figures 2-4). PFS in patients with R0 resection was significantly longer than that of the R1/2 resection group [12 (8.83, 15.17)

8 (2.27, 13.73) months;

= 0.001]. PFS was significantly longer in patients receiving postoperative chemotherapy than in those without postsurgical chemotherapy [11(9.33, 12.67)

2 mo;

= 0.018] (Figure 2). OS was significantly prolonged in patients with R0 resection compared with those with R1/2 resection [39 (15.36, 62.64)

15 (8.71, 21.29) months;

= 0.021]. OS was significantly longer in patients administered postoperative chemotherapy than those without postoperative chemotherapy [32 (17.68, 46.32)

2 mo;

＜ 0.001] (Figure 3). CFI in patients with R0 resection was significantly prolonged than that of the R1/2 resection group [9 (6.22, 11.78)

6 (2.48,9.52) months;

= 0.013]. Taken together, these results indicated that R0 resection and postoperative chemotherapy could significantly prolong PFS and OS, while R0 resection also significantly increased the CFI.

Complications

Grade ≥ 3 complications were observed, including rectovaginal fistula (

= 1), intestinal and urinary fistulas (

= 1), and renal failure-associated death (

= 1). Except for the patient who died after surgery,all other patients with complications were successfully managed. Two patients developed intestinal obstruction and showed improvement after conservative treatment. One patient with an intestinal fistula was relieved after ileostomy. One patient with an intestinal fistula complicated with a ureteral fistula showed improvement after ileal fistulation and ureteral stent placement under cystoscopy. One patient developed abdominal hemorrhage and was relieved after another surgery. Two patients with effusion of the spleen fossa and pelvic abscess were relieved by ultrasound-guided puncture drainage of the effusion and anti-inflammatory treatment. One patient developed renal dysfunction and electrolyte imbalance and showed improvement after medical treatment.

DlSCUSSlON

There are few treatment options for platinum-resistant recurrent EOC[10], and the available treatments have unsatisfactory efficacy, resulting in a poor prognosis. Cytoreductive surgery for advanced gynecologic tumors could be a good option[17,19-24], but controversies remain about its clinical value[16,17]. Therefore, this study aimed to evaluate the feasibility of secondary cytoreductive surgery for treating platinum-resistant recurrent EOC. The results suggested that R0 resection and postoperative chemotherapy could significantly prolong PFS and OS, while R0 resection also significantly prolonged the CFI. Therefore, secondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. This study provides references for the selection of clinical therapeutic regimens.

網絡整體內向接近中心度標準差為7.164，外向接近中心度標準差為6.940，差異較小，且節點間差異沒有很大差異，說明三峽地區旅游節點的通暢程度較高，并沒有出現明顯的阻礙現象。個體節點以白帝城、解放碑、小三峽、三峽大壩、神女峰、重慶紅巖的內外向中心度最高，表明這幾個節點與三峽地區其他景點通達性較好，受其他節點控制較弱，近20年過去了，游客在三峽旅游的游線組合中仍然包含這幾個經典景區。相對這些景區，三峽旅游的經典景區中衰落較快的景區為張飛廟、萬州港、大昌古鎮、小小三峽、三游洞、葛洲壩、名山、涪陵新城、三峽大瀑布。這些景區節點與其他景區節點依賴性較強，旅游目的地競爭力相對較弱。

For platinum non-resistant patients, the NCCN guidelines suggest that secondary cytoreductive surgery could be considered[10]. However, in patients with platinum-resistant recurrent EOC, further studies are needed to verify the feasibility of cytoreductive surgery in prolonging survival. Indeed, the value of cytoreductive surgery in such patients remains controversial[16,17]. Nevertheless, recent studies suggested a survival benefit in selected patients, especially those with minimal residual disease after surgery[17-24]. This finding was also supported by a meta-analysis[25].

As shown above, median PFS post-cytoreductive surgery was 10 mo, and median OS was 28 mo; a median CFI of 9 mo was recorded. Different studies have reported variable outcomes after surgery for recurrent EOC. Nevertheless, complicating the analysis of available results, many reports were not specifically focused on platinum-resistant EOC, and the obtained OS values were significantly longer than those described in the present study. Therefore, caution must be taken when comparing the shorter survival observed in this study with the literature. The current treatment option for platinum-resistant EOC is usually chemotherapy. Because there was no control group in the current study, no data were available for a chemotherapy group. Available data indicate that the effect of chemotherapy on platinum-resistant EOC is poor. Considering that the OS of patients with platinum-resistant EOC is about 1 year[10,15], an OS of 28 mo found in the present study could be seen as promising, despite the lack of a control group. This 28-mo median OS is shorter than that observed for EOC in general (without distinction on platinum resistance), 32-67 mo[17,19,21,23,24,29]. Additional multicenter studies could be carried out to examine those factors.

Secondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. These findings provide important references for the selection of clinical therapeutic regimens.

In platinum-sensitive EOC, Canaz

[30] reported that ascites and R0 resection are associated with longer PFS. In addition, Schorge

[21] demonstrated that residual lesion ＜ 5 mm, and ＜ 5 sites of disease relapse are associated with improved OS. Furthermore, Salani

[19] showed that disease-torecurrence interval ＜ 18 mo, 1-2 recurrent sites, and R0 resection are associated with improved survival.Moreover, Eisenkop

[23] showed that a long disease-free interval after the primary treatment, R0 resection, salvage chemotherapy, and recurrent lesions ＜ 10 cm are associated with improved survival.Besides, Onda

[24] showed that R0 resection, disease-free interval ＞ 12 mo, no liver metastasis,solitary lesion, and lesion ＜ 6 cm are associated with improved survival. Shih

[22] highlighted that maximum cytoreductive efforts should be made in patients with recurrent EOC. On the other hand, in platinum-resistant EOC, ascites and tumor size kinetics during chemotherapy appear to be the two most influential factors associated with OS[10]. Optimal tumor debulking improves patient prognosis in patients with platinum resistance after neoadjuvant chemotherapy[31]. In the present study, R0 resection and postoperative chemotherapy were associated with longer PFS and OS, while R0 resection also significantly prolonged the CFI. Taken together, these results indicate that R0 resection is a critical factor for the success of salvage cytoreduction therapy in patients with platinum-resistant recurrent EOC. The above results suggested that in case of satisfactory effects achieved by cytoreductive surgery for platinum-resistant EOC, the patients would benefit from the surgery regardless of previous FIGO stage, pathological type, neoadjuvant chemotherapy, the number of chemotherapy lines, and the type of drug resistance. Furthermore, studies reported that the management of malignant ascites and malignant bowel obstruction could by itself improve survival in patients with treatment-resistant disease[32-36].Such supportive and palliative treatments could also play a role in survival.

Surgical complications in platinum-resistant recurrent EOC cases undergoing secondary cytoreductive surgery also influence the postoperative quality of life and survival. Therefore, the safety of the surgical treatment, the resectability of the recurrent lesions, and the incidence of perioperative complications are important indicators of treatment safety and feasibility. In the present study, the complication rate was 24%, which corroborates previous studies[17,19-24].

The present study examined CFI, but this outcome has some limitations. Indeed, some patients with poor chemotherapy tolerance or insensitivity to chemotherapy could show long CFI but a short OS. On the other hand, a short CFI could be associated with a long OS because of previous treatments.Nevertheless, the CFI may reflect the patient’s quality of life[37]. In some patients with platinumresistant ovarian cancer, post-chemotherapy CFI was prolonged by secondary cytoreductive surgery. In addition, for some patients with elevated CA125 amounts but no evidence of disease in clinical and imaging examinations, the CFI could be prolonged, thereby keeping possibly effective options once symptoms occur.

1.2.1.2 治療護理 椎動脈型的頸椎病患者主要采取活血化瘀類口服或靜脈給藥，以及局部中藥熏蒸和夾脊穴電針物理治療。護理措施:急性期或癥狀較重者靜臥為主，準確給藥和中藥熏蒸治療，配合醫師電針理療，并做好生活照顧。

This study was a retrospective case series, and the absence of a control group was the main limitation.There were few patients with platinum-resistant recurrent EOC in our center, and many had incomplete chemotherapy data because they returned to their local hospitals after the first chemotherapy cycles.This study did not have a control group. Therefore, additional large prospective, multicenter,randomized clinical trials are needed to provide further high-level evidence.

A total of 38 patients were included. Their characteristics are presented in Table 1. The resection type at the initial surgery was R0 in 20 (52.6%) patients, R1 in 10 (26.3%), and R2 in 8 (21.1%). Among these patients, 16 (42.1%) had recurrence within 3 mo of the initial treatment, and 22 (57.9%) between 3 and 6 mo. Twenty-seven (71.1%) patients had secondary platinum resistance, while 11 (28.9%) had primary resistance.

語境的創設，也稱為語境構建，是表達者對表達的有意識的準備。在理解了言語的目的和語境可能受限的情況之后，語言表達者在條件許可的范圍內有意識地為自己準備充分的外部條件。它是由語言表達者構建的語境，是在真實條件的前提下進行的創造性活動。在課堂教學中，教師根據表達的實際需要，在主客觀條件許可的情況下，進行的課前教學活動的預設和準備就是課堂教學語境的創設。

CONCLUSlON

In patients with platinum-resistant recurrent EOC, secondary cytoreductive surgery could significantly improve PFS, OS, and CFI in case of no macroscopic residual lesions. Postoperative chemotherapy could further improve PFS and OS. Therefore, secondary cytoreductive surgery has certain clinical feasibility,providing a potential treatment option for these patients.

鬼話，我看你日得牛死。鎮長拍著牛皮糖的肩膀，牛皮糖沒躲避，鎮長意味深長地安慰說，你快點把傷診好。這個年紀了身體還是要緊。

ARTlCLE HlGHLlGHTS

Research motivation

At least two senior gynecological oncologists assessed postoperative progression. In case of disagreement, the department conducted discussions until consensus. At each follow-up reexamination,comprehensive assessments were performed: CA125 Level determination, gynecological examination,and imaging.

Research objectives

This study aimed to evaluate the feasibility of secondary cytoreductive surgery to treat platinumresistant recurrent EOC.

其一，從五年規劃完成率的視角來看，中國各省區的完成率總體提高，且各地差距呈現縮小趨勢。這從長時序的定量實證的角度展現了五年規劃在中國的發展情況。更重要的是，如果將五年規劃完成率作為各地區治理績效的一個代表變量，這一發現從實證角度表明了中國各省區地方政府在2001-2015年期間治理能力的變化。此前分析地區治理差距多通過地區經濟差距、民生差距等結果性差距來論述，本文將地區完成率差距作為變量，為以政府行政能力為代表的過程性變量相關研究開辟了思路，可以為從宏觀層面闡釋中國地區差距變化背后的因果機制提供數據支持。

用中國蘇州紐邁電子科技有限公司生產的MesoMR23-060H-I核磁共振分析儀測定。該儀器的共振頻率為23.4033 MHz，磁體強度為0.5 T，線圈直徑為60 mm，磁體溫度為32℃。

Research methods

It was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Cancer Hospital of the University of Chinese Academy of Sciences between September 2012 and June 2018.

Research results

R0 resection and postoperative chemotherapy significantly prolonged progression-free survival and overall survival (all

＜ 0.05), and R0 resection also significantly prolonged chemotherapy-free interval (

＜ 0.05).

Research conclusions

Secondary cytoreductive surgery is feasible for the treatment of platinum-resistant recurrent EOC.

1.1.2 預測試對象 采用目的抽樣，擬選取2017年11月～2018年1月某綜合性醫院127名護士進行預測試。納入標準：目前在職工作并取得資格證書的護士；工作時間至少滿1年；知情同意。排除標準：1年內在2家及以上醫院工作的護士；不愿意參加本次調研。預測試對象127名，男1名(0.8%)、女126名(99.2%)；年齡22～49(31.14±5.24)歲；初始學歷：大專78名(61.4%)，本科47名(37.0)%，研究生2名(1.6%)；工作年限1～20(7.71±6.47)年。

Research perspectives

The findings provide important references for the selection of clinical therapeutic regimens.

ACKNOWLEDGEMENTS

The authors acknowledge help from Prof. Ping Zhang and Prof. Fei-Jiang Yu.

FOOTNOTES

Zhao LQ and Gao W contributed to conceptualization, data curation, and writing - review &editing; CY Fang, Zhang P contributed to formal analysis and methodology; Zhao LQ, Gao W, YL Zhang, and Shou HF contributed to writing - original draft; Zhao LQ and Gao W contributed equally to this work; all authors read and approved the final manuscript.

the Medical Science Project of Zhejiang Province, No. 2018KY027.

The research adhered to the principles of the Declaration of Helsinki and Title 45, United States. Code of Federal Regulations, Part 46, Protection of Human Subjects. The present study was approved by the Medical Ethics Committee of Zhejiang Cancer Hospital. The study has obtained informed consent for all individual participants that appear in this manuscript.

All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

The authors of this work have nothing to disclose.

Technical appendix, statistical code, and dataset available from the corresponding author at shouhuafeng@hmc.edu.cn.

The authors have read the STROBE Statement—a checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—a checklist of items.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Ling-Qin Zhao 0000-0001-7029-2887; Wen Gao 0000-0002-8518-5299; Ping Zhang 0000-0002-1707-2866;Ying-Li Zhang 0000-0003-2002-6083; Chen-Yan Fang 0000-0001-5383-1797; Hua-Feng Shou 0000-0002-4664-2733.

Liu JH

A

3)針對來壓時動載系數大，頂煤冒落嚴重，對頂梁結構進行優化設計，解決大采高綜放工作面煤壁片幫的防護及片幫問題[20]。

Liu JH

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