S3-Guideline on Diagnostics, Therapy and Follow-up of Malignant Ovarian Tumours

1 Information about this Short Version

1.1 Editors

German Guideline Programme in Oncology (OL) of the Association of the Scientific Medical Societies in Germany (AWMF), the German Cancer Society (DKG) and German Cancer Aid (DKH).

1.2 Leading professional society

Germany Society for Gynaecology and Obstetrics (DGGG).

1.3 Funding

This guideline was funded by German Cancer Aid as part of the German Guideline Programme in Oncology.

1.4 Contact

Office of the German Guideline Programme in Oncology

c/o Deutsche Krebsgesellschaft e. V.

Kuno-Fischer-Straße 8

14 057 Berlin, Germany

[e-mail]

www.leitlinienprogramm-onkologie.de

1.5 Citation

The German Guideline Programme in Oncology (German Cancer Society, German Cancer Aid, AWMF): S3-Guideline on Diagnostics, Therapy and Follow-up of Malignant Ovarian Tumors, short version 1.0 (2013), AWMF registration number: 032–035OL, http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html

1.6 Note

Medicine is continually subject to a process of development and change so that all information, particularly all information on diagnostic and therapeutic treatments, can only reproduce the state of knowledge at the time of printing of this guideline on care. The greatest possible care was taken when compiling these recommendations on therapy and the choice and dosage of medications. Users are requested to consult the package leaflets and check the summary of product characteristics provided by manufacturers and, when in doubt, to consult a specialist. In the interests of all concerned, please contact the OL editorial office if you find discrepancies or controversial issues. Users are responsible for all diagnostic and therapeutic applications, medications and dosages.

Registered trademarks (brand names) mentioned in this guideline have not been specifically labelled. When a specific indication lacks a trade name it should not be concluded that the brand name has not been registered. This guideline and all of its constituent parts is protected under copyright law. Any utilisation contrary to the provisions of copyright law without the written permission of the OL editorial office is prohibited and liable to prosecution. No part of this guideline may be reproduced in any form without the written permission of the OL editorial office. This applies in particular to copies, translations, microfilms and all storage, utilization and processing in electronic systems, intranets and the internet.

1.7 Additional guideline documents

The contents of this short version refer to the long version of the S3-Guideline on Diagnostics, Therapy and Follow-up of Malignant Ovarian Tumours available in German on the following websites

• AWMF (http://www.awmf.org/leitlinien/aktuelle-leitlinien.html)

• German Guideline Programme in Oncology http://www.leitlinienprogramm-onkologie.de/OL/leitlinien.html

• German Cancer Society http://www.krebsgesellschaft.de/wub_llevidenzbasiert,120884.html

• German Cancer Aid (http://www.krebshilfe.de/)

• Guidelines International Network (www.g-i-n.net)

• Contributing German scientific medical societies (e.g. http://www.dggg.de/leitlinien/)

In addition to the short version, a number of other, supplementary documents are also available:

• Guideline report on the compilation of the guideline

• Long version

• Patient guideline

All of these documents will also be available on the websites listed above.

1.8 Responsibilities

1.8.1 Authors of the guideline

Editorial team

• Prof. Dr. Uwe Wagner (Co-ordinator, DGGG), Uni-Frauenklinik, Baldingerstraße, 35 043 Marburg, Germany

• Dr. Philipp Harter (DGGG), Kliniken Essen-Mitte, Henricistraße 92, 45 136 Essen, Germany

• PD Dr. Felix Hilpert (DGGG), Universitätsklinikum Schleswig Holstein, Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Arnold-Heller-Straße 3, Haus 24, 24 105 Kiel, Germany

• PD Dr. Sven Mahner (DGGG), Universitätsklinikum Hamburg-Eppendorf, Klinik für Gynäkologie, Martinistraße 52, 20 246 Hamburg, Germany

• Alexander Reuß, Koordinierungszentrum für Klinische Studien, Philipps-Universität Marburg, Karl-von Frisch-Straße 4, 35 043 Marburg, Germany

Participating scientific societies and authors

• Prof. Dr. Andreas du Bois – Arbeitsgemeinschaft Gynäkologische Onkologie e. V. (AGO) [Gynaecological Oncology Working Group]

• Prof. Dr. Edgar Petru – Arbeitsgemeinschaft für Gynäkologische Onkologie Austria (AGO AT) [Gynaecological Oncology Working Group Austria]

• Prof. Dr. Werner Meier – AGO Study Group

• Dr. Petra Ortner – Arbeitsgemeinschaft Supportive Maßnahmen in der Onkologie, Rehabilitation und Sozialmedizin (ASORS) [Working Group for Supportive Measures in Oncology, Rehabilitation and Epidemiology]

• Dr. Klaus König – Berufsverband der Frauenärzte e. V. (BVF) [Professional Organisation of German Gynaecologists]

• PD Dr. Katja Lindel – Deutsche Gesellschaft für Radioonkologie (DEGRO) [German Society for Radio-oncology]

• Prof. Dr. Dieter Grab – Deutsche Gesellschaft für Ultraschall in der Medizin e. V. (DEGUM) [German Society for Ultrasound in Medicine]

• Prof. Dr. Pompiliu Piso – Deutsche Gesellschaft für Allgemein- u. Viszeralchirurgie (DGAV) [German Society for General and Abdominal Surgery]

• Prof. Dr. Olaf Ortmann – Deutsche Gesellschaft für Endokrinologie (DGE) [German Society for Endocrinology]

• Prof. Dr. Ingo Runnebaum – Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) [Germany Society for Gynaecology and Obstetrics]

• Prof. Dr. Jacobus Pfisterer – Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) [Germany Society for Gynaecology and Obstetrics]

• PD Dr. Diana Lüftner – Deutsche Gesellschaft f. Hämatologie und Onkologie e. V. (DGHO) [German Society for Haematology and Oncology]

• Prof. Dr. Norbert Frickhofen – Deutsche Gesellschaft für Innere Medizin e. V. (DEGIM) [German Society for Internal Medicine]

• Prof. Dr. Frank Grünwald – Deutsche Gesellschaft für Nuklearmedizin e. V. (DGN) [German Society for Nuclear Medicine]

• Dr. Bernd Oliver Maier – Deutsche Gesellschaft für Palliativmedizin e. V. (DGP) [German Society for Palliative Medicine]

• Prof. Dr. Joachim Diebold, Prof. Dr. Steffen Hauptmann, Prof. Dr. Friedrich Kommoss – Deutsche Gesellschaft für Pathologie e. V. (DGP) [German Pathology Society]

• Prof. Dr. Günter Emons – Deutsche Menopausengesellschaft e. V. (DMG) Deutsche Gesellschaft für Pathologie [German Pathology Society]

• Dr. Boris Radeleff – Deutsche Röntgengesellschaft (DRG) [German Radiology Society]

• Marion Gebhardt (patientsʼ representative) – Bundesverband der Frauenselbsthilfe nach Krebs e. V. [Federation of Womenʼs Self-help after Cancer Organisations]

• Prof. Dr. Norbert Arnold – Deutsche Gesellschaft für Humangenetik (GfH) [German Society for Human Genetics]

• Dr. Gabriele Calaminus – Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) [Society for Paediatric Oncology and Haematology]

• Isolde Weisse – Konferenz Onkologischer Kranken- und Kinderkrankenpflege (KOK) [Conference for Oncologic Patient Care and Paediatric Patient Care]

• Prof. Dr. Joachim Weis – Arbeitsgemeinschaft für Psychosoziale Onkologie (PSO) [Psycho-social Oncology Working Group]

• Prof. Dr. Jalid Sehouli – Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie (NOGGO) [Northeast German Society for Gynaecological Oncology]

• Prof. Dr. Daniel Fink – Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe (SGGG) [Swiss Society for Gynaecology and Obstetrics]

• Dr. Alexander Burges – as an independent expert

• Prof. Dr. Annette Hasenburg – as an independent expert

• Dr. C. Eggert from the Medizinischen Dienst der Krankenversicherung in Hessen (MDK Hessen) [Medical Service of the Health Insurance Companies in Hesse] contributed to the discussions at the Consensus Conferences as an expert without voting rights.

Methodological Support

1. The German Guideline Programme on Oncology

   • Prof. Dr. Ina Kopp, Marburg (AWMF)

   • Dr. Markus Follmann MPH MSc, Berlin (DKG) [German Cancer Society]

   • Dipl.-Soz.Wiss Thomas Langer (DKG) [German Cancer Society]

2. External agencies:

3. Coordination Centre for Clinical Studies of Philipps University Marburg, A. Reuß, Dr. D. Lubbe

4. Bremen Institute for Prevention Research and Epidemiology (BIPS), Dr. K. Giersiepen

5. The leading professional society:

6. Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) [German Society for Gynaecology and Obstetrics], Prof. Dr. R. Kreienberg

2 Introduction

2.1 Target audience

The guideline was compiled with the aim of providing high-risk groups with advice on diagnostics, surgical and systemic therapy in early and advanced stages of disease together with the treatment of rare histological subtypes. A lot of emphasis has been placed on follow-up care, rehabilitation, palliative therapy and psycho-oncological counselling. The recommendations are for physicians working both in hospitals and outpatient clinics, nursing staff and other medical partners involved in treating patients with malignant ovarian tumours. As it also covers the topics ‘Screening’ and ‘Follow-up’, registered physicians working in their own practice are also an important target audience of this guideline. It is additionally intended to offer guidance to affected patients and persons seeking more information as well as providing a basis for the gynaecological cancer centres currently being set up in Germany.

For the first time, scientific medical societies in Switzerland and Austria were also consulted, expanding the scope of this guideline.

2.2 Methodology

The methodological approach used to compile the guideline has been described in the guideline report. The guideline report is freely available online (in German), for example on the website of the German Guideline Programme in Oncology (http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html) and the pages of the AWMF (http://www.awmf.org/).

2.2.1 SIGN level of evidence system

To classify the risk of bias or confounding in the identified studies, this guideline has used the level of evidence system of the Scottish Intercollegiate Guidelines Network (SIGN, Version 2009) (http://www.sign.ac.uk/pdf/sign50.pdf) as described in [Table 1] below.

Table 1 SIGN system for level of evidence grading (Version 2009).

Level	Description
1++	High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias
1+	Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1−	Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2++	High quality systematic reviews of case-control or cohort studies, or high quality case control or cohort studies with a very low risk of confounding or bias (“chance”) and a high probability that the relationship is causal
2+	Well conducted case-control or cohort studies with a low risk of of confounding or bias (“chance”) and a moderate probability that the relationship is causal
2−	Case-control or cohort studies with a high risk of confounding or bias (“chance”) and a significant risk that the relationship is not causal
3	Non-analytic studies, e.g. case reports, case series
4	Expert opinion

2.2.2 System of grading recommendations

The OL methodology uses the grades of recommendation awarded by the authors of the guideline. The level of recommendation is decided on in a formal consensus process, using a multi-step nominal group technique moderated by the AWMF.

The guideline includes the level of evidence (SIGN, see 2.2.1) of the studies on which they are based as well as the strength of the recommendation (grade of recommendation) for all evidence-based statements (see chapter 2.2.3) and recommendations. This guideline has three different ‘strength of recommendation’ ratings (see [Table 2] below), which are also reflected in the formulation of the recommendation.

Table 2 Grades of recommendations.

Grade of recommendation	Description	Syntax
A	strongly recommended/or not recommended	must/necessary
B	recommended/or not recommended	should
0	neither recommended nor not recommended	can

2.2.3 Statements

Statements are expositions or explanations of specific facts or issues which do not constitute a call for action. They are approved in a similar manner to that used for recommendations in a formal consensus process and may be based either on study results or expert opinions.

2.2.4 Clinical consensus (CC)

Statements/recommendations which were drawn up on the basis of a consensus of experts from the guideline group are identified by the term “clinical consensus”. No symbols were used to grade the clinical consensus; the strength of the consensus is indicated by the formulations used (must, necessary/should/can) as described for the gradations in [Table 2].

2.2.5 Independence and disclosure of possible conflicts of interest

German Cancer Aid provided the funding through the German Guideline Programme in Oncology (OL). Funds were used for staffing costs, office materials, literature and consensus conferences (costs of venue, the media technology required at conferences, catering, moderatorʼs fees, travelling expenses of participants). Travelling expenses were reimbursed in accordance with the German law on travel expenses when on company business or according to standard practice for the DKG [German Hospital Federation]. Editorial decisions and the compilation of the guideline were carried out entirely independent of the funding organisation. During the guideline process, all members provided a written disclosure of possible conflicts of interest. The conflicts of interest disclosed are included in the guideline report to this guideline (http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html). We would like to take this opportunity of thanking all contributors for their contribution to the project, which was entirely voluntary and unsalaried.

2.2.6 Period of validity and update process

This S3-guideline will remain valid until it is next updated; its estimated period of validity is 3 years. Regular updates are planned; if an urgent need for changes to the guideline occurs in between update times, these changes will be published separately. Comments and advice for the update process are expressly requested and should be sent to the following address:

Prof. Dr. Uwe Wagner, Klinik für Gynäkologie, gynäkologische Endokrinologie und Onkologie, Baldingerstraße, D-35043 Marburg, Germany; phone: [phone], fax: [phone], e-mail: [e-mail].

2.3 List of abbreviations

Abbreviation	Meaning
AUC	Area under the Curve
GR	Grade of Recommendation, A = strongly recommended, B = recommended, 0 = neither recommended nor not recommended
HIPEC	Hyperthermal Intraperitoneal Chemotherapy
HT	Hormone Therapy
CC	Clinical Consensus
GL	Guideline
LoE	Level of Evidence
OL	German Guideline Programme in Oncology
OP	Operation
ST	Statement
TVS	Transvaginal sonography
WHO	World Health Organisation

3 Epidemiology, Screening and Diagnostics

3.1 Screening

No.	Recommendations/Statements	GR	LoE	Sources
3.1.	Screening with CA-125 and TVS has not resulted in any drop in mortality to date.	ST	1++	Guidelines: [1], [2] Primary studies: [3], [4], [5], [6], [7], [8], [9]
3.2.	General screening is not necessary.	A	1++	Guidelines: [1], [2] Primary studies: [3], [4], [5], [6], [7], [8], [9]
3.3.	Multidisciplinary consultation (gynaecologist and human geneticist) and genetic testing must be offered if a patient is in the at-risk population.	CC
3.4.	Screening with CA-125 and TVS was not proven to reduce mortality in risk groups.	ST	3	Guidelines: [1] Primary studies: [10], [11], [12], [13]
3.5.	Screening of groups at risk is not necessary.	A	3	Guidelines: [1] Primary studies: [10], [11], [12], [13]

3.2 Diagnostics

No.	Statements	GR	LoE	Sources
3.6.	Further examinations should be initiated if the following symptoms occur repeatedly and persistently, particularly in women above the age of 50: Bloatedness Flatulence Vague abdominal pain or discomfort Increased frequency of micturition	CC
3.7.	If there is a suspicion of an ovarian mass, pelvic examination (palpation, speculum) must be carried out, followed by transvaginal sonography.	CC
3.8.	No diagnostic examination exists which can take the place of operative staging for ovarian cancer and give a reliable assessment of the tumourʼs operability.	CC

3.3 Diagnosis of recurrence

No.	Recommendations	GR	LoE	Sources
3.9.	Asymptomatic patients: If, contrary to the recommendations of the guideline, there is a suspicion of recurrence based on increased CA-125 levels, the further procedure should be discussed with the individual patient. An early, pre-symptomatic start of treatment for recurrence is not associated with improved survival rates.	B	1+	Primary studies: [14]
3.10.	Symptomatic patients: If symptoms are present, additional diagnostic investigations can be initiated. We were unable to identify evidence which would indicate improved survival for any of the available procedures.	0	2+	Primary studies: [15], [16], [17], [18], [19], [20], [21], [22], [23]

4 Patient Consent and Information

No.	Statements	GR	LoE	Sources
4.1.	The information provided by the physician to the patient must include information on the disease, the results of the examination(s), the course of treatment to date, the diagnostic and therapeutic options including expected side-effects as well as the assessment of the associated prognosis and the impact on the patientʼs life plans and quality of life. Written materials and other suitable media can be used to help explain all of this to the patient and as aids in decision-making.	CC
4.2.	Conveying this information and explaining it to the patient must be done based on the following principles of patient-centred communication: The physician must show empathy and use active listening Difficult topics must be touched upon directly and sensitively Avoid using specialised medical vocabulary; explain specialist terminology where necessary Use strategies to improve the patientʼs comprehension (repetition, summarising of important information, use of diagrams and graphs) Encourage the patient to ask questions Permit and encourage the patient to express her feelings, particularly her worries and fears Offer further help	CC
4.3.	The patientʼs wishes about being involved in the process of medical decision-making must be taken into account.	CC

5 Genetics, Prevention and Risk Factors

No.	Recommendations/Statements	GR	LoE	Sources
5.1.	Bilateral salpingo-oophorectomy is the most effective method to reduce the risk of developing the disease and to reduce mortality in patients with hereditary ovarian cancer.	ST	2+	Guidelines: [1], [2] Primary studies: [11], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]
5.2.	Patients with BRCA1/2 mutation should be offered prophylactic bilateral salpingo-oophorectomy; surgery should be done once the patient plans to have no more children, after the patient has either turned 40 years of age or 5 years prior to the youngest age at which a member of the patientʼs family developed ovarian cancer.	B	2+	Guidelines: [2] Primary studies: [11], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]

6 Pathological Diagnosis and Prognostic Factors

No.	Recommendations/Statements	GR	LoE	Sources
6.1.	To date, the evidence for an association between detected biochemical parameters and prediction/prognosis has been insufficient.	ST	2+	Primary studies: [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50]
6.2.	The established prognostic factors for ovarian cancer listed below must be used: Tumour stage Postoperative residual tumour Age General condition Histological type Tumour grading Guideline-based therapy	CC

7 Surgical Treatment

7.1 Surgical treatment of early ovarian cancer

No.	Recommendations	GR	LoE	Sources
7.1.	Optimal staging must include the following surgical steps: Longitudinal laparotomy Inspection and palpation of the entire abdominal cavity Peritoneal cytology Biopsies from all abnormal sites Peritoneal biopsies from unremarkable regions Bilateral excision of adnexa of uterus Hysterectomy, using an extraperitoneal approach where necessary Infracolic omentectomy Appendectomy (for mucinous/unclear tumour types) Bilateral pelvic and paraaortal lymphonodectomy	CC
7.2.	If ovarian cancer is unexpectedly diagnosed, this must be confirmed histologically and the extent of spread described. The definitive treatment must then be carried out by a gynaecological oncologist.	CC
7.3.	In patients with unilateral FIGO I stage tumours, fertility-preserving surgery can be done if staging was adequate.	0	4	Primary studies: [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65]
7.4.	Patients with early stage ovarian cancer must be informed about the increased risk associated with fertility-preserving treatment, a risk which also depends on additional prognostic factors.	CC
7.5.	Laparoscopic staging must not be done outside of studies.	A	3	Guidelines: [2] Primary studies: [66], [67], [68], [69], [70], [71], [72]

7.2 Surgical treatment of advanced ovarian cancer

No.	Recommendations/Statements	GR	LoE	Sources
7.6.	The goal of primary surgery to treat advanced ovarian cancer must be macroscopically complete resection.	CC
7.7.	Multivisceral resection must be carried out if complete resection (free of residual macroscopic tumour) can be achieved or if it can be used to remove an obstruction and is not contraindicated in this patient.	CC
7.8.	If advanced ovarian cancer is unexpectedly diagnosed, this must be confirmed histologically and the extent of spread described. The definitive treatment must then be carried out by a gynaecological oncologist in a suitable facility.	A	4	Guidelines: [2] Primary studies: [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89]
7.9.	Patients obtain no benefit from primary chemotherapy followed by interval operation.	ST	1+	Guidelines: [1] Primary studies: [90], [91], [92], [93], [94], [95]
7.10.	The sequence of therapy must consist first of primary surgery followed by chemotherapy.	A	1+	Guidelines: [1] Primary studies: [90], [91], [92], [93], [94], [95]
7.11.	Second-look operations must not be carried out.	CC

8 Systemic Primary Therapy

8.1 Systemic primary therapy for early ovarian cancer

No.	Recommendations	GR	LoE	Sources
8.1.	Patients with stage IA grade 1 ovarian cancer after complete operative staging must not receive adjuvant chemotherapy.	A	1+	Primary studies: [96], [97], [98], [99], [100], [101], [102], [103], [104]
8.2.	Patients with stage IC or IA/B, grade 3 ovarian cancer must receive platinum-based chemotherapy (6 cycles).	A	1+	Primary studies: [96], [97], [98], [99], [100], [101], [102], [103], [104]
8.3.	Patients with stage IAG2, IB G1/2 ovarian cancer can be offered platinum-based chemotherapy.	0	1+	Primary studies: [96], [97], [98], [99], [100], [101], [102], [103], [104]
8.4.	The therapy should include carboplatin and consist of 6 cycles.	B	1+	Guidelines: [1], [2] Primary studies: [67], [99], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117]

8.2 Systemic primary therapy for advanced ovarian cancer[]

No.	Recommendations	GR	LoE	Sources
* Data on the effectiveness of consolidation or maintenance therapy to increase progression-free survival (PFS) is only available for bevacizumab (see 8.6.)
8.5.	The first-line chemotherapy for patients with advanced ovarian cancer (II b-IV) must consist of carboplatin AUC5 and paclitaxel 175 mg/m2 for 3 h i. v. over a total of 6 cycles, with one cycle every 3 weeks.	A	1++	Guidelines: [118], [119] Primary studies: [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131]
8.6.	Additional therapy with bevacizumab can be considered in patients with advanced ovarian cancer (IIIB-IV).	0	1+	Primary studies: [132], [133]
8.7.	Changes in dose density or intensity should only be done as part of a clinical trial.	B	1+	Guidelines: [2] Primary studies: [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146]
8.8.	No maintenance or consolidation therapies must be carried out after primary therapy has been completed.*	A	1+	Primary studies: [132], [133], [147], [148], [149], [150], [151], [152], [153], [154]
8.9.	Systematic recording of the patientʼs quality of life can be helpful to identify difficulties during treatment.	CC

9 Treatment for Recurrence

9.1 Populations with recurrence

No.	Statement	GR	LoE	Sources
9.1.	Platinum-sensitive ovarian cancer: Disease responds primarily to platinum-based first-line chemotherapy with recurrence occurring at the earliest 6 months after conclusion of platinum-based chemotherapy. This also includes the subgroup of partially platinum-sensitive recurrences of ovarian cancer. In this subgroup, disease also responds primarily to platinum-based first-line chemotherapy but recurrence occurs between 6 and 12 months after concluding platinum-based chemotherapy. Platinum-resistant ovarian cancer: Disease recurs within the first 6 months after concluding initial platinum-based chemotherapy. This also includes the subgroup with platinum-refractory recurrence of ovarian cancer. In this subgroup, disease does not respond to platinum-based chemotherapy or disease progresses within 4 weeks after therapy has been concluded.	ST	1+	Guidelines: [1], [119] Primary studies: [14], [155], [156], [157], [158], [159], [160], [161], [162], [163]

9.2 Systemic therapy for recurrence

9.2.1 Platinum-resistant recurrence

No.	Recommendations/Statements	GR	LoE	Sources
9.2.	Combination therapy offers no advantages compared to monotherapy.	ST	1+	Guidelines: [119] Primary studies: [155], [156], [158], [164], [165], [166], [167], [168], [169], [170], [171]
9.3.	Endocrine therapies are inferior to a monochemotherapy.	ST	1+	Guidelines: [119] Primary studies: [155], [156], [158], [164], [165], [166], [167], [168], [169], [170], [171]
9.4.	Patients with platinum-resistant and/or refractory recurrence of ovarian cancer must not receive platinum-based monotherapy, if chemotherapy is indicated. The following cytostatic drugs can be used: pegylated liposomal doxorubicin topotecan gemcitabine paclitaxel weekly	A	1+	Guidelines: [119] Primary studies: [155], [156], [158], [164], [165], [166], [167], [168], [169], [170], [171]

9.2.2 Platinum-sensitive recurrence

No.	Recommendations	GR	LoE	Sources
* to treat patients with primary recurrence who did not have previous VEGF-targeted therapy
9.5.	Patients with platinum-sensitive recurrence of ovarian cancer should have platinum-based combination therapy if chemotherapy is indicated. The following combinations can be used: carboplatin + gemcitabine + bevacizumab* carboplatin + pegylated liposomal doxorubicin carboplatin + paclitaxel carboplatin + gemcitabine	CC

9.3 Surgery for recurrence

No.	Recommendations	GR	LoE	Sources
9.6.	The value of surgery to treat ovarian cancer recurrence cannot be verified by data from prospective studies with a high level of evidence, but retrospective data indicate a potential clinical benefit.	A	2+	Guidelines: [1] Primary studies: [172], [173], [174], [175], [176], [177]
9.7.	The goal of surgery for recurrence should be macroscopically complete resection.	B	2+	Guidelines: [1] Primary studies: [172], [173], [174], [175], [176], [177]

10 Follow-up Care, Rehabiliation, Psycho-oncology, Palliative Medicine

10.1 Follow-up care and rehabilitation

No.	Recommendations/Statements	GR	LoE	Sources
10.1.	Patients with ovarian cancer must be informed about the various options for rehabilitation and offered support from social counselling services; patients must be offered suitable options after their individual need has been assessed.	CC
10.2.	The goal of follow-up care is to detect and treat therapy-associated side-effects, to offer rehabilitation, psychosocial care and reintegration, to improve the patientʼs quality of life and to detect any recurrence.	CC
10.3.	Routine use of the determination of CA-125 does not result in longer survival.	ST	1+	Guidelines: [1] Primary studies: [14], [178], [179]
10.4.	Routine sophisticated diagnostics and determination of markers is not required during follow-up when patients are symptom-free.	A	1+	Leitlinien: [1] Primary studies: [14], [178], [179]
10.5.	Follow-up must include detailed medical history, physical examination including gynaecological examination with speculum and palpation, rectal examination and vaginal sonography.	CC
10.6.	There is no reliable information about the safety of hormone therapy after treatment for ovarian cancer.	ST	2+	Primary studies: [180], [181], [182], [183]
10.7.	Hormone therapy cannot be recommended after treatment for ovarian cancer. It can be considered in individual cases, particularly in patients with considerable limitations in their quality of life.	0	2+	Primary studies: [180], [181], [182], [183]

10.2 Psycho-oncology

No.	Recommendations	GR	LoE	Sources
10.8.	Psychosocial interventions have a positive impact on the patientʼs quality of life, psychological condition and capacity to cope emotionally with the disease.	CC
10.9.	Psycho-oncological care of patients with ovarian cancer is an integral part of the oncological diagnosis, therapy and follow-up care and requires an interdisciplinary approach.	CC
10.10.	Psycho-oncological counselling and support should be offered to all patients and their family members based on their needs.	CC
10.11.	The topic of sexuality should always be actively explored to identify when further support is required and to provide additional support as required.	CC

10.3 Palliative medicine

No.	Recommendations	GR	LoE	Sources
10.12.	The right moment to initiate palliative medical care depends first and foremost on the patientʼs needs and the individual stage of disease.	CC
10.13.	Patients who primarily require palliative medical care should be included in a programme of specialised palliative care.	CC
10.14.	Palliative medical care includes the medical control of symptoms, palliative care and psychosocial support till death. It is offered as needed in the form of general or specialised palliative care.	CC
10.15.	In a palliative setting all necessary measures taken must be geared to the patientʼs individual therapeutic aims and aims in life.	CC

11 Borderline Tumours (BOT)

No.	Recommendations/Statements	GR	LoE	Sources
11.1.	Borderline tumours must be distinguished according to the WHO classification and categorised into subtypes. This should include the categorisation of any existing implants (invasive – non invasive) as well as information about microinvasion.	CC		[184]
11.2.	Careful surgical staging is necessary and, in addition to complete removal of the tumour (including bilateral salpingo-oophorectomy), should include inspection of the abdomen with peritoneal wash cytology, resection of all abnormal areas, peritoneal biopsies of unremarkable areas and omentectomy. In mucinous borderline tumours, metastasis of extraovarian tumours must be excluded; an appendectomy is necessary to exclude a primary appendiceal neoplasm.	B	2+	Primary studies: [185], [186], [187], [188], [189]
11.3.	There are some indications that performing cystectomy instead of ovarectomy and carrying out a fertility-preserving procedure instead of bilateral salpingo-oophorectomy is associated with higher rates of recurrence.	ST	2+	Primary studies: [190]
11.4.	If the patient wishes to have children/wishes to preserve endocrine functions, a fertility- preserving procedure can be carried out. The patient must be informed about the increased risk of recurrence associated with this procedure.	0	2+	Guidelines: [2] Primary studies: [191]
11.5.	There is no persuasive evidence for the effectiveness of adjuvant therapy for the treatment of borderline tumours.	ST	1+	Guidelines: [2] Primary studies: [192]
11.6.	Patients with borderline tumours must not receive adjuvant therapy.	A	1+	Guidelines: [2] Primary studies: [192]

12 Ovarian Germ Cell and Stromal Tumours

No.	Recommendations/Statements	GR	LoE	Sources
12.1.	The diagnosis of germ cell and stromal tumours must done in a similar manner as the diagnosis of ovarian cancer.	CC
12.2.	Optimal staging must include the following procedures: Lower median laparotomy Inspection and palpation of the entire abdominal cavity Peritoneal cytology Removal of the tumour with salpingo-oophorectomy For potentially malignant tumours (granulosa cell tumours, Sertoli-Leydig cell tumours G2/G3 or steroid cell tumours NOS): Definitive operative staging analogous to that for ovarian cancer. The benefit of systematic lymphonodectomy when lymph nodes are unremarkable has not been proven. If the uterus is not removed, hysteroscopy and curettage are recommended (to exclude endometrial hyperplasias or endometrial carcinoma).	A	2+	Primary studies: [193], [194], [195], [196]
12.3.	Fertility-preserving procedures should be considered when treating younger patients.	B	2+	Primary studies: [53]
12.4.	The benefit of adjuvant radiotherapy, chemotherapy or endocrine therapy after complete resection has not been proven and is controversially discussed in the literature.	ST	2+	Primary studies: [197], [198]
12.5.	Platinum-based chemotherapy should be considered for tumours which are stage IC or higher or if residual tumour is still present.	B	2+	Primary studies: [199], [200], [201], [202]

13 Ovarian Germ Cell Tumours

No.	Recommendations/Statements	GR	LoE	Sources
* Chemotherapy must always include platinum and etoposide. The 3rd cytostatic drug can be either bleomycin or ifosfamide.
13.1.	The diagnosis of ovarian germ cell tumours must done in a similar manner as the diagnosis for ovarian cancer.	CC
13.2.	The goal of surgical treatment is, in addition to histological typification, complete resection of the tumour and adequate staging while preserving fertility if the remaining genital area is unremarkable. The benefit of systematic lymphonodectomy when lymph nodes are unremarkable has not been proven.	ST	2+	Primary studies: [53], [203], [204], [205], [206], [207], [208], [209], [210], [211], [212]
13.3.	No adjuvant chemotherapy is required for stage IA tumours.	A	2+	Primary studies: [213]
13.4.	For cancers > FIGO IA, platinum-based risk-adapted chemotherapy must be carried out, consisting of 2–4 cycles of 2 or 3 cytostatic drugs*.	A	2+	Primary studies: [213], [214]
13.5.	In patients with advanced stage tumours, primary chemotherapy can be administered to preserve fertility. Resection of the residual tumour and of residual metastases must be planned after 3 or 4 cycles of chemotherapy have been concluded.	CC
13.6.	In addition to standard follow-up examinations, follow-up must also include the determination of specific tumour markers.	CC

14 Care Facilities

No.	Recommendations/Statements	GR	LoE	Sources
14.1.	Patients with ovarian cancer should be treated by a gynaecological oncologist (specialist) in a specialist facility which includes interdisciplinary diagnostic and therapeutic services.	CC

15 Quality Indicators

Quality indicator	Recommendation reference	Evidence base/additional information
* for patients with primary recurrence who did not previously receive VEGF-targeted therapy
Quality indicator 1: Operative staging of early ovarian cancer
Z: Number of pts. with operative staging using: laparotomy peritoneal cytology peritoneal biopsies bilateral excision of adnexa of uterus hysterectomy, using an extraperitoneal approach where necessary infracolic omentectomy bilateral pelvic and paraaortal lymphonodectomy N: All pts. with a primary diagnosis of ovarian cancer FIGO I – IIIA	7.1. Optimal staging must including the following procedures: longitudinal laparotomy inspection and palpation of the entire abdominal cavity peritoneal cytology biopsies from all abnormal sites peritoneal biopsies from unremarkable regions bilateral excision of adnexa of uterus hysterectomy, using an extraperitoneal approach where necessary infracolic omentectomy appendectomy (for mucinous/unclear tumour types) bilateral pelvic and paraaortal lymphonodectomy	a) Quality target Operative staging to be done as often as possible b) Evidence base CC Guidelines: NICE 2 011 [118] Primary studies: [215], [216], [217], [218], [219], [220], [221], [222], [223]
Quality indicator 2: Intraoperative tumour rupture
Z: Number of pts. with intraoperative tumour rupture N: All pts. with a primary diagnosis of ovarian cancer FIGO IA or IB	Background text to 7.5. “When an unclear ovarian carcinoma is removed laparoscopically, complete removal is important with no tumour rupture.”	a) Quality target No intraoperative tumour rupture b) Evidence base Leitlinien: [1],[2] Primärstudien: [139], [140], [141], [142], [143]
Quality indicator 3: Macroscopically complete resection of advanced ovarian cancer
Z: Number of pts. with macroscopically complete resection N: All pts. with a primary diagnosis of ovarian cancer ≥ FIGO IIB and surgical removal of the tumour	7.6. The goal of primary surgery must be to achieve macroscopically complete resection.	a) Quality target Macroscopically complete resection to be achieved as often as possible b) Evidence base CC Guidelines: [1], [2] Primary studies: [75], [83], [95], [174], [224], [225], [226], [227], [228], [229], [230], [231], [232], [233], [234], [235], [236]
Quality indicator 4: Surgery for advanced ovarian cancer
Z: Number of pts. whose definitive surgery was done by a gynaecological oncologist N: All pts. with a primary diagnosis of ovarian cancer FIGO ≥ IIB after surgical therapy has been completed	7.8. The diagnosis for patients unexpectedly diagnosed with advanced ovarian cancer must be confirmed histologically and the extent of spread described. The definitive treatment must then be carried out by a gynaecological oncologist in a suitable facility.	a) Quality target Surgery to be performed as often as possible by a gynaecological oncologist b) Evidence base LoE 4, A Guidelines: [2] Primary studies: [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89]
Note: Gynaecological oncologist = Medical specialist for gynaecology and obstetrics with a special focus on gynaecological oncology
Quality indicator 5: Postoperative chemotherapy for advanced ovarian cancer
Z: Number of pts. who received postoperative chemotherapy N: All pts. with a primary diagnosis of ovarian cancer ≥ FIGO IIB and receiving chemotherapy	7.10. The sequence of therapy must consist of primary surgery followed by chemotherapy.	a) Quality target Postoperative chemotherapy to be administered as often as possible in patients with advanced stage ovarian cancer b) Evidence base LoE 1+, A Guidelines: [1] Primary studies: [90], [91], [92], [93], [94], [95]
Quality indicator 6: No adjuvant chemotherapy for early ovarian cancer
Z: Number of pts. who received adjuvant chemotherapy N: All pts. with a primary diagnosis of ovarian cancer FIGO IA, G 1 und complete operative staging	8.1. Patients with stage IA grade 1 ovarian cancer after complete operative staging must not receive adjuvant chemotherapy.	a) Quality target If possible, no adjuvant chemotherapy to be administered to patients with FIGO IA, G 1 ovarian cancer who have had complete operative staging b) Evidence base LoE 1+, A Primary studies: [96], [97], [98], [99], [100], [101], [102], [103], [104]
Note: Please note that the FIGO classification has been updated! (position as of 12/2 012)
Quality indicator 7: Platinum-based chemotherapy for early ovarian cancer
Z: Number of pts. who received platinum-based chemotherapy N: All pts. with a primary diagnosis of ovarian cancer FIGO IC or IA/B and grade 3	8.2. Patients with stage IC or IA/B and grade 3 ovarian cancer must receive 6 cycles of platinum-based chemotherapy.	a) Quality target Patients with a primary diagnosis of IC or IA/B and grade 3 ovarian cancer to receive platinum-based chemotherapy as often as possible b) Evidence base LoE 1+, A Primary studies: [96], [97], [98], [99], [100], [101], [102], [103], [104]
Quality indicator 8: First-line chemotherapy for advanced ovarian cancer
Z: Number of pts. who received 6 cycles of first-line chemotherapy carboplatin AUC5 and paclitaxel 175 mg/m2 N: All pts. with a primary diagnosis of ovarian cancer ≥ FIGO IIB	8.5. First-line chemotherapy for patients with advanced ovarian cancer (II b-IV) must consist of carboplatin AUC5 and paclitaxel 175 mg/m2 for 3 h i. v. over a total of 6 cycles, with one cycle every 3 weeks.	a) Quality target Patients with a primary diagnosis of ovarian cancer ≥ FIGO IIB to receive 6 cycles of first-line chemotherapy with carboplatin AUC5 and paclitaxel 175 mg/m2 as often as possible b) Evidence base LoE 1++, A Guidelines: NICE 2 011 [118], NHS TA91 [119] Primary studies: [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131]
Quality indicator 9: Chemotherapy for platinum-resistant and/or refractory primary recurrence
Z: Number of pts. who received non platinum-based monotherapy with pegylated liposomal doxorubicin, topotecan, gemcitabine or paclitaxel weekly N: All pts. with platinum-resistant and/or refractory primary recurrence of ovarian cancer receiving chemotherapy for primary recurrence outside clinical trials	9.4. Patients with platinum-resistant and/or refractory recurrence of ovarian cancer must receive non platinum-based monotherapy if chemotherapy is indicated: The following cytostatic drugs can be considered: pegylated liposomal doxorubicin topotecan gemcitabine paclitaxel weekly	a) Quality target Non platinum-based monotherapy (s. left) to be administered as often as possible to treat patients with platinum-resistant and/or refractory primary recurrence of ovarian cancer receiving chemotherapy for primary recurrence outside clinical trials b) Evidence base LoE 1+, A Guidelines: NHS TA91 [119] Primary studies: [155], [156], [158], [164], [165], [166], [167], [168], [169], [170], [171]
Note: Platinum-resistant recurrence: recurrence within 6 months after completing primary therapy
Quality indicator 10: Combination therapy for platinum-sensitive recurrence
Z: Number of pts. receiving platinum-based combination therapy N: All pts. with platinum-sensitive recurrence of ovarian cancer receiving chemotherapy for recurrence outside clinical trials	9.5 Patients with platinum-sensitive recurrence of ovarian cancer must receive platinum-based combination therapy, if chemotherapy is indicated. The following combinations of cytostatic drugs can be considered: carboplatin/gemcitabine/bevacizumab* carboplatin/pegylated liposomal doxorubicin carboplatin/paclitaxel carboplatin/gemcitabine	a) Quality target Platinum-based combination therapy to be administered as often as possible to treat patients with platinum-sensitive recurrence receiving chemotherapy for recurrence outside clinical trials b) Evidence base CC Guidelines: [1] Primary studies: [155], [157], [171], [237], [238]
Note: Platinum-based combination therapy: carboplatin/gemcitabine/bevacizumab*, carboplatin/pegylated liposomal doxorubicin, carboplatin/paclitaxel, carboplatin/gemcitabine
Quality indicator 11: Counselling by social services
Z: Number of pts who received counselling by social services N: All pts. with a primary diagnosis of ovarian cancer being treated in the facility	10.1. Patients with ovarian cancer must receive information about the available rehabilitation and support from social services and must be offered suitable support based on their individual need.	a) Quality target Patients with a primary diagnosis of ovarian cancer to receive counselling from social services as often as possible b) Evidence base CC Guidelines: [1] Primary studies: [14], [178], [179]
Quality indicator 12: No adjuvant therapy for BOT
Z: Number of pts. with adjuvant therapy N: All pts. with a primary diagnosis of BOT	11.6. Patients with borderline tumours must not receive adjuvant therapy.	a) Quality target No adjuvant therapy to be given to patients with BOT b) Evidence base LoE 2+, A Guidelines: [2] Primary studies: [192]

• 16 References

• 1 Scottish Intercollegiate Guidelines Network. SIGN #75: Epithelial ovarian cancer. A national clinical guideline. Scottish Intercollegiate Guidelines Network; 2003
• 2 The Australian Cancer Network and National Breast Cancer Centre. Clinical practice guidelines for the management of women with epithelial ovarian cancer. Camperdown, NSW: National Breast Cancer Centre; 2004
• 3 Menon U et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 2009; 10: 327-340
• 4 Kobayashi H et al. A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer 2008; 18: 414-420
• 5 Buys SS et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 2011; 305: 2295-2303
• 6 Fung MF et al. Screening postmenopausal women for ovarian cancer: a systematic review. J Obstet Gynaecol Can 2004; 26: 717-728
• 7 van Nagell Jr. JR et al. Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol 2011; 118: 1212-1221
• 8 Timmerman D et al. Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol 2008; 31: 681-690
• 9 Timmerman D et al. Terms, definitions and measurements to describe the sonographic features of adnexal tumors: a consensus opinion from the International Ovarian Tumor Analysis (IOTA) Group. Ultrasound Obstet Gynecol 2000; 16: 500-505
• 10 Karlan BY et al. Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer: implications for ovarian cancer screening. Am J Obstet Gynecol 1999; 180: 917-928
• 11 Moller P et al. The BRCA1 syndrome and other inherited breast or breast-ovarian cancers in a Norwegian prospective series. Eur J Cancer 2001; 37: 1027-1032
• 12 Taylor L, Schwarz H. Identification of a soluble OX40 isoform: development of a specific and quantitative immunoassay. J Immunol Methods 2001; 255: 67-72
• 13 van der Velde NM et al. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?. Int J Cancer 2009; 124: 919-923
• 14 Rustin GJ et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC55955): a randomised trial. Lancet 2010; 376: 1155-1163
• 15 Forstner R et al. ESUR guidelines: ovarian cancer staging and follow-up. Eur Radiol 2010; 20: 2773-2780
• 16 Peng NJ et al. Early detection of recurrent ovarian cancer in patients with low-level increases in serum CA-125 levels by 2-[F-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography. Cancer Biother Radiopharm 2011; 26: 175-181
• 17 Gu P et al. CA 125, PET alone, PET-CT, CT and MRI in diagnosing recurrent ovarian carcinoma: a systematic review and meta-analysis. Eur J Radiol 2009; 71: 164-174
• 18 Partridge EE, Barnes MN. Epithelial ovarian cancer: prevention, diagnosis, and treatment. CA Cancer J Clin 1999; 49: 297-320
• 19 ESMO. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of ovarian cancer. Ann Oncol 2001; 12: 1205-1207
• 20 Jacobs I, Bast Jr. RC. The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod 1989; 4: 1-12
• 21 IQWIG. Positronenemissionstomographie (PET) und PET/CT bei Ovarialkarzinom. 2011. http://www.iqwiq.de
• 22 Torizuka T et al. Ovarian cancer recurrence: role of whole-body positron emission tomography using 2-[fluorine-18]-fluoro-2-deoxy-D-glucose. Eur J Nucl Med Mol Imaging 2002; 29: 797-803
• 23 Takekuma M et al. Positron emission tomography with 18F-fluoro-2-deoxyglucose for the detection of recurrent ovarian cancer. Int J Clin Oncol 2005; 10: 177-181
• 24 Rebbeck TR et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346: 1616-1622
• 25 Kauff ND et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346: 1609-1615
• 26 Haber D. Prophylactic oophorectomy to reduce the risk of ovarian and breast cancer in carriers of BRCA mutations. N Engl J Med 2002; 346: 1660-1662
• 27 Finch A et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 2006; 296: 185-192
• 28 Rebbeck TR et al. PROSE Study Group. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005; 23: 7804-7810
• 29 Madalinska JB et al. The impact of hormone replacement therapy on menopausal symptoms in younger high-risk women after prophylactic salpingo-oophorectomy. J Clin Oncol 2006; 24: 3576-3582
• 30 Parker WH et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nursesʼ health study. Obstet Gynecol 2009; 113: 1027-1037
• 31 Madalinska JB et al. Quality-of-life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 2005; 23: 6890-6898
• 32 Wagner TM et al. Attitude towards prophylactic surgery and effects of genetic counselling in families with BRCA mutations. Austrian Hereditary Breast and Ovarian Cancer Group. Br J Cancer 2000; 82: 1249-1253
• 33 Hallowell N. A qualitative study of the information needs of high-risk women undergoing prophylactic oophorectomy. Psychooncology 2000; 9: 486-495
• 34 Fry A et al. Prophylactic oophorectomy versus screening: psychosocial outcomes in women at increased risk of ovarian cancer. Psychooncology 2001; 10: 231-241
• 35 Antoniou A et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72: 1117-1130
• 36 Bonadona V et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305: 2304-2310
• 37 Chen S et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 2006; 24: 863-871
• 38 Dreyer G. Screening for gynaecologic cancers in genetically predisposed women. Best Pract Res Clin Obstet Gynaecol 2012; 26: 267-282
• 39 Tinelli A et al. Hereditary ovarian cancers: from BRCA mutations to clinical management. A modern appraisal. Cancer Metastasis Rev 2010; 29: 339-350
• 40 Malamou-Mitsi V et al. Prognostic significance of HER-2, p 53 and Bcl-2 in patients with epithelial ovarian cancer. Anticancer Res 2007; 27: 1157-1165
• 41 Kommoss S et al. Independent prognostic significance of cell cycle regulator proteins p 16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group. Br J Cancer 2007; 96: 306-313
• 42 Secord AA et al. Co-expression of angiogenic markers and associations with prognosis in advanced epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2007; 106: 221-232
• 43 Bellati F et al. Immunology of gynecologic neoplasms: analysis of the prognostic significance of the immune status. Curr Cancer Drug Targets 2009; 9: 541-565
• 44 Cree IA. Chemosensitivity and chemoresistance testing in ovarian cancer. Curr Opin Obstet Gynecol 2009; 21: 39-43
• 45 Harry VN, Gilbert FJ, Parkin DE. Predicting the response of advanced cervical and ovarian tumors to therapy. Obstet Gynecol Surv 2009; 64: 548-560
• 46 Itamochi H, Kigawa J, Terakawa N. Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci 2008; 99: 653-658
• 47 Liu N, Wang X, Sheng X. ‘Triple negative epithelial ovarian cancer and pathologic markers for prognosis. Curr Opin Obstet Gynecol 2011; 23: 19-23
• 48 Sabatier R et al. Gene expression profiling and prediction of clinical outcome in ovarian cancer. Crit Rev Oncol Hematol 2009; 72: 98-109
• 49 Tian C et al. CA-125 change after chemotherapy in prediction of treatment outcome among advanced mucinous and clear cell epithelial ovarian cancers: a Gynecologic Oncology Group study. Cancer 2009; 115: 1395-1403
• 50 Trainer AH et al. Moving toward personalized medicine: treatment-focused genetic testing of women newly diagnosed with ovarian cancer. Int J Gynecol Cancer 2010; 20: 704-716
• 51 Shaw MC et al. Development of an evidence-based algorithm for the management of ovarian cancer. Eur J Gynaecol Oncol 2003; 24: 117-125
• 52 Ayhan A et al. Oncologic and reproductive outcome after fertility-saving surgery in ovarian cancer. Eur J Gynaecol Oncol 2003; 24: 223-232
• 53 Gershenson DM. Fertility-sparing surgery for malignancies in women. J Natl Cancer Inst Monogr 2005; 34: 43-47
• 54 Morice P et al. Conservative treatment in epithelial ovarian cancer: results of a multicentre study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer) and SFOG (Societe Francaise dʼOncologie Gynecologique). Hum Reprod 2005; 20: 1379-1385
• 55 Leitao Jr. MM, Chi DS. Fertility-sparing options for patients with gynecologic malignancies. Oncologist 2005; 10: 613-622
• 56 Dexeus S, Labastida R, Dexeus D. Conservative management of epithelial ovarian cancer. Eur J Gynaecol Oncol 2005; 26: 473-478
• 57 Monk BJ, Disaia PJ. What is the role of conservative primary surgical management of epithelial ovarian cancer: the United States experience and debate. Int J Gynecol Cancer 2005; 15 (Suppl. 03) 199-205
• 58 Colombo N et al. Role of conservative surgery in ovarian cancer: the European experience. Int J Gynecol Cancer 2005; 15 (Suppl. 03) 206-211
• 59 Marhhom E, Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv 2007; 62: 58-72
• 60 Denschlag D et al. Clinical recommendation on fertility preservation in borderline ovarian neoplasm: ovarian stimulation and oocyte retrieval after conservative surgery. Gynecol Obstet Invest 2010; 70: 160-165
• 61 Sarnacki S, Brisse H. Surgery of ovarian tumors in children. Horm Res Paediatr 2011; 75: 220-224
• 62 Zanetta G et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 1997; 104: 1030-1035
• 63 Schilder JM et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol Oncol 2002; 87: 1-7
• 64 Morice P et al. Results of conservative management of epithelial malignant and borderline ovarian tumours. Hum Reprod Update 2003; 9: 185-192
• 65 Duska LR et al. Epithelial ovarian carcinoma in the reproductive age group. Cancer 1999; 85: 2623-2629
• 66 Medeiros LR et al. Laparoscopy versus laparotomy for FIGO Stage I ovarian cancer. Cochrane Database Syst Rev 2008; (4) CD005344
• 67 Trope C, Kaern J. Adjuvant chemotherapy for early-stage ovarian cancer: review of the literature. J Clin Oncol 2007; 25: 2909-2920
• 68 Panici PB et al. Laparoscopy compared with laparoscopically guided minilaparotomy for large adnexal masses: a randomized controlled trial. Obstet Gynecol 2007; 110 (2 Pt 1) 241-248
• 69 Ghezzi F et al. Should adnexal mass size influence surgical approach? A series of 186 laparoscopically managed large adnexal masses. BJOG 2008; 115: 1020-1027
• 70 Fagotti A et al. Should laparoscopy be included in the work-up of advanced ovarian cancer patients attempting interval debulking surgery?. Gynecol Oncol 2010; 116: 72-77
• 71 Kindermann G, Maassen V, Kuhn W. Laparoscopic management of ovarian tumors subsequently diagnosed as malignant: a survey from 127 German departments of obstetrics and gynecology. J Pelvic Surgery 1996; 2: 245-251
• 72 Canis M et al. Laparoscopic management of adnexal masses: a gold standard?. Curr Opin Obstet Gynecol 2002; 14: 423-428
• 73 Randall TC, Rubin SC. Surgical management of ovarian cancer. Semin Surg Oncol 1999; 17: 173-180
• 74 Axtell AE et al. Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J Clin Oncol 2007; 25: 384-389
• 75 Wimberger P et al. Influence of residual tumor on outcome in ovarian cancer patients with FIGO stage IV disease: an exploratory analysis of the AGO-OVAR (Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group). Ann Surg Oncol 2010; 17: 1642-1648
• 76 Gadducci A et al. Relationship between time interval from primary surgery to the start of taxane- plus platinum-based chemotherapy and clinical outcome of patients with advanced epithelial ovarian cancer: results of a multicenter retrospective Italian study. J Clin Oncol 2005; 23: 751-758
• 77 Trope C, Kaern J. Primary surgery for ovarian cancer. Eur J Surg Oncol 2006; 32: 844-852
• 78 Bristow RE et al. Delaying the primary surgical effort for advanced ovarian cancer: a systematic review of neoadjuvant chemotherapy and interval cytoreduction. Gynecol Oncol 2007; 104: 480-490
• 79 Wimberger P et al. Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2007; 106: 69-74
• 80 Vernooij F et al. The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review. Gynecol Oncol 2007; 105: 801-812
• 81 Elit LM et al. Surgical outcomes in women with ovarian cancer. Can J Surg 2008; 51: 346-354
• 82 Gerestein CG et al. The prediction of progression-free and overall survival in women with an advanced stage of epithelial ovarian carcinoma. BJOG 2009; 116: 372-380
• 83 du Bois A et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe dʼInvestigateurs Nationaux Pour les Etudes des Cancers de lʼOvaire (GINECO). Cancer 2009; 115: 1234-1244
• 84 Gerestein CG et al. Causes of postoperative mortality after surgery for ovarian cancer. Eur J Cancer 2009; 45: 2799-2803
• 85 Einenkel J et al. Characteristics and management of diaphragm involvement in patients with primary advanced-stage ovarian, fallopian tube, or peritoneal cancer. Int J Gynecol Cancer 2009; 19: 1288-1297
• 86 Tixier H et al. Evaluation of pelvic posterior exenteration in the management of advanced-stage ovarian cancer. Arch Gynecol Obstet 2010; 281: 505-510
• 87 Gerestein CG et al. Prediction of residual disease after primary cytoreductive surgery for advanced-stage ovarian cancer: accuracy of clinical judgment. Int J Gynecol Cancer 2009; 19: 1511-1515
• 88 Aletti GD et al. Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment. Gynecol Oncol 2011; 120: 23-28
• 89 du Bois A et al. Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review. Gynecol Oncol 2009; 112: 422-436
• 90 Vergote I et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943-953
• 91 Schwartz PE et al. Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 1999; 72: 93-99
• 92 van der Burg ME et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 1995; 332: 629-634
• 93 Rose PG et al. Gynecologic Oncology Group. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004; 351: 2489-2497
• 94 Redman CW et al. Intervention debulking surgery in advanced epithelial ovarian cancer. Br J Obstet Gynaecol 1994; 101: 142-146
• 95 Tangjitgamol S et al. Interval debulking surgery for advanced epithelial ovarian cancer. Cochrane Database Syst Rev 2010; (10) CD006014
• 96 Winter-Roach BA, Kitchener HC, Dickinson HO. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Syst Rev 2009; (3) CD004706
• 97 Young RC et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 1990; 322: 1021-1027
• 98 Trope C et al. Are borderline tumors of the ovary overtreated both surgically and systemically? A review of four prospective randomized trials including 253 patients with borderline tumors. Gynecol Oncol 1993; 51: 236-243
• 99 Trimbos JB et al. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 2003; 95: 113-125
• 100 Timmers PJ et al. Clear cell carcinoma compared to serous carcinoma in early ovarian cancer: same prognosis in a large randomized trial. Int J Gynecol Cancer 2009; 19: 88-93
• 101 Trimbos B et al. Surgical staging and treatment of early ovarian cancer: long-term analysis from a randomized trial. J Natl Cancer Inst 2010; 102: 982-987
• 102 Adams G et al. Platinum-based adjuvant chemotherapy for early-stage epithelial ovarian cancer: single or combination chemotherapy?. BJOG 2010; 117: 1459-1467
• 103 Takano M et al. Less impact of adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: a retrospective Japan Clear Cell Carcinoma Study. Int J Gynecol Cancer 2010; 20: 1506-1510
• 104 Garcia-Saenz JA et al. Platinum-based adjuvant chemotherapy on moderate- and high-risk stage I and II epithelian ovarian cancer patients. Long-term single institution experience and literature review. Clin Transl Oncol 2011; 13: 121-132
• 105 Trimbos JB et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003; 95: 105-112
• 106 Colombo N et al. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 2003; 95: 125-132
• 107 Vergote I et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001; 357: 176-182
• 108 Ho CM et al. Evaluation of complete surgical staging with pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy for improvement of survival in stage I ovarian clear cell carcinoma. Gynecol Oncol 2003; 88: 394-399
• 109 Kitchener HC. Adjuvant chemotherapy improves survival after resection of stage 1 ovarian cancer. Cancer Treat Rev 2005; 31: 323-327
• 110 Shimada M et al. Outcome of patients with early ovarian cancer undergoing three courses of adjuvant chemotherapy following complete surgical staging. Int J Gynecol Cancer 2005; 15: 601-605
• 111 Bell J et al. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2006; 102: 432-439
• 112 Obermair A et al. A new prognostic model for FIGO stage 1 epithelial ovarian cancer. Gynecol Oncol 2007; 104: 607-611
• 113 Skirnisdottir I, Sorbe B. Survival and prognostic factors in early-stage epithelial ovarian carcinoma treated with taxane-based adjuvant chemotherapy. Int J Gynecol Cancer 2007; 17: 1231-1237
• 114 Chan JK et al. Prognostic factors for high-risk early-stage epithelial ovarian cancer: a Gynecologic Oncology Group study. Cancer 2008; 112: 2202-2210
• 115 Takano M et al. Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging. Br J Cancer 2006; 94: 1369-1374
• 116 Chan JK et al. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol 2010; 116: 301-306
• 117 Mannel RS et al. A randomized phase III trial of IV carboplatin and paclitaxel × 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol 2011; 122: 89-94
• 118 NICE. NICE clinical guideline 122. The recognition and initial management of ovarian cancer. 2011 [cited 2012 September 7]. http://guidance.nice.org.uk/CG122 Stand: 07.09.2012
• 119 NHS National Institute for Health and Clinical Excellence. Technology Appraisal Guidance 91 Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. 2005 [cited 2012 September 7]. http://www.nice.org.uk/TA091 Stand: 07.09.2012
• 120 ICON Collaborators. ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. ICON Collaborators. International Collaborative Ovarian Neoplasm Study. Lancet 1998; 352: 1571-1576
• 121 ICON Collaborators. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002; 360: 505-515
• 122 McGuire WP et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1-6
• 123 Muggia FM et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000; 18: 106-115
• 124 Neijt JP et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000; 18: 3084-3092
• 125 Piccart MJ et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699-708
• 126 West RJ, Zweig SF. Meta-analysis of chemotherapy regimens for ovarian carcinoma: a reassessment of cisplatin, cyclophosphamide and doxorubicin versus cisplatin and cyclophosphamide. Eur J Gynaecol Oncol 1997; 18: 343-348
• 127 Ozols RF. Chemotherapy for ovarian cancer. Semin Oncol 1999; 26 (6 Suppl. 18) 34-40
• 128 du Bois A, Neijt JP, Thigpen JT. First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer – a new standard of care?. Ann Oncol 1999; 10 (Suppl. 01) 35-41
• 129 Aabo K et al. Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialistsʼ Group. Br J Cancer 1998; 78: 1479-1487
• 130 du Bois A et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320-1329
• 131 Ozols RF et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003; 21: 3194-3200
• 132 Burger RA et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473-2483
• 133 Perren TJ et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484-2496
• 134 McGuire 3rd WP. High-dose chemotherapeutic approaches to ovarian cancer management. Semin Oncol 2000; 27(3 Suppl. 7): 41-46
• 135 Mobus V et al. Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol 2007; 25: 4187-4193
• 136 Katsumata N et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331-1338
• 137 Hoskins P et al. Advanced ovarian cancer: phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs. carboplatin-paclitaxel. J Natl Cancer Inst 2010; 102: 1547-1556
• 138 Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2006; (1) CD005340
• 139 Buyse M et al. Using the expected survival to explain differences between the results of randomized trials: a case in advanced ovarian cancer. J Clin Oncol 2003; 21: 1682-1687
• 140 Aravantinos G et al. Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study. Ann Oncol 2005; 16: 1116-1122
• 141 Dizon DS et al. Two for good measure: six versus eight cycles of carboplatin and paclitaxel as adjuvant treatment for epithelial ovarian cancer. Gynecol Oncol 2006; 100: 417-421
• 142 Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34-43
• 143 Grenman S et al. A randomised phase III study comparing high-dose chemotherapy to conventionally dosed chemotherapy for stage III ovarian cancer: the Finnish Ovarian Cancer (FINOVA) study. Eur J Cancer 2006; 42: 2196-2199
• 144 Spriggs DR et al. Phase III randomized trial of intravenous cisplatin plus a 24- or 96-hour infusion of paclitaxel in epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2007; 25: 4466-4471
• 145 Lhomme C et al. Phase III study of valspodar (PSC833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer. J Clin Oncol 2008; 26: 2674-2682
• 146 Safra T et al. Combined weekly carboplatin and paclitaxel as primary treatment of advanced epithelial ovarian carcinoma. Gynecol Oncol 2009; 114: 215-218
• 147 Lambert HE et al. A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study. Ann Oncol 1997; 8: 327-333
• 148 Sorbe B. Swedish-Norgewian Ovarian Cancer Study Group. Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment. Int J Gynecol Cancer 2003; 13: 278-286
• 149 Mei L et al. Maintenance chemotherapy for ovarian cancer. Cochrane Database Syst Rev 2010; (9) CD007414
• 150 Berek J et al. Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol 2009; 27: 418-425
• 151 Pecorelli S et al. Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1. J Clin Oncol 2009; 27: 4642-4648
• 152 Penson RT et al. Phase II study of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab as first-line chemotherapy for advanced mullerian tumors. J Clin Oncol 2010; 28: 154-159
• 153 Pomel C et al. Hyperthermic intra-peritoneal chemotherapy using oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective multicentre trial. CHIPOVAC study. Eur J Surg Oncol 2010; 36: 589-593
• 154 Hess LM et al. Continued chemotherapy after complete response to primary therapy among women with advanced ovarian cancer: a meta-analysis. Cancer 2010; 116: 5251-5260
• 155 Williams C, Simera I, Bryant A. Tamoxifen for relapse of ovarian cancer. Cochrane Database Syst Rev 2010; (3) CD001034
• 156 ten Bokkel Huinink W et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997; 15: 2183-2193
• 157 Parmar MK et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361: 2099-2106
• 158 Gordon AN et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19: 3312-3322
• 159 Cantu MG et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 2002; 20: 1232-1237
• 160 Blackledge G et al. Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials. Br J Cancer 1989; 59: 650-653
• 161 Eisenhauer EA et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247
• 162 Rustin GJ et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 2011; 21: 419-423
• 163 Friedlander M et al. Gynecologic Cancer InterGroup. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011; 21: 771-775
• 164 Meier W et al. Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2009; 114: 199-205
• 165 ten Bokkel Huinink W, Lane SR, Ross GA. Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma. Ann Oncol 2004; 15: 100-103
• 166 Vergote I et al. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. 2009. (1879-0852 [Electronic])
• 167 Ferrandina G et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008; 26: 890-896
• 168 Mutch DG et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25: 2811-2818
• 169 du Bois A et al. Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer. Ann Oncol 2002; 13: 251-257
• 170 Sehouli J et al. Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2008; 26: 3176-3182
• 171 Peng LH, Chen XY, Wu TX. Topotecan for ovarian cancer. Cochrane Database Syst Rev 2008; (2) CD005589 DOI: 10.1002/14651858.CD005589.pub2.
• 172 Eisenkop SM, Friedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma. Cancer 2000; 88: 144-153
• 173 Harter P et al. Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Committee; AGO Ovarian Cancer Study Group. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol 2006; 13: 1702-1710
• 174 Sehouli J et al. Role of secondary cytoreductive surgery in ovarian cancer relapse: who will benefit? A systematic analysis of 240 consecutive patients. J Surg Oncol 2010; 102: 656-662
• 175 Galaal K et al. Cytoreductive surgery plus chemotherapy versus chemotherapy alone for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev 2010; (6) CD007822
• 176 Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol 2009; 112: 265-274
• 177 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 Gynecol Cancer 2011; 21: 289-295
• 178 Kew F et al. Evaluation of follow-up strategies for patients with epithelial ovarian cancer following completion of primary treatment. Cochrane Database Syst Rev 2011; (6) CD006119
• 179 Gadducci A et al. Surveillance procedures for patients treated for epithelial ovarian cancer: a review of the literature. Int J Gynecol Cancer 2007; 17: 21-31
• 180 Guidozzi F, Daponte A. Estrogen replacement therapy for ovarian carcinoma survivors: A randomized controlled trial. Cancer 1999; 86: 1013-1018
• 181 Eeles RA et al. Hormone replacement therapy and survival after surgery for ovarian cancer. BMJ 1991; 302: 259-262
• 182 Ursic-Vrscaj M, Bebar S, Zakelj MP. Hormone replacement therapy after invasive ovarian serous cystadenocarcinoma treatment: the effect on survival. Menopause 2001; 8: 70-75
• 183 Mascarenhas C et al. Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival. Int J Cancer 2006; 119: 2907-2915
• 184 WHO. Classification of Tumours. Pathology and Genetics of Tumours of the Breast and female genital Organs. 3rd. ed. Switzerland: WHO-Press; 2003
• 185 Kaern J, Trope CG, Abeler VM. A retrospective study of 370 borderline tumors of the ovary treated at the Norwegian Radium Hospital from 1970 to 1982. A review of clinicopathologic features and treatment modalities. Cancer 1993; 71: 1810-1820
• 186 Leake JF et al. Long-term follow-up of serous ovarian tumors of low malignant potential. Gynecol Oncol 1992; 47: 150-158
• 187 Odegaard E et al. Surgery of borderline tumors of the ovary: retrospective comparison of short-term outcome after laparoscopy or laparotomy. Acta Obstet Gynecol Scand 2007; 86: 620-626
• 188 Camatte S et al. Impact of surgical staging in patients with macroscopic “stage I” ovarian borderline tumours: analysis of a continuous series of 101 cases. Eur J Cancer 2004; 40: 1842-1849
• 189 Menczer J, Chetrit A, Sadetzki S. The effect of hysterectomy on survival of patients with borderline ovarian tumors. Gynecol Oncol 2012; 125: 372-375
• 190 du Bois A, Ewald-Riegler N. Borderline-Tumoren des Ovars – eine systematische Übersicht. Geburtsh Frauenheilk 2009; 69: 807-833
• 191 Morice P et al. Recommendations of the Fertility Task Force of the European Society of Gynecologic Oncology about the conservative management of ovarian malignant tumors. Int J Gynecol Cancer 2011; 21: 951-963
• 192 Faluyi O et al. Interventions for the treatment of borderline ovarian tumours. Cochrane Database Syst Rev 2010; (9) CD007696
• 193 Miller BE et al. Prognostic factors in adult granulosa cell tumor of the ovary. Cancer 1997; 79: 1951-1955
• 194 Nosov V et al. Predictors of recurrence of ovarian granulosa cell tumors. Int J Gynecol Cancer 2009; 19: 628-633
• 195 Colombo N et al. Management of ovarian stromal cell tumors. J Clin Oncol 2007; 25: 2944-2951
• 196 Sehouli J et al. Granulosa cell tumor of the ovary: 10 years follow-up data of 65 patients. Anticancer Res 2004; 24 (2C) 1223-1229
• 197 Zanagnolo V, Pasinetti B, Sartori E. Clinical review of 63 cases of sex cord stromal tumors. Eur J Gynaecol Oncol 2004; 25: 431-438
• 198 Evans 3rd AT et al. Clinicopathologic review of 118 granulosa and 82 theca cell tumors. Obstet Gynecol 1980; 55: 231-238
• 199 Zhang M et al. Prognostic factors responsible for survival in sex cord stromal tumors of the ovary – an analysis of 376 women. Gynecol Oncol 2007; 104: 396-400
• 200 Fotopoulou C et al. Adult granulosa cell tumors of the ovary: tumor dissemination pattern at primary and recurrent situation, surgical outcome. Gynecol Oncol 2010; 119: 285-290
• 201 Zambetti M et al. cis-platinum/vinblastine/bleomycin combination chemotherapy in advanced or recurrent granulosa cell tumors of the ovary. Gynecol Oncol 1990; 36: 317-320
• 202 Colombo N et al. Cisplatin, vinblastine, and bleomycin combination chemotherapy in metastatic granulosa cell tumor of the ovary. Obstet Gynecol 1986; 67: 265-268
• 203 Mahdi H et al. Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary. Br J Cancer 2011; 105: 493-497
• 204 Gershenson DM. Management of ovarian germ cell tumors. J Clin Oncol 2007; 25: 2938-2943
• 205 Pectasides D, Pectasides E, Kassanos D. Germ cell tumors of the ovary. Cancer Treat Rev 2008; 34: 427-441
• 206 Kumar S et al. The prevalence and prognostic impact of lymph node metastasis in malignant germ cell tumors of the ovary. Gynecol Oncol 2008; 110: 125-132
• 207 Oltmann SC et al. Pediatric ovarian malignancies: how efficacious are current staging practices?. J Pediatr Surg 2010; 45: 1096-1102
• 208 Gobel U et al. Treatment of germ cell tumors in children: results of European trials for testicular and non-testicular primary sites. Crit Rev Oncol Hematol 1990; 10: 89-98
• 209 Marina NM et al. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: a Pediatric Oncology Group/Childrenʼs Cancer Group Intergroup Study. J Clin Oncol 1999; 17: 2137-2143
• 210 Gershenson DM et al. Second-look laparotomy in the management of malignant germ cell tumors of the ovary. Obstet Gynecol 1986; 67: 789-793
• 211 Billmire D et al. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg 2004; 39: 424-429 discussion 424–429
• 212 Beiner ME et al. Cystectomy for immature teratoma of the ovary. Gynecol Oncol 2004; 93: 381-384
• 213 Cushing B et al. Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the Pediatric Oncology Group and the Childrenʼs Cancer Group. Am J Obstet Gynecol 1999; 181: 353-358
• 214 Kang H et al. Outcome and reproductive function after cumulative high-dose combination chemotherapy with bleomycin, etoposide and cisplatin (BEP) for patients with ovarian endodermal sinus tumor. Gynecol Oncol 2008; 111: 106-110
• 215 Chan JK et al. Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstet Gynecol 2007; 109: 12-19
• 216 Kim HS et al. Systematic lymphadenectomy for survival in epithelial ovarian cancer: a meta-analysis. Int J Gynecol Cancer 2010; 20: 520-528
• 217 Maggioni A et al. Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer 2006; 95: 699-704
• 218 Suzuki S et al. Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients?. Ann Oncol 2008; 19: 1284-1287
• 219 Yang X et al. Prognosis in epithelial ovarian cancer: clinical analysis of 287 pelvic and para-aortic lymphadenectomy. Chinese-German Journal of Clinical Oncology 2007; 6: 492-496
• 220 Yokoyama Y et al. Evaluation of cytoreductive surgery with pelvic and paraaortic lymphadenectomy and intermittent cisplatin-based combination chemotherapy for improvement of long-term survival in ovarian cancer. Eur J Gynaecol Oncol 1999; 20: 361-366
• 221 Young RC et al. Staging laparotomy in early ovarian cancer. JAMA 1983; 250: 3072-3076
• 222 Piver MS, Barlow JJ, Lele SB. Incidence of subclinical metastasis in stage I and II ovarian carcinoma. Obstet Gynecol 1978; 52: 100-104
• 223 Buchsbaum HJ et al. Surgical staging of carcinoma of the ovaries. Surg Gynecol Obstet 1989; 169: 226-232
• 224 Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975; 42: 101-104
• 225 Hoskins WJ et al. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992; 47: 159-166
• 226 Hacker NF et al. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983; 61: 413-420
• 227 Hunter RW, Alexander ND, Soutter WP. Meta-analysis of surgery in advanced ovarian carcinoma: is maximum cytoreductive surgery an independent determinant of prognosis?. Am J Obstet Gynecol 1992; 166: 504-511
• 228 Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol 1995; 16: 349-356
• 229 Voest EE, van Houwelingen JC, Neijt JP. A meta-analysis of prognostic factors in advanced ovarian cancer with median survival and overall survival (measured with the log (relative risk] as main objectives. Eur J Cancer Clin Oncol 1989; 25: 711-720
• 230 Nguyen HN et al. National survey of ovarian carcinoma. Part V. The impact of physicianʼs specialty on patientsʼ survival. Cancer 1993; 72: 3663-3670
• 231 Junor EJ et al. Specialist gynaecologists and survival outcome in ovarian cancer: a Scottish national study of 1866 patients. Br J Obstet Gynaecol 1999; 106: 1130-1136
• 232 Bristow RE et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002; 20: 1248-1259
• 233 Elattar A et al. Optimal primary surgical treatment for advanced epithelial ovarian cancer. Cochrane Database Syst Rev 2011; (8) CD007565
• 234 Ang C et al. Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer. Cochrane Database Syst Rev 2011; (4) CD007697
• 235 Bashir S et al. Surgical technique of diaphragm full-thickness resection and trans-diaphragmatic decompression of pneumothorax during cytoreductive surgery for ovarian cancer. Gynecol Oncol 2010; 119: 255-258
• 236 Sehouli J et al. Primary versus interval debulking surgery in advanced ovarian cancer: results from a systematic single-center analysis. Int J Gynecol Cancer 2010; 20: 1331-1340
• 237 Pfisterer J et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006; 24: 4699-4707
• 238 Pujade-Lauraine E et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010; 28: 3323-3329