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Article  文章

Current Treatment Practices and Prognostic Factors in Early-Stage Ovarian Cancer-An Analysis of the NOGGO/JAGO
目前早期卵巢癌的治疗实践和预后因素-对 NOGGO/JAGO 的分析

Sabine Heublein , Joanna Baum , Anna Jaeger , Donata Grimm-Glang 3,6, Julia Olthoff ,Elena Ioana Braicu , Osama Azzam Nieto , Kathrin Hassdenteufel , Barbara Schmalfeldt , Lars Hanker ,Markus Wallwiener , Andreas Schneeweiss , Jalid Sehouli (D) and Klaus Pietzner 1 Department of Gynecology and Obstetrics, University of Heidelberg, 69120 Heidelberg, Germany2 National Center for Tumor Diseases, University Hospital and German Cancer Research Center Heidelberg,69120 Heidelberg, Germany3 Young Academy of Gynecologic Oncology (JAGO), 13359 Berlin, Germany4 Department of Gynecology, Center for Oncological Surgery, Campus Virchow Klinikum,Charite-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zuBerlin, Berlin Institute of Health, 13353 Berlin, Germany5 Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf,20246 Hamburg, Germany6 Department of Obstetrics and Gynecology, University Medical Center Luebeck, 23562 Luebeck, Germany7 Department of Obstetrics and Gynecology, University Hospital Brandenburg an der Havel,14770 Brandenburg an der Havel, Germany* Correspondence: sabine.heublein@med.uni-heidelberg.de
Sabine Heublein ,Joanna Baum ,Anna Jaeger ,Donata Grimm-Glang 3,6,Julia Olthoff ,Elena Ioana Braicu ,Osama Azzam Nieto ,Kathrin Hassdenteufel ,Barbara Schmalfeldt ,Lars Hanker ,Markus Wallwiener ,Andreas Schneeweiss ,Jalid Sehouli (D)和 Klaus Pietzner 1 德国海德堡大学妇产科学系,69120 海德堡 2 德国海德堡大学医院和德国癌症研究中心国家肿瘤疾病中心,69120 海德堡 3 德国柏林 JAGO 妇科肿瘤学青年学院,13359 柏林 4 柏林洪堡大学医学院弗里大学柏林,洪堡大学柏林健康研究所,13353 柏林癌症中心妇科学系,20246 汉堡,德国 6 吕贝克大学医学中心妇产科学系,23562 吕贝克,德国 7 勃兰登堡哈维尔大学医院妇产科学系,14770 勃兰登堡德国哈维尔堡*通讯:sabine.heublein@med.uni-heidelberg.de

Citation: Heublein, S.; Baum, J.; Jaeger, A.; Grimm-Glang, D.; Olthoff, J.; Braicu, E.I.; Azzam Nieto, O.; Hassdenteufel, K.; Schmalfeldt, B.; Hanker, L.; et al. Current Treatment Practices and Prognostic Factors in Early-Stage Ovarian Cancer-An Analysis of the NOGGO/JAGO. Cancers 2023, 15, 2038. https:// doi.org /cancers15072038
引用:Heublein,S.;Baum,J.;Jaeger,A.;Grimm-Glang,D.;Olthoff,J.;Braicu,E.I.;Azzam Nieto,O.;Hassdenteufel,K.;Schmalfeldt,B.;Hanker,L.;等。早期卵巢癌的当前治疗实践和预后因素-NOGGO/JAGO 分析。癌症 2023 年,15 卷,2038 页。https://doi.org /cancers15072038
Academic Editor: Edward J. Pavlik
学术编辑:Edward J. Pavlik
Received: 5 February 2023
收到:2023 年 2 月 5 日
Revised: 12 March 2023
修订日期:2023 年 3 月 12 日
Accepted: 21 March 2023
接受日期:2023 年 3 月 21 日
Published: 29 March 2023
发布日期:2023 年 3 月 29 日
Simple Summary: Patients diagnosed with early-stage ovarian cancer (OC) are treated by surgery and, if appropriate, by adjuvant chemotherapy. However, in practice, there is disagreement about both the extent of surgical staging and the indication of adjuvant chemotherapy. Therefore, we sought to structurally assess clinically relevant parameters of treatment practice and aimed to identify individual patient factors that may influence decisions regarding the extent of treatment. This study confirmed that a relevant proportion ) of early-stage OC patients were not operated on in compliance with the current standard. This was independent of patient age and hospital healthcare level. The reasons for omitting complete surgical staging were balanced. Only a subset of cases underwent BRCA1/2 testing. Though mono-chemotherapy is recommended for early-stage OC, almost every second patient receives combination treatment. Our study underlines the high need for further prospective registries and educational programs to increase awareness for adequate clinical management of patients with early-stage OC.
简要总结:早期卵巢癌(OC)患者通过手术治疗,并在适当情况下接受辅助化疗。然而,在实践中,关于手术分期的范围和辅助化疗的适应症存在争议。因此,我们试图结构评估治疗实践中的临床相关参数,并旨在确定可能影响治疗范围决策的个体患者因素。这项研究证实,早期 OC 患者中有相当比例的患者未按照当前标准进行手术治疗。这与患者年龄和医院医疗水平无关。省略完整手术分期的原因是平衡的。只有一部分病例进行了 BRCA1/2 测试。尽管单一化疗被推荐用于早期 OC,但几乎每两名患者中就有一名接受联合治疗。我们的研究强调了进一步进行前瞻性登记和教育计划的迫切需要,以增加对早期 OC 患者的充分临床管理意识。

Abstract 摘要

Background: Surgery is the backbone of early-stage ovarian cancer (OC) management. However, in practice, there is disagreement about the extent of surgical staging and whether additional adjuvant treatment should be provided. As omitting relevant diagnostic or therapeutic procedures might lead to undertreatment, we aimed to structurally investigate treatment practice in addition to prognostic factors in a multicentre series of patients (pts) diagnosed with early-stage OC. Patients: Within this retrospective, multicentre study, medical records of 379 pts who had undergone surgery for suspected early-stage OC between January 2014 and March 2020 were analysed. Results: Of the 379 patients, 292 had pT stage 1a-2a and had complete data on the extent of surgical staging At least one surgical step was omitted in 100 pts (34.2%). Complete surgical staging ( ; (65.8%)) was more often performed in high-grade serous OC and was independent of the healthcare level of the hospital where the initial diagnosis was made. Missing to take peritoneal biopsies was associated with reduced relapse-free-survival in incompletely staged, pT1 cases ( ). About every second patient ) with a final stage lower than FIGO IIB and treated with adjuvant chemotherapy received combination chemotherapy. BRCA1 and BRCA2 testing was only performed in a subset of pts, and mutations were detected in and pts, respectively. Conclusions: This study helps to increase our understanding of early-stage OC treatment and prognosis. In addition to
背景:手术是早期卵巢癌(OC)管理的支柱。然而,在实践中,关于手术分期的程度以及是否应提供额外的辅助治疗存在分歧。由于省略相关的诊断或治疗程序可能导致治疗不足,我们旨在结构性地调查早期 OC 诊断患者(pts)的治疗实践以及预后因素。患者:在这项回顾性、多中心研究中,分析了 2014 年 1 月至 2020 年 3 月间接受疑似早期 OC 手术的 379 名患者(pts)的病历。结果:在 379 名患者中,292 名患者的 pT 分期为 1a-2a,并且完整数据显示手术分期的程度。100 名患者(34.2%)中至少省略了一个手术步骤。高级别浆液性 OC 更常进行完整手术分期( ;(65.8%)),并且与初步诊断所在医院的医疗水平无关。未进行腹膜活检与未完全分期的 pT1 病例( )相关联,与复发无关。 关于每第二位最终阶段低于 FIGO IIB 并接受辅助化疗治疗的患者 )中,接受了联合化疗。仅在部分患者中进行了 BRCA1 和 BRCA2 测试,并分别在 患者中检测到突变。结论:这项研究有助于增进我们对早期卵巢癌治疗和预后的理解。除此之外

treating patients in compliance with current guidelines, the need for testing should also be considered for early-stage OC.
根据当前指南对患者进行治疗时,也应考虑对早期卵巢癌进行 检测的需要。
Keywords: early-stage ovarian cancer; surgery; BRCA; adjuvant treatment
关键词:早期卵巢癌;手术;BRCA;辅助治疗

1. Introduction 1. 介绍

Approximately one-third of ovarian cancer (OC) patients are diagnosed at a time when the cancer is still limited to the pelvis [i.e., Federation of Gynaecology and Obstetrics (FIGO) IA to IIB] [1]. Although the overall prognosis for these patients is markedly better than those with more advanced disease, about of them will experience disease relapse, and approximately will even die due to OC . Among all guidelines, it is widely accepted that surgery is the preferred treatment for early-stage OC. In Germany, optimal surgical staging has been defined by the national guideline, which is released by the German Society of Gynaecology and Obstetrics every 4 years [4]. According to the current guideline, surgical staging in early-stage OC should comprise laparotomy, bilateral adnexectomy, hysterectomy, omentectomy, pelvic and para-aortic lymphadenectomy, peritoneal sampling, cytology specimen retrieval, and appendectomy in the case of mucinous histology. As the guideline does not consider systematic lymphadenectomy to be obligatory for welldifferentiated (Grade 1) mucinous disease, our definition of complete staging did not require systematic lymphadenectomy for them.
大约三分之一的卵巢癌(OC)患者在癌症仍然局限于盆腔时被诊断出来【即妇产科联合会(FIGO)IA 至 IIB】[1]。尽管这些患者的总体预后明显优于那些病情更为严重的患者,但其中约 会经历疾病复发,约 会因 OC 而死亡 。在所有指南中,广泛认为手术是早期卵巢癌的首选治疗方法。在德国,最佳手术分期已被国家指南定义,该指南每 4 年由德国妇产科学会发布[4]。根据当前指南,早期卵巢癌的手术分期应包括腹腔镜检查、双侧附件切除术、子宫切除术、网膜切除术、盆腔和腹主动脉淋巴结清扫术、腹膜取样、细胞学标本检索,以及在粘液性组织学中进行阑尾切除。由于该指南认为对于良性分化(1 级)粘液性疾病,系统性淋巴结清扫术并非必需,因此我们对于完整分期的定义不要求对其进行系统性淋巴结清扫术。
Complete surgical staging followed by stage-adapted adjuvant treatment significantly improves patients' 4-year survival [5]. Omitting surgical steps is critical for two reasons. First, if cancer staging is suboptimal, its spread to a certain organ might remain undetected if the organ is not resected as recommended. This is especially true regarding microscopic spread. Therefore, underestimating cancer spread might lead to falsely classifying the patient as being in an early FIGO stage and prevent the patient from receiving adequate adjuvant chemotherapy. Second, through suboptimal staging, the surgeon accepts the risk of leaving tumour residuals in the body. Although the importance of optimal surgical staging seems reasonable and surgical steps are clearly defined by the guideline [4], a relevant number of early-stage OC patients are not treated in accordance with the official recommendations. This seems to be an international dilemma, as several reports from different countries claim that treatment standards are insufficiently applied in the case of early-stage OC [5,6]. Only recently, a nationwide survey by the QS Ovar revealed that only about of patients diagnosed with early-stage OC were operated on in compliance with the national guideline . Although this rate has improved over the last decade, approximately every third of patients diagnosed with apparent early-stage OC has not been treated according to the established standards [7].
完整的手术分期后,根据分期调整的辅助治疗显著提高患者的 4 年生存率[5]。省略手术步骤有两个关键原因。首先,如果癌症分期不够完善,其对某个器官的扩散可能会未被检测到,如果该器官未按建议切除。这在微观扩散方面尤为真实。因此,低估癌症扩散可能导致错误地将患者分类为早期 FIGO 阶段,并阻止患者接受足够的辅助化疗。其次,通过不完善的分期,外科医生接受了在体内留下肿瘤残留物的风险。尽管最佳手术分期的重要性似乎合理,并且手术步骤已在指南中明确定义[4],但相当数量的早期卵巢癌患者未按照官方建议接受治疗。这似乎是一个国际性困境,因为来自不同国家的几份报告声称早期卵巢癌的治疗标准在应用方面不足[5,6]。 最近,QS Ovar 进行的一项全国调查显示,只有约 的早期卵巢癌患者接受了符合国家指南 的手术治疗。尽管这一比例在过去十年有所改善,但大约三分之一的明显早期卵巢癌患者并未按照既定标准接受治疗。
Inspired by the results of the nationwide, descriptive analysis by the QS Ovar, we sought to structurally assess clinically relevant parameters of treatment practice in earlystage OC. Moreover, we aimed to identify individual patient factors (e.g., conservation of fertility and comorbidities) that may influence decisions regarding the extent of treatment. These analyses are fundamental to improving our understanding of treatment for earlystage OC.
受 QS Ovar 进行的全国性描述性分析结果的启发,我们试图结构性评估早期卵巢癌治疗实践中的临床相关参数。此外,我们旨在确定个体患者因素(例如,保留生育能力和合并症),这些因素可能影响有关治疗范围的决策。这些分析对于改善我们对早期卵巢癌治疗的理解至关重要。

2. Materials and Methods
2. 材料和方法

2.1. Characteristics of the Study Sample
2.1. 研究样本的特征

This multicentre registry study retrospectively analysed medical records of patients diagnosed with early-stage OC. Centres participating in this study included the Department of Gynaecology and Gynaecologic Oncology, Charité University Hospital Berlin, the Department of Obstetrics and Gynaecology, University of Heidelberg, the Department of Gynaecology and Gynaecologic Oncology, University Medical Centre HamburgEppendorf Hamburg, the Department of Obstetrics and Gynaecology, University Medical
这项多中心登记研究对早期卵巢癌患者的医疗记录进行了回顾性分析。参与本研究的中心包括柏林夏里特大学医院妇科和妇科肿瘤科、海德堡大学产科和妇科、汉堡埃本多夫大学医学中心妇科和妇科肿瘤科、以及汉堡大学医学中心产科和妇科。
Centre Luebeck, and the Department of Obstetrics and Gynaecology, University Hospital Brandenburg an der Havel. This study was performed in collaboration with the JAGO ('Young Academy of Gynaecologic Oncologists') of the NOGGO ('North-Eastern German Society of Gynaecological Oncology') study group.
卢贝克中心,勃兰登堡哈维尔大学医院妇产科。本研究是与 NOGGO(东北德国妇科肿瘤学会)研究小组的 JAGO(青年妇科肿瘤学家学会)合作进行的。
All patients with apparent early-stage OC in whom surgical cancer resection was performed between January 2014 and March 2020 were included in this study. We decided to use pT rather than FIGO stage to pre-select patients with presumable early-stage disease in the first place. Selection by final FIGO stage (e.g., only analysing those patients with FIGO I and II) would have biased our results since those patients with microscopic lymphonodular or peritoneal spread are detected only after complete surgical staging (i.e., by systemic lymphadenectomy or peritoneal sampling) and hence finally up-staged as FIGO III would be missed. As a second selection step, clinical files, including surgery reports, were carefully analysed. Only cases with to without macroscopic peritoneal spread or in terms of without macroscopic peritoneal spread outside the pelvis were defined as apparently early-stage and analysed in this study.
在本研究中,包括 2014 年 1 月至 2020 年 3 月之间接受手术癌症切除的明显早期卵巢癌患者。我们决定首先使用 pT 而不是 FIGO 分期来预先筛选具有可能早期疾病的患者。通过最终 FIGO 分期进行选择(例如,仅分析那些 FIGO I 和 II 患者)会使我们的结果产生偏差,因为只有在完成手术分期(即通过系统性淋巴清扫或腹膜取样)后才能检测到那些具有微观淋巴结或腹膜扩散的患者,因此最终升级为 FIGO III 的患者会被忽略。作为第二个选择步骤,临床文件,包括手术报告,被仔细分析。只有那些没有宏观腹膜扩散或在盆腔外没有宏观腹膜扩散的病例被定义为明显早期阶段,并在本研究中进行分析。
Stage is not covered by the definition of early-stage OC as defined by the German guideline in its current version [4]. pT2b tumours range between clearly early (pT1a-pT2a) and obviously advanced staged ( ). As most clinical trials focus on advanced staged OC and maintenance treatment is only approved for these individuals, clinical management of FIGO II patients has not been studied well. Hence, we decided to analyse them together with the early-stage OC cases mainly investigated here. Women younger than 18 years of age and women diagnosed with a tumour of low malignant potential or non-epithelial OC were excluded. An overview of sample characteristics is presented in Figure 1 as a flow chart.
阶段 不在德国指南当前版本[4]中对早期卵巢癌的定义范围内。 pT2b 肿瘤介于明显早期(pT1a-pT2a)和明显晚期( )之间。由于大多数临床试验侧重于晚期卵巢癌,并且维持治疗仅适用于这些患者,FIGO II 患者的临床管理尚未得到充分研究。因此,我们决定将他们与此处主要研究的早期卵巢癌病例一起进行分析。排除了年龄小于 18 岁的女性和诊断为低恶性潜能肿瘤或非上皮性卵巢癌的女性。样本特征的概述如图 1 所示的流程图中呈现。
Patient charts, aftercare files, and data stemming from the local tumour registry were used to produce clinical annotations. Patients' symptoms and location of primary diagnosis (basic/regular care vs. maximum hospital care) and diagnostic procedures (tumour markers and CT/MRT) were documented. Completeness of surgical staging was defined as stated in the German S3 guideline [4], which demands the following procedures: bilateral adnexectomy, hysterectomy, systematic lymphadenectomy, omentectomy, collection of peritoneal fluid, and peritoneal biopsies. Surgical staging was defined as complete when adnexectomy, hysterectomy, systematic lymphadenectomy (except for mucinous disease graded as G1), omentectomy, peritoneal fluid sampling, and peritoneal biopsies ( biopsy sample) were performed. Since information on the mode of surgery (i.e., laparotomic or laparoscopic) had not been collected for this registry, this was not included in the definition of complete surgical staging. For mucinous cancers, appendectomy was considered an obligatory step. The current version of the German guideline states that for early-stage mucinous disease graded as G1, systematic lymphadenectomy is not mandatory as long as no clinical signs of disease are found in the lymph nodes (LNs) [4].
患者病历、术后护理文件以及来自当地肿瘤登记处的数据被用来制作临床注释。记录了患者的症状和原发诊断位置(基本/常规护理 vs. 最大医院护理)以及诊断程序(肿瘤标记物和 CT/MRT)。手术分期的完整性定义如德国 S3 指南[4]所述,要求进行以下程序:双侧附件切除术、子宫切除术、系统性淋巴结清扫术、网膜切除术、腹腔液采集以及腹膜活检。手术分期被定义为完整,当进行了附件切除术、子宫切除术、系统性淋巴结清扫术(黏液性疾病分级为 G1 除外)、网膜切除术、腹腔液采样以及腹膜活检( 活检样本)。由于对手术方式(即腹腔开放术或腹腔镜手术)的信息未被收集到该登记处,因此这并未包括在完整手术分期的定义中。对于黏液性癌症,阑尾切除术被视为必要步骤。 德国指南的当前版本指出,对于被分级为 G1 的早期黏液性疾病,只要淋巴结(LNs)中没有疾病的临床表现,系统性淋巴清扫并非强制性。
The number of positive LNs, location of peritoneal biopsies, histologic subtype, and tumour grade were documented. Although we thoroughly screened tumour databases and patient files, certain information was missing in the final data set. For instance, we could not always exclude that a patient documented as not having had a hysterectomy during cancer surgery might indeed have previously had a hysterectomy in the past. When highand low-grade cases were compared across histologic subtypes, high grade was defined according to the 2020 definition of the World Health Organisation (WHO): high-grade serous (HGSOC), clear cell (no grading), poorly differentiated (G3) endometroid, and poorly differentiated (G3) mucinous disease. The remaining subtypes and grades were defined as low grades. A total of 9 cases showing serous histology and histologic grade 2 were grouped into the HGSOC subsample. All patients were staged according to the 2014 FIGO staging system for ovarian, fallopian tube, and peritoneal cancer. To increase the validity of the data, FIGO stage was controlled using the documentation of cancer cell spread in completely staged patients. Those with inconclusive FIGO stage were removed from survival analysis and analysis involving FIGO stage (Figure 1). Information on the
阳性淋巴结数量、腹膜活检位置、组织学亚型和肿瘤分级均有记录。尽管我们彻底筛查了肿瘤数据库和患者档案,但最终数据集中缺少某些信息。例如,我们无法始终排除患者在癌症手术期间被记录为未接受子宫切除手术的情况,实际上可能过去曾接受过子宫切除手术。在比较高级别和低级别病例在组织学亚型之间时,高级别根据世界卫生组织(WHO)2020 年定义进行定义:高级别浆液性(HGSOC)、透明细胞(无分级)、低分化(G3)子宫内膜样和低分化(G3)粘液性疾病。其余亚型和分级被定义为低分级。共有 9 例显示浆液性组织学和组织学分级 2 的病例被分组为 HGSOC 子样本。所有患者均根据 2014 年国际妇产科学会(FIGO)卵巢、输卵管和腹膜癌分期系统进行分期。为增加数据的有效性,通过完全分期患者的癌细胞扩散记录来控制 FIGO 分期。 那些 FIGO 分期不明确的人被从生存分析和涉及 FIGO 分期的分析中移除(图 1)。关于信息

method of testing (i.e., germ line or somatic) was not available. Furthermore, we documented whether adjuvant chemotherapy had been performed, the chemotherapy protocol, and number of cycles. Finally, follow-up data on relapse-free and overall survival were collected.
测试方法(即生殖系或体细胞)不可用。此外,我们记录了是否进行了辅助化疗,化疗方案以及周期数。最后,收集了复发无病生存和总体生存的随访数据。
Figure 1. Consort Diagram. Data sets from 379 ovarian cancer patients with pT1-2 stage were collected. Since 22 cases finally did not fulfil inclusion criteria or had macroscopically visible peritoneal carcinomatosis outside the pelvis, they had to be excluded (Figure 1). In total, 357 patients with apparent early-stage OC were analysed. For analysing details on surgery, those patients with full medical records on surgical staging and—as long as not stated otherwise-apparent stage pT1-pT2a were selected (Figure 1).
图 1. 合并图。收集了 379 名 pT1-2 期卵巢癌患者的数据集。由于最终有 22 例病例未达到纳入标准或在盆腔外有肉眼可见的腹膜癌转移,它们必须被排除(图 1)。总共分析了 357 名明显早期 OC 患者。为了分析手术细节,选择那些有完整手术分期医疗记录的患者,以及——只要没有另有说明——明显的 pT1-pT2a 期(图 1)。

2.2. Statistical Methods
2.2. 统计方法

Relapse-free survival (RFS) and disease-specific survival (DSS) were defined as the interval between first diagnosis and disease relapse or cancer-related death, respectively. In case of neither cancer-related death nor disease relapse, the data were censored.
复发无生存 (RFS) 和疾病特异性生存 (DSS) 被定义为首次诊断和疾病复发或癌症相关死亡之间的间隔。如果既没有癌症相关死亡也没有疾病复发,数据将被截尾。
Statistical analysis was performed using SPSS v29 (IBM Corp., Armonk, NY, USA), and data were plotted using SPSS and Microsoft Excel (Microsoft Corp., Redmond, SEA). Sankey-plot was drawn using SankeyMATIC (https:// sankeymatic.com/ accessed on 4 March 2023 [8]). The 2-sided -values lower than were considered statistically significant. Pearson's chi-squared test wase applied to assess whether there was a relationship between two categorical variables. Pair wise comparison of unlinked non-parametric values was performed using Mann-Whitney-U test. To evaluate differences in RFS for statistical significance, log-rank test was employed. The bivariate Kaplan-Meier method was extended to the multivariate Cox regression model to test for association with RFS in the presence of more than one predictor variable.
使用 SPSS v29(IBM Corp.,纽约州阿蒙克,美国)进行统计分析,数据使用 SPSS 和 Microsoft Excel(Microsoft Corp.,雷德蒙德,SEA)绘制。使用 SankeyMATIC 绘制桑基图(https://sankeymatic.com/,于 2023 年 3 月 4 日访问[8])。双侧 值低于 被认为具有统计学意义。应用 Pearson 卡方检验评估两个分类变量之间是否存在关系。使用曼-惠特尼 U 检验对非相关的非参数值进行成对比较。为了评估 RFS 的差异是否具有统计学意义,采用 log-rank 检验。双变量 Kaplan-Meier 方法扩展到多变量 Cox 回归模型,以测试与 RFS 相关的多个预测变量。

3. Results 3. 结果

3.1. Study Sample Characteristics
3.1. 研究样本特征

Initially, data sets were collected from 379 patients that had pT stage pT1-2. During initial data assessment, 22 cases were excluded as they ultimately did not fulfil the inclusion criteria or due to the presence of macroscopically visible peritoneal carcinomatosis outside the pelvis, suggesting an a priori advanced-stage disease (Figure 1). Finally, the data from 357 patients with apparent early-stage OC (i.e., pT1-2 and disease macroscopically limited to the pelvis) were analysed within this retrospective registry (Table 1). For analysing details on surgery, those patients with full medical records on surgical staging and apparent stage pT1-pT2a were selected (Figure 1).
最初,从 379 名 pT 阶段为 pT1-2 的患者收集了数据集。在最初的数据评估中,有 22 例被排除,因为它们最终未能满足纳入标准,或者由于在盆腔外存在宏观可见的腹膜癌病变,表明有先验的晚期疾病(图 1)。最终,对 357 名表现为早期卵巢癌(即 pT1-2 且疾病在宏观上仅限于盆腔)的患者的数据进行了分析(表 1)。为了分析手术细节,选择了那些拥有完整手术分期医疗记录的患者和明显 pT1-pT2a 阶段的患者(图 1)。
Table 1. Patient Characteristics.
表 1. 患者特征。
(Data Available) or Range  或范围
Patient age (median) 患者年龄(中位数)
357
145 40.6
14 3.9
1c 126 35.3
42 11.8
30 8.4
Grading 评分 335
HGSOC 117 34.9
LGSOC 21 6.3
G1 60 17.9
G2 65 19.4
G3 72 21.5
Histology 组织学 353
serous 浆液 141 39.9
endometrioid 子宫内膜样 93 26.3
mucinous 粘液性 54 15.3
clear cell 清晰的细胞 46 13.0
mixed 混合 10 2.8
other 其他 9 2.5
Clinicopathological data of patients diagnosed with apparent early-stage epithelial ovarian cancer (second top box in Figure 1, ) are shown. HGSOC high-grade serous ovarian cancer; LGSOC low-grade serous ovarian cancer
患有明显早期上皮性卵巢癌(图 1 中的第二个顶部框, )诊断的患者的临床病理数据显示。HGSOC 高级别浆液性卵巢癌;LGSOC 低级别浆液性卵巢癌
The median patient age was 55.8 years (range 19.1-88.1). The mean follow-up time was 2.0 years. During the follow-up period, 7 patients died of their OC, and the mean DSS was 6.5 years. Due to the rare number of DSS events, survival analysis was only run for RFS. The mean RFS was 5.5 years, and 35 relapses were documented. Most patients were diagnosed with stage pT1a (40.6%; 145/357) or 1c disease . Regarding histologic subtypes (documented in 353 cases), serous histology was the most common (39.9%; 141/353) followed by endometroid ( ; 93/353), mucinous ( ), and clear cell subtypes. Of the serous cases with known information on grade patients were diagnosed with the low-grade disease. pT stage above pT1 and high-grade ( ) were prognostic for shortened RFS in the non-stratified cohort. In the multivariate analysis, considering , grade/histologic subtype, and age, only the stage ( ; HR 5.7) predicted disease recurrence.
患者的中位年龄为 55.8 岁(范围 19.1-88.1 岁)。平均随访时间为 2.0 年。在随访期间,有 7 名患者因卵巢癌去世,平均疾病特异生存率为 6.5 年。由于疾病特异生存率事件数量稀少,只对无复发生存率进行了分析。平均无复发生存率为 5.5 年,共有 35 次复发记录。大多数患者被诊断为 pT1a 期(40.6%;145/357)或 1c 期疾病。关于组织学亚型(在 353 例中记录),浆液性组织学是最常见的(39.9%;141/353),其次是子宫内膜样(;93/353)、粘液性()、透明细胞亚型。在已知等级信息的浆液性病例中,患者被诊断为低等级疾病。pT1 以上的 pT 分期和高等级()在非分层队列中预示无复发生存率缩短。在多变量分析中,考虑等级/组织学亚型和年龄,只有分期(;HR 5.7)预测疾病复发。

3.2. Symptoms, Clinical Setting and Diagnostic Procedures
3.2. 症状、临床表现和诊断程序

Almost every second patient was diagnosed [42.8% (151/353)] or operated on [41.3% (143/354)] in an external clinic before being admitted to one of the centres running this registry. Seeking a second opinion was documented to be the reason for presentation at our centres in 126 [37.7% (126/334)] cases. Clinical symptoms at the time of initial diagnosis were documented in 252 patients (Figure 2A). Unclear abdominal pain was the symptom
几乎每第二位患者在被送入运行该登记处之一的中心之前,已在外部诊所被诊断[42.8%(151/353)]或接受手术[41.3%(143/354)]。寻求第二意见被记录为在我们中心就诊的原因,共有 126 例[37.7%(126/334)]。初次诊断时的临床症状已在 252 名患者中记录(图 2A)。不明确的腹痛是症状。

most often noted ( ). Abdominal bloating was another common sign ; 31/252), while abnormal vaginal bleeding ( ; 14/252), B-symptoms (3.17%; 8/252), and embolic disease were reported less frequently. Incidental diagnosis or diagnosis via transvaginal ultrasound performed for an unknown reason was documented in of cases.
大多数时候注意到( )。腹部胀气是另一个常见的症状 ;31/252),而异常阴道出血( ;14/252)、B 症状(3.17%;8/252)和栓塞疾病 报道较少。偶然诊断或通过不明原因进行的经阴道超声检查诊断在 例中有记录。
A
C
B
D
Figure 2. Diagnostics. Prevalence of symptoms is shown in pie chart (A). Distribution of CA125 blood levels as split up by pT stage is depicted in bar chart (B). Stacked bar charts in show BRCA1 and BRCA2 testing rates. Fraction of patients that underwent BRCA1 or BRCA2 testing is marked in orange, while those within the blue fraction were documented to have not undergone testing Whether testing was performed at all was unknown (not documented) for patients represented by the grey bars. Small pie charts in (C) depict BRCA1/2 mutation frequency (BRCA1 upper pie, lower pie) relative to the cases with known test result of analysis, respectively. Testing rates for both BRCA1 and BRCA2 increased over time (D). TVUS = transvaginal ultrasound; wildtype; mut mutant.
图 2. 诊断。症状的患病率显示在饼图中(A)。根据 pT 分期划分的 CA125 血液水平分布显示在条形图中(B)。 中的堆叠条形图显示 BRCA1 和 BRCA2 的测试率。进行 BRCA1 或 BRCA2 测试的患者比例标记为橙色,而蓝色部分中的患者据称未进行 测试。对于灰色条表示的患者,是否进行了 测试是未知的(未记录)。小饼图(C)显示相对于已知 分析测试结果的病例,BRCA1/2 突变频率(BRCA1 上方饼图, 下方饼图)。BRCA1 和 BRCA2 的测试率随时间增加(D)。TVUS = 经阴道超声; 野生型;mut 突变型。
Evaluated serum tumour markers included CA125, HE4, and CEA. HE4 was only determined in 13 cases (10 patients with normal range and 3 with elevated [ ULN] HE4) and CEA in 103 patients ( 92 patients with normal range and 11 patients with elevated [ ULN] CEA). CA125 was the serum tumour marker most often assessed, with testing performed on 179 patients, and most patients ( ) showed clearly elevated (defined as ) CA125 levels (Figure 2B). Though median CA125 levels were not different when pT1 and pT2 stages were compared, CA125 was more commonly found to be significantly elevated ( ) in cases . In addition to tumour marker testing, imaging examinations other than ultrasound were documented for staging in the large majority of patients
评估的血清肿瘤标志物包括 CA125、HE4 和 CEA。HE4 仅在 13 例中确定(10 例患者 HE4 正常范围,3 例 HE4 升高[ ULN]),CEA 在 103 例患者中确定(92 例患者 CEA 正常范围,11 例 CEA 升高[ ULN])。CA125 是最常评估的血清肿瘤标志物,共有 179 例患者进行了检测,大多数患者( )显示明显升高(定义为 )的 CA125 水平(图 2B)。尽管比较 pT1 和 pT2 期时,CA125 的中位数水平没有差异,但在 例中,CA125 更常见地被发现明显升高( )。除了肿瘤标志物检测外,大多数患者还记录了除超声以外的影像检查用于分期
Whether BRCA1 or BRCA2 mutation testing had been performed or not was only known for 255 and 227 cases, respectively. The number of women that indeed had undergone testing was even lower. Only (93/255) and (87/227) were documented to have been tested for BRCA1 or BRCA2 (Figure 2C). Notably, testing rates gradually increased over time (Figure 2D). Test results were recorded in 79 (BRCA1) and 85 (BRCA2) cases. BRCA1 mutation was detected in of patients, and BRCA2 mutation was detected in (7/85) of patients. Neither the diagnostic setting, the BRCA1/2 status, nor the CA125 level was of prognostic significance (Supplementary Figure S1).
无论是否进行了 BRCA1 或 BRCA2 突变测试,只有 255 例和 227 例的情况是已知的。实际进行测试的女性数量甚至更少。只有 (93/255)和 (87/227)被记录为接受了 BRCA1 或 BRCA2 的测试(图 2C)。值得注意的是,随着时间的推移,测试率逐渐增加(图 2D)。79 例(BRCA1)和 85 例(BRCA2)的测试结果被记录下来。BRCA1 突变在 名患者中被检测出来,BRCA2 突变在 (7/85)名患者中被检测出来。无论是诊断设置、BRCA1/2 状态还是 CA125 水平都不具有预后意义(附图 S1)。

3.3. Surgery 3.3. 手术

As defined by the inclusion criteria, surgical tumour resection was performed in all patients . The healthcare level of the hospital where the initial surgery was performed was documented in 335 cases. In 119 of 335 patients ( ), the primary surgery was performed in a hospital of basic or regular care level. Whether one- or two-step surgery was performed was known for 349 cases. About one-half of the patients received 2-step surgery. In the case of 2-step surgery, the median interval between the first and second operations was 32.5 days. Notably, an interval between the first and second surgery of longer than 60 days was associated with reduced RFS ( ).
根据纳入标准的定义,所有患者均进行了手术切除肿瘤 。记录了初次手术所在医院的医疗水平共 335 例。在 335 例患者中,有 119 例( )在基本或普通护理水平的医院进行了初次手术。对于 349 例病例,已知是否进行了一步或两步手术。大约一半的患者 接受了两步手术。在两步手术的情况下,第一次和第二次手术之间的中位间隔为 32.5 天。值得注意的是,第一次和第二次手术之间的间隔超过 60 天与减少的 RFS( )相关。
Complete medical records on the extent of surgical staging were available for 317 patients (Figure 1). Among these cases, completeness of surgical staging as defined above was analysed in patients staged lower than pT2b (Figure 1, Table 2). While 192 ( ) were staged according to the interpretation of the current guideline [4] employed in this work (see Method section for details), were missing at least 1 surgical step recommended by the guideline (Figure 1). The reason for breaking with the guideline was documented in only 34 (of 100) cases. Reasons were approximately evenly distributed: declined by the patient , presence of comorbidities , fertility conservation , and recommended by the physician (Figure 3A). When comparing patients with complete and incomplete surgical staging, completely staged patients more often had serous histology or were classified as high-grade, while no significant differences regarding stage were detected (Table 2). The type of hospital where (primary) surgery was performed did not impact the rate of complete surgical staging. Furthermore, there was no difference regarding the surgical setup (one- vs. two-step), application of chemotherapy, and patient age (Table 2). The rate of incomplete surgical staging over time ranged between and (Figure 3B).
317 名患者的手术分期范围完整的医疗记录可用(图 1)。在这些病例中,根据上述定义,对低于 pT2b 的患者进行的手术分期的完整性进行了分析 (图 1,表 2)。其中,有 192 例( )根据本研究中采用的当前指南[4]的解释进行分期(有关详细信息,请参见方法部分), 至少缺少了指南建议的 1 个手术步骤(图 1)。与指南背道而驰的原因仅在 100 例中的 34 例中有记录。原因大致均匀分布:患者拒绝 ,合并症 ,保留生育 ,医生建议 (图 3A)。在比较完整和不完整手术分期的患者时,完全分期的患者更常见为浆液组织学或被分类为高级别,而在分期方面没有检测到明显差异 (表 2)。进行(初级)手术的医院类型对完整手术分期的比例没有影响。此外,在手术设置方面也没有差异(单一 vs. 两步法),化疗应用和患者年龄(表 2)。随着时间推移,不完全手术分期的比率在 之间波动(图 3B)。
Table 2. Clinicopathological Characteristics of Patients with Complete vs. Incomplete Surgical Staging (stages pT1-pT2a only).
表 2. 完整手术分期与不完整手术分期患者的临床病理特征(仅限 pT1-pT2a 期)。
Data Available ( )
数据可用 ( )
Surgical Staging 手术分期
Complete 完成 Incomplete 不完整
pT1 292 165 91 ns
pT2 27 9
Histology 组织学
other 其他 291 110 71 0.016
serous 浆液 82 28
Grade 等级
low 281 68 48 0.013
high  120 45
(Primary) Surgery (主要) 手术
regular care hospital 定期护理医院 291 130 58
maximal care hospital 最大护理医院 62 41
Surgical Setup 手术准备
one-step 一步到位 291 85 43
two-step 两步 107 56
Received CHT 收到 CHT
no 243 135 54 ns
yes 36 18
Patient Age 患者年龄
years  288 104 46 ns
years  87 51
Completeness of surgical staging (complete vs. incomplete) was tested for independence from , histology grade, location of (primary) surgery, surgical setup, application of chemotherapy (CHT), and patient age. -values derived from Chi2 tests are displayed. ns = not significant
手术分期的完整性(完整 vs. 不完整)与 、组织学分级、(原发)手术部位、手术设置、化疗(CHT)的应用以及患者年龄进行了独立性检验。 Chi2 检验得出的 P 值显示在下面。ns = 不显著

A

C

B

D
Figure 3. Incompletely Staged Patients. Reasons for incomplete staging are illustrated as a pie chart (A). (B) shows rate of incomplete surgical staging (i.e., missing at least one surgical procedure recommended, as specified in Materials and Methods) over time. Incompletely staged patients missed at least one surgical step (adnexectomy, hysterectomy, systematic lymphadenectomy (except for mucinous disease graded as G1), omentectomy, peritoneal fluid sampling, peritoneal biopsies ( biopsy sample), or appendectomy (in the case of mucinous subtype)). How often a certain surgical staging step was missed is depicted in (C). Missing peritoneal sampling was associated with reduced RFS in incompletely staged cases with stage ) but failed to be prognostic in the non-stratified cohort (Supplementary Table S1). Bilat. AE = bilateral adnexectomy; hysterectomy; omentectomy; per.fluid peritoneal fluid sampling; peritoneal biopsies; sys. LNE = systemic lymphadenectomy; AppE = appendectomy; acc = according; * data from mucinous cases only.
图 3. 未完全分期的患者。未完全分期的原因以饼图形式呈现(A)。 (B) 显示了随时间推移未完全手术分期的比例(即,缺少至少一项手术程序,如材料和方法中规定的)。未完全分期的患者至少错过了一项手术步骤(adnexectomy,子宫切除术,系统性淋巴清扫术(除了黏液性疾病分级为 G1 的情况),网膜切除术,腹腔液体采样,腹膜活检( 活检样本),或阑尾切除术(在粘液亚型的情况下))。某个手术分期步骤被错过的频率如(C)所示。未进行腹腔采样与未完全分期病例中 )的 RFS 降低有关,但在非分层队列中未能成为预后因素(附表 S1)。Bilat. AE = 双侧 adnexectomy; 子宫切除术; 网膜切除术; per.fluid 腹腔液体采样; 腹膜活检; sys. LNE = 系统性淋巴清扫术; AppE = 阑尾切除术; acc = 根据; *仅来自粘液病例的数据。
Within the subgroup of incompletely staged patients ( ), resection was the procedure most often omitted . Regarding the mucinous subtype, the step most often skipped was appendectomy ( ; Figure 3C).
在未完全分期患者亚组中( ), 切除术是最常被省略的程序 。就黏液样亚型而言,最常被跳过的步骤是阑尾切除( ;图 3C)。
The prevalence of missed surgical procedures was not dependent on histology or grade. Hysterectomy was more commonly omitted in cases staged pT1a-c ( , while peritoneal fluid sampling was more frequently missed in pT2a ( ). Upon comparing incompletely staged patients with one- vs. two-step surgery, those with two-step surgery did less often miss omentectomy ( ) and peritoneal biopsies ( ). Neglecting to take peritoneal samples was prognostic for shortened RFS in patients that had been assigned stage 1 (Figure 3D). In contrast-upon including -omitting systematic lymphadenectomy was critical for patients with apparent stage or pT2b. In terms of the non-stratified cohort of incompletely staged patients, the prognostic effect of neglecting to take peritoneal biopsies ) or performing systematic lym-
手术程序遗漏的普遍性并不取决于组织学或分级。在分期为 pT1a-c 的病例中更常省略子宫切除术( ),而在 pT2a 中更常遗漏腹腔液采样( )。将未完全分期的患者与一步手术和两步手术进行比较,两步手术的患者更少遗漏腹膜切除术( )和腹膜活检( )。忽略取腹膜样本对已被分配为 1 期的患者的 RFS 缩短有预后意义( )(图 3D)。相反,包括 在内,对于表观 分期 或 pT2b 的患者,遗漏系统性淋巴清扫是关键的 。在未完全分期患者的非分层队列中,忽略取腹膜活检 )或进行系统性淋巴清扫的预后效应。

phadenectomy ( ) did not reach statistical significance (Supplementary Table S1). Neither stage nor histology/grade was of prognostic significance in incompletely staged patients. Finally, we analysed whether incom