Geburtshilfe Frauenheilkd 2022; 82(02): 139-180
DOI: 10.1055/a-1671-2158
GebFra Science
Guideline/Leitlinie

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) – Part 1 with Recommendations on Epidemiology, Screening, Diagnostics and Therapy

Article in several languages: English | deutsch
Matthias W. Beckmann
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Frederik A. Stübs
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Martin C. Koch
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Peter Mallmann
2   Universitätsklinikum Köln, Frauenklinik, Köln, Germany
,
Christian Dannecker
3   Universitätsklinikum Augsburg, Frauenklinik, Augsburg, Germany
,
Anna Dietl
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Anna Sevnina
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Franziska Mergel
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Laura Lotz
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Carolin C. Hack
1   Universitätsklinikum Erlangen, Frauenklinik, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
,
Anne Ehret
4   Universitätsklinikum Düsseldorf, Frauenklinik, Düsseldorf, Germany
,
Daniel Gantert
4   Universitätsklinikum Düsseldorf, Frauenklinik, Düsseldorf, Germany
,
Franca Martignoni
4   Universitätsklinikum Düsseldorf, Frauenklinik, Düsseldorf, Germany
,
Jan-Philipp Cieslik
4   Universitätsklinikum Düsseldorf, Frauenklinik, Düsseldorf, Germany
,
Jan Menke
5   SHG-Kliniken Völklingen, Klinik für Radiologie, Völklingen, Germany
,
Olaf Ortmann
6   Arbeitsgemeinschaft Deutscher Tumorzentren, Germany
,
Carmen Stromberger
7   Charité – Universitätsmedizin Berlin, Klinik für Radioonkologie und Strahlentherapie, Berlin, Germany
,
Karin Oechsle
8   Universitätsklinikum Hamburg-Eppendorf, II. Medizinische Klinik und Poliklinik, Hamburg, Germany
,
Beate Hornemann
9   Universitätsklinikum Dresden, Psychoonkologischer Dienst, Dresden, Germany
,
Friederike Mumm
10   Medizinische Klinik und Poliklinik III und Comprehensive Cancer Center (CCC München LMU), Klinikum der Universität München, LMU München, München, Germany
,
Christoph Grimm
11   Abteilung für allgemeine Gynäkologie und gynäkologische Onkologie, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medizinische Universität Wien, Wien, Austria
,
Alina Sturdza
12   Universitätsklinikum AKH-Wien, Klinik für Radioonkologie, Wien, Austria
,
Edward Wight
13   Universitätsspital Basel, Frauenklinik, Basel, Switzerland
,
Kristina Loessl
14   Universitätsklinik Bern, Klinik für Radio-Onkologie, Bern, Switzerland
,
Michael Golatta
15   Universitätsklinikum Heidelberg, Frauenklinik, Heidelberg, Germany
,
Volker Hagen
16   St. Johannes Hospital Dortmund, Klinik für Innere Medizin II, Dortmund, Germany
,
Timm Dauelsberg
17   Universitätsklinikum Freiburg, Klinik für Onkologische Rehabilitation, Freiburg, Germany
,
Ingo Diel
18   Praxisklinik am Rosengarten, Mannheim, Germany
,
Karsten Münstedt
19   Klinikum Ortenau, Frauenklinik, Ortenau, Germany
,
Eberhard Merz
20   Zentrum für Ultraschalldiagnostik und Pränatalmedizin Frankfurt, Frankfurt am Main, Germany
,
Dirk Vordermark
21   Universitätsklinikum Halle (Saale), Klinik für Strahlentherapie, Halle (Saale), Germany
,
Katja Lindel
22   Städtisches Klinikum Karlsruhe, Klinik für Radioonkologie und Strahlentherapie, Karlsruhe, Germany
,
Christian Wittekind
23   Universitätsklinikum Leipzig, Institut für Pathologie, Leipzig, Germany
,
Volkmar Küppers
24   Frauenarztpraxis, Zytologisches Labor, Düsseldorf, Germany
,
Ralph Lellé
25   Universitätsklinikum Münster, Frauenklinik, Münster, Germany
,
Klaus Neis
26   Frauenärzte am Staden, Saarbrücken, Germany
,
Henrik Griesser
27   Labor Dr. Wisplinghoff, Köln, Germany
,
Birgit Pöschel
28   Praxis für Zytodiagnostik, Cölpin, Germany
,
Manfred Steiner
29   Frauenarztpraxis, Ihringen, Germany
,
Ulrich Freitag
30   Frauenarztpraxis, Wismar, Germany
,
Tobias Gilster
31   Frauenärzte am Stadtpark, Nürnberg, Germany
,
Alexander Schmittel
32   Onkologie Seestrasse, Praxis für Onkologie, Berlin, Germany
,
Michael Friedrich
33   Helios Klinikum Krefeld, Frauenklinik, Krefeld, Germany
,
Heidemarie Haase
34   Bundesverband Frauenselbsthilfe nach Krebs, Germany
,
Marion Gebhardt
34   Bundesverband Frauenselbsthilfe nach Krebs, Germany
,
Ludwig Kiesel
25   Universitätsklinikum Münster, Frauenklinik, Münster, Germany
,
Michael Reinhardt
35   Pius Hospital Oldenburg, Klinik für Nuklearmedizin, Oldenburg, Germany
,
Michael Kreißl
36   Universitätsklinikum Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany
,
Marianne Kloke
37   Kliniken Essen-Mitte, Klinik für Palliativmedizin, Essen, Germany
,
Lars-Christian Horn
23   Universitätsklinikum Leipzig, Institut für Pathologie, Leipzig, Germany
,
Regina Wiedemann
38   Fliedner Fachhochschule Düsseldorf, Pflegewissenschaft, Düsseldorf, Germany
,
Simone Marnitz
39   Universitätsklinikum Köln, Klinik für Radioonkologie, Cyberknife- und Strahlentherapie, Köln, Germany
,
Anne Letsch
40   Universitätsklinikum Schleswig-Holstein, Klinik für Innere Medizin II, Kiel, Germany
,
Isabella Zraik
41   Kliniken Essen-Mitte, Klinik für Urologie, Essen, Germany
,
Bernhard Mangold
42   ZytoLabor Ludwigsburg, Ludwigsburg, Germany
,
Jochen Möckel
43   Labor Schneider, Freiburg im Breisgau, Germany
,
Céline Alt
44   Wolfgarten Radiologie Bonn, Bonn, Germany
,
Pauline Wimberger
45   Department of Gynecology and Obstetrics, Technische Universität Dresden and National Center for Tumor Diseases (NCT/UCC), Dresden, Germany
,
Peter Hillemanns
46   Medizinische Hochschule Hannover, Frauenklinik, Hannover, Germany
,
Kerstin Paradies
47   Konferenz onkologischer Kranken- und Kinderkrankenpflege (KOK), Germany
,
Alexander Mustea
48   Universitätsklinikum Bonn, Frauenklinik, Bonn, Germany
,
Dominik Denschlag
49   Hochtaunus Kliniken, Frauenklinik, Bad Homburg, Germany
,
Ulla Henscher
50   Deutscher Verband für Physiotherapie (ZVK) e. V., Germany
,
Reina Tholen
50   Deutscher Verband für Physiotherapie (ZVK) e. V., Germany
,
Simone Wesselmann
51   Deutsche Krebsgesellschaft e. V., Berlin, Germany
,
Tanja Fehm
4   Universitätsklinikum Düsseldorf, Frauenklinik, Düsseldorf, Germany
› Author Affiliations
 

Abstract

Aim This update of the interdisciplinary S3 guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL) was published in March 2021. This updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group on Gynecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie, AGO) of the German Cancer Society (Deutsche Krebsgesellschaft, DKG).

Method The process of updating the S3 guideline dating from 2014 was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or – if evidence was lacking – on a consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which took account of more recently published literature and the appraisal of the new evidence.

Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, screening, diagnostic workup and therapy of patients with cervical cancer. The most important new aspects included in this updated guideline include the newly published FIGO classification of 2018, the radical open surgery approach for cervical cancers up to FIGO stage IB1, and use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.


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I  Guideline Information

Publishing body

The German Guideline Program in Oncology of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., AWMF), the German Cancer Society (Deutsche Krebsgesellschaft e. V., DKG) and German Cancer Aid (Deutsche Krebshilfe, DKH).


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Guidelines program of the DGGG, OEGGG and SGGG

For more information, please refer to the end of this guideline.


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Guideline funding

This guideline was funded by German Cancer Aid (Deutsche Krebshilfe, DKH) as part of the German Guideline Program in Oncology.


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Citation format

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) – Part 1 with Recommendations on Epidemiology, Screening, Diagnostics and Therapy. Geburtsh Frauenheilk 2022; 82: 139 – 180


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Guideline documents

The complete long version, a version for patients and a slide version of this guideline, all of them in German, together with a list of the conflicts of interest of all of the authors are available on the homepage of the AWMF: https://www.awmf.org/leitlinien/detail/ll/032-033OL.html

The German-language version of the guideline is also available via the App of the German Guideline Program in Oncology: https://www.leitlinienprogramm-onkologie.de/app/


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Guideline authors

The organizations listed in [Tables 1] and [2] and their representatives were involved in the compilation of this guideline and are the authors of the guideline. The guideline was compiled with the direct involvement of a patient representative with voting rights. Physicians from the Oncology Competence Center of the National Association of Statutory Health Insurance Funds in Germany (GKV-Spitzenverband) and the Medical Advisory Service of the German Health Insurance Funds (MDK-Gemeinschaft) were involved in the preparation of this guideline in an advisory capacity on various socio-medical aspects. They did not participate in the voting on individual recommendations and are not responsible for the contents of this guideline.

Tab. 1 Lead and/or coordinating guideline author.

Author

AWMF professional society

Prof. Dr. Matthias W. Beckmann

German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V., DGGG); Working Group on Gynecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie e. V., AGO)

Prof. Dr. Tanja Fehm

German Society of Gynecology and Obstetrics (DGGG)

Tab. 2 Contributing guideline authors.

Author

Mandate holder

DGGG working group (AG)/AWMF/non-AWMF professional society/organization/association

Prof. Dr. Jan Menke

Imaging in Oncology Working Group (Arbeitsgemeinschaft Bildgebung in der Onkologie, ABO)

Prof. Dr. Olaf Ortmann

Working Group of German Tumor Centers (Arbeitsgemeinschaft Deutscher Tumorzentren, ADT)

PD Dr. Carmen Stromberger

Proxy: Prof. Dr. Karin Oechsle

Working Group for Palliative Medicine (Arbeitsgemeinschaft für Palliativmedizin, APM)

Dipl.-Psych. Beate Hornemann

Proxy: Dr. Friederike Mumm

Working Group for Psychooncology (Arbeitsgemeinschaft für Psychoonkologie, PSO)

Prof. Dr. Peter Mallmann (senior coordinator)

Prof. Dr. Tanja Fehm (mandate holder)

Working Group on Gynecological Oncology (AGO)

Prof. Dr. Christoph Grimm (mandate holder)

Dr. Alina Sturdza (deputy)

Working Group on Gynecological Oncology of the Austrian Society of Gynecology and Obstetrics (Arbeitsgemeinschaft Gynäkologische Onkologie der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe, AGO der OEGGG)

PD Dr. Edward Wight (mandate holder)

Dr. Kristina Loessl (deputy)

Working Group on Gynecological Oncology of the Swiss Society of Gynecology and Obstetrics (Arbeitsgemeinschaft Gynäkologische Onkologie der Schweizer Gesellschaft für Gynäkologie und Geburtshilfe, AGO der SGGG)

Prof. Dr. Michael Golatta (until 03/20)

Working Group on Gynecological Radiology (Arbeitsgemeinschaft für gynäkologische Radiologie, AGR)

Dr. Volker Hagen

Working Group on Internal Oncology (Arbeitsgemeinschaft Internistische Onkologie, AIO)

Dr. Timm Dauelsberg (mandate holder)

Prof. Dr. Ingo Diel (deputy)

Working Group on Oncological Rehabilitation and Social Medicine (Arbeitsgemeinschaft Onkologische Rehabilitation und Sozialmedizin, AGORS)

Prof. Dr. Ingo Diel

Working Group on Supportive Measures in Oncology (Arbeitsgemeinschaft Supportive Maßnahmen in der Onkologie, AGSMO)

Prof. Dr. Karsten Münstedt

Working Group on Prevention and Integrative Oncology (Arbeitsgemeinschaft Prävention und integrative Onkologie, PRIO)

Prof. Dr. Eberhard Merz

Working Group on Ultrasound Diagnostics in Gynecology and Obstetrics, (Arbeitsgemeinschaft für Ultraschalldiagnostik in Gynäkologie und Geburtshilfe, ARGUS)

Prof. Dr. Dirk Vordermark (mandate holder)

Prof. Dr. Katja Lindel (deputy)

Working Group on Radiological Oncology (Arbeitsgemeinschaft Radiologische Onkologie, ARO)

Prof. Dr. Christian Wittekind

Working Group on Tumor Classification in Oncology (Arbeitsgemeinschaft Tumorklassifikation in der Onkologie, ATO)

PD Dr. Volkmar Küppers (mandate holder)

Prof. Dr. Ralph Lellé (deputy)

Working Group on Cervical Pathology and Colposcopy (Arbeitsgemeinschaft Zervixpathologie und Kolposkopie, AG-CPC)

Prof. Dr. med. Klaus Joachim Neis (until August 31, 2019)

Prof. Dr. Henrik Griesser (from September 1, 2019)

Professional Association of German Physicians Working in Cytology (Arbeitsgemeinschaft zytologisch tätiger Ärzte in Deutschland, AZÄD)

Birgit Pöschel

Federal Association of German Pathologists (Bundesverband Deutscher Pathologen e. V., BDP)

Dr. Manfred Steiner (mandate holder)

Dipl.-Med. Ulrich Freitag (deputy)

Professional Association of Gynecologists in Germany (Berufsverband der Frauenärzte, BVF)

Tobias Gilster

Professional Association of Gynecological Oncologists in Private Practice in Germany (Berufsverband Niedergelassener Gynäkologischer Onkologen in Deutschland, BNGO)

PD Dr. Alexander Schmittel

Professional Association of Hematologists in Private Practice (Berufsverband der niedergelassenen Hämatologen, BNHO)

Prof. Dr. Michael Friedrich

Federal Working Group of Leading Doctors in Gynecology and Obstetrics (Bundesarbeitsgemeinschaft Leitender Ärztinnen und Ärzte in der Frauenheilkunde und Geburtshilfe, BLFG)

Heidemarie Haase (mandate holder)

Marion Gebhardt (deputy)

Federal Association of Womenʼs Self-help After Cancer (Bundesverband Frauenselbsthilfe nach Krebs, FSH)

Prof. Dr. Ludwig Kiesel

German Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie, DGE)

Prof. Dr. Matthias W. Beckmann (guideline coordinator)

Prof. Dr. Christian Dannecker (mandate holder)

German Society of Gynecology and Obstetrics (DGGG)

Prof. Dr. Michael Reinhardt (mandate holder)

Prof. Dr. Michael Kreißl (deputy)

German Society for Nuclear Medicine (Deutsche Gesellschaft für Nuklearmedizin, DGN)

Dr. Marianne Kloke

German Society for Palliative Medicine (Deutsche Gesellschaft für Palliativmedizin, DGP)

Prof. Dr. Lars-Christian Horn

German Society for Pathology (Deutsche Gesellschaft für Pathologie, DGP)

Prof. Dr. Regina Wiedemann

German Society for Nursing Science (Deutsche Gesellschaft für Pflegewissenschaft, DGP)

Prof. Dr. Simone Marnitz-Schulze

German Society for Radiooncology (Deutsche Gesellschaft für Radioonkologie, DEGRO)

Prof. Dr. Eberhardt Merz

German Society for Ultrasound in Medicine (Deutsche Gesellschaft für Ultraschall in der Medizin e. V., DEGUM)

Prof. Dr. Anne Letsch

German Society for Hematology and Oncology (Deutsche Gesellschaft für Hämatologie und Onkologie, DGHO)

Dr. Isabella Zraik

German Society for Urology (Deutsche Gesellschaft für Urologie, DGU)

Dr. Bernhard Mangold (mandate holder)

Dr. Jochen Möckel (deputy)

German Society for Cytology (Deutsche Gesellschaft für Zytologie, DGZ)

PD Dr. Céline Alt

German X-Ray Society (Deutsche Röntgengesellschaft, DRG)

Prof. Dr. Pauline Wimberger

European Society for Gynaecological Oncology (ESGO)

Prof. Dr. Peter Hillemanns

Complementary Guideline on Screening, Certification Commission for Gynecological Cancer Centers (Zertifizierungskommission gynäkologischer Krebszentren)

Kerstin Paradies

Conference on Oncology Nursing and Pediatric Nursing (Konferenz onkologischer Kranken- und Kinderkrankenpflege, KOK)

Prof. Dr. Alexander Mustea

North-Eastern German Society for Gynecological Oncology (Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie, NOGGO)

Prof. Dr. Dominik Denschlag

Study Group of the Gynecological Oncology Working Group (Studiengruppe der Arbeitsgemeinschaft Gynäkologische Onkologie, AGO)

Ulla Henscher (mandate holder)

Reina Tholen (deputy)

Central Association of Physiotherapists (Zentralverband der Physiotherapeuten/Krankengymnasten, ZVK)

The Office of the German Guideline Program in Oncology and the AWMF provided the methodological supervision ([Table 3]). The guideline authors were supported by the project team and the Guidelines Office ([Table 4]).

Tab. 3 Methodological supervision.

Name

City

Dr. Markus Follmann MPH M. Sc. (Office of the German Guideline Program in Oncology – German Cancer Society)

Berlin

Dipl.-Soz. Wiss. Thomas Langer (Office of the German Guideline Program in Oncology – German Cancer Society)

Berlin

Dr. Monika Nothacker MPH (Deputy Head – AWMF Institute for Medical Knowledge Management)

Berlin

PD Dr. Simone Wesselmann, MBA (German Cancer Society – certification, quality indicators)

Berlin

Biologist Gregor Wenzel

Berlin

Tab. 4 Guidelines Office and project team.

Name

City

Dr. Martin C. Koch (Guidelines Office)

Erlangen

Dr. Frederik A. Stübs (Guidelines Office)

Erlangen

Dr. Anna K. Dietl (project team)

Erlangen

Anna Sevnina (project team)

Erlangen

Dr. Franziska Mergel (project team)

Erlangen

PD Dr. Laura Lotz (project team)

Erlangen

PD Dr. Carolin C. Hack (project team)

Erlangen

Dr. Anne Ehret (project team)

Düsseldorf

Dr. Daniel Gantert (project team)

Düsseldorf

Dr. Franca Martignoni (project team)

Düsseldorf


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Abbreviations

AIS: adenocarcinoma in situ
CAM: complementary and alternative medicine
CHT: chemotherapy
CI: confidence interval
CIN: cervical intraepithelial neoplasia
CT: computed tomography
EC: expert consensus
FIGO: Fédération Internationale de Gynécologie et dʼObstétrique (International Federation of Gynecology and Obstetrics)
GKV: statutory health insurance in Germany (Gesetzliche Krankenversicherung)
GoR: grade of recommendation
HE: hysterectomy
HPV: human papillomavirus
ICG: indocyanine green
IECC: International Endocervical Adenocarcinoma Classification
LoE: level of evidence
MDK: Medical Advisory Service of the German Association of Health Insurance Funds (Medizinischer Dienst der Krankenkassen)
MRI: magnetic resonance imaging
NECC: neuroendocrine cervical carcinoma
Pap: cervical cytology by Pap smear
PET: positron emission tomography
R(CH)T: simultaneous radio(chemo)therapy
SMILE: stratified mucin-producing intraepithelial lesion
SNB: sentinel lymph node biopsy
STIKO: German Standing Committee on Vaccinations at the Robert Koch Institute
TNM: tumor–nodes–metastasis
UICC: Union internationale contre le cancer
 


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II  Guideline Application

Purpose and objectives

The rationale for this guideline was problems relating to security of care as well as the fact that mortality and morbidity rates have not decreased much in the last 15 years, and that the current therapies administered to patients with cervical cancer can vary greatly. The aim of this updated guideline remains the same as that of the previous version of 2014. This guideline on Diagnosis, Therapy and Follow-up of Cervical Cancer is an evidence- and consensus-based instrument for the care of patients with cervical cancer. It provides patients with scientific, up-to-date, economically viable procedures for diagnosis, therapy, follow-up and rehabilitation which are appropriate for the various stages of disease. The current version of the guideline aims to provide a basis for clinical decision-making on the appropriate treatment. The guideline also incorporates the concept of shared decision-making.


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Targeted areas of patient care

The area covered by the guideline ranges from diagnosis to therapy and the follow-up of patients with cervical cancer and includes patients with microinvasive lesions/high-grade precursor lesions (but excludes patients with early precursor lesions/preinvasive lesions). The guideline has an intersectoral scope. It covers both outpatient and in-patient care as well as rehabilitation.


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Target user groups

This S3 guideline addresses all patients with cervical cancer (including microinvasive lesions/high-grade precursor lesions but excluding early precursor lesions/preinvasive lesions) and their families.


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Intended audience

The recommendations of the guideline are for all physicians and professional groups involved in the outpatient and/or in-patient care and rehabilitation of patients with cervical cancer.

The guideline is also intended for

  • medical and scientific specialist societies and professional associations,

  • special interest groups representing women (womenʼs health organizations, patient organizations and self-help organizations),

  • quality assurance institutions and federal and state-level projects (e.g., AQUA, ADT, IQWiG, GEKID, gesundheitsziele.de, IQTIG),

  • health policy institutions and decision-making bodies at federal and state levels,

  • certification institutions (e.g., DKG)

  • funding bodies


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Adoption and period of validity

The validity of this guideline was confirmed by the executive boards/heads of the participating medical professional societies, working groups, organizations and associations as well as by the boards of the DGGG, SGGG and OEGGG and the DGGG/OEGGG/SGGG guidelines commission and was thus approved in its entirety. This guideline is valid until October 2025. Because of the contents of this guideline, this period of validity is only an estimate. If changes are urgently required, the guideline can be updated earlier; if the information in the guideline still represents the current state of knowledge, then the guidelineʼs period of validity can be extended.


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III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches. This guideline has been classified as: S3.

The methodological approach used when compiling this guideline is described in the guideline report. The guideline report is freely available on the homepage of the German Guideline Program in Oncology (https://www.leitlinienprogramm-onkologie.de/leitlinien/zervixkarzinom/) and the homepage of the AWMF (http://www.awmf.org/).


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Grading of evidence based on SIGN

To classify the risk of bias in identified studies, this guideline used the system of the Scottish Intercollegiate Guidelines Network (SIGN) shown in [Table 5] (cf. https://www.sign.ac.uk/media/1050/sign50_2019.pdf).

Tab. 5 Classification of levels of evidence according to SIGN.

Level

Description

1++

High-quality meta-analyses, systematic review of RCTs, or RCTs with a very low risk of bias.

1+

Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias.

1−

Meta-analyses, systematic reviews, 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, bias or “chance” and a high probability that the relationship is causal.

2+

Well-conducted case-control studies or cohort studies with a low risk of confounding, bias or “chance” and a moderate probability that the relationship is causal.

2−

Case-control studies or cohort studies with a high risk of confounding, bias or “chance” and a significant risk that the relationship is not causal.

3

Non-analytical studies, e.g., case reports, case series

4

Expert opinion


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Grading of recommendations

In this guideline, the level of evidence (using the SIGN classification) in the underlying studies and, when making recommendations, the strength of the recommendation (grade of recommendation) is given for all evidence-based statements and recommendations. As regards the strength of recommendations, the guideline differentiates between three grades of recommendation ([Table 6]), and the level of recommendation is reflected in the wording used in the respective recommendation:

Tab. 6 Grade of recommendation.

Symbol

Description of level of obligation to comply with the recommendation

Term

A

Strong recommendation

must/must not

B

Simple recommendation

should/should not

0

Open recommendation, not binding

may/may not

In principle, the grade of recommendation is based on the strength of the available evidence. For example, if there is a high level of evidence (provided by high-quality meta-analyses/systematic reviews of RCTs or several methodologically high-quality RCTs), then a strong recommendation is given (grade of recommendation: A, “must”).

But the following criteria are also taken into account and can result in the level of recommendation being upgraded or downgraded:

Consistency of study results

  • Example: The effect estimates for study results diverge, showing no consistent tendency.

Clinical relevance of endpoints and effect sizes

  • Example: Although studies with results which point in a specific direction are available, the importance of the selected endpoints and/or effect sizes are not considered relevant.

Benefit-to-risk ratio

  • Example: Although the intervention has a proven benefit, it is also associated with a relevant harm which mitigates against giving an unqualified recommendation.

Ethical obligations

  • Example: Downgrading: For ethical reasons, an intervention with a proven benefit cannot be offered without restrictions. Upgrading: Strong recommendation based on case-control studies, because an RCT cannot be carried out for ethical reasons.

Patient preferences

  • Example: An intervention with a proven benefit is not strongly recommended as it is rejected by patients who consider it to be onerous or not feasible.

Applicability, practicability of care

  • Example: An intervention with proven positive effects cannot be recommended because it is not available in regional healthcare systems for structural reasons.


#

Statements

Statements are expositions or explanations of specific facts, circumstances or problems without directly calling to action. They are adopted using the same approach used for recommendations and following a formal consensus procedure, and they may be based either on study results or on expert opinions.


#

Achieving consensus and level of consensus

At structured NIH-type (S2k/S3 level) consensus conferences, authorized participants attending the conference voted on draft statements and recommendations. Conferences are structured as follows: a recommendation is presented; participants can ask about the contents of the recommendation; amendments can be proposed; all proposed amendments are voted on. If a consensus (> 75% of votes) cannot be reached, there is another round of discussions, followed by another vote. At the end of the session, the strength of the consensus is determined based on the number of persons who participated in the session ([Table 7]).

Tab. 7 Strength of consensus based on the extent of consensus.

Symbols

Level of consensus

Extent of agreement in percent

+++

Strong consensus

> 95% of participants agree

++

Consensus

> 75 – 95% of participants agree

+

Majority agreement

> 50 – 75% of participants agree

No consensus

< 51% of participants agree


#

Expert consensus

When the guideline authors decide to make statements/recommendations based on the expert consensus of the guideline authors, such statements/recommendations are identified by the phrase “expert consensus” (EC). No symbols are used to grade such recommendations; the strength of the expert consensus is indicated by the wording used (must/should/may) in accordance with the grading shown in [Table 6].


#
#

IV  Guideline

1  Epidemiology

Data from the Robert Koch Institute and the GEKID from 2019 show that in 2016, 4380 women developed cervical cancer and 1562 women died from cervical cancer in Germany. Compared to the figures for 2002, the incidence of cervical cancer (6500 vs. 4380) has declined significantly although the number of deaths (1700 vs. 1562) from cervical cancer has decreased only slightly. It is expected that the general administration of HPV vaccinations to girls between the ages of 9 and 14 years in 2007 will reduce future incidence and mortality rates even more. Since June 2018, the STIKO has also recommended that boys between the ages of 9 to 14 years be vaccinated. The herd protection obtained by vaccinating a sufficient number of people should further reduce the incidence and mortality of cervical cancer. In 2016, the relative 5-year survival rate for cervical cancer was 67% and the 10-year survival rate was 63% [1], [2]. The age distribution showed a peak between the ages of 40 and 59 years. The mean age at first diagnosis of cervical cancer is currently 55 years and has dropped by 15 years in the last 25 years [1]. Further information on regional differences, histological subtypes and risk factors are available in the long (English-language) version of the guideline.


#

2  Prevention and Screening

Because complementary S3 guidelines are already available, this guideline did not develop its own recommendations on prevention and screening. Interested parties should refer to the relevant S3 guidelines “Vaccination for the Prevention of HPV-associated Neoplasia (AWMF Registry No. 082/002)” and “Prevention of Cervical Cancer (AWMF Registry No. 015/027OL)” [3], [4].

No.

Recommendations/Statements

GoR

LoE

Sources

4.1.

reviewed 2021

Consensus-based statement

Recommendations on the prevention and early detection of cervical carcinoma are presented in the Level 3 guidelines (S3) “Vaccine Prevention of HPV-Associated Neoplasia” (AWMF register no. 082/002) and “Prevention of Cervical Carcinoma” (AWMF register no. 015/027OL).

EC


#

3  Patient Information

3.1  Informing patients and substance of the information

No.

Recommendations/Statements

GoR

LoE

Sources

5.1.

reviewed 2021

Consensus-based recommendation

High-quality and pertinent information materials (using print or Internet media) must be produced in accordance with defined quality criteria for health information and made available to patients, to support them in independent decision-making for or against medical measures by providing generally comprehensible risk information (e.g., with details of absolute risk reductions).

EC

3.1.1  Informing the patient of the diagnosis

No.

Recommendations/Statements

GoR

LoE

Sources

5.2.

reviewed 2021

Consensus-based recommendation

The patient must be informed that her partner or a relative can be invited to be included in the discussion(s).

EC

5.3.

reviewed 2021

Consensus-based recommendation

During the medical discussion, the patientʼs individual preferences, needs, worries and anxieties must be identified and taken into account. If a patient needs several discussions for the purpose, an offer of further discussions must be available.

EC

5.4.

modified 2021

Consensus-based recommendation

Providing the patient with medical information is primarily a task for the attending physician, but for specific topics it should be provided by other professional groups such as nurses, psycho-oncologists, etc.

EC

5.5.

modified 2021

Consensus-based recommendation

Information must be communicated and provided to the patient as early as possible on the basis of the following basic principles of patient-centered communication allowing participatory decision-making:

  • Expressing empathy and active listening

  • Direct, empathetic raising of difficult topics

  • Avoiding specialist medical vocabulary, with specialist terms being explained if needed

  • Using strategies for improving comprehension (repetition, summing up important information, using diagrams, etc.)

  • Encouraging the patient to ask questions

  • Permitting and encouraging expressions of emotion

  • Offering further assistance

EC

5.6.

reviewed 2021

Consensus-based recommendation

The patient should be offered psychosocial and psycho-oncological support for psychological, sexual, and relationship problems.

EC

5.7.

reviewed 2021

Consensus-based recommendation

The patient must be informed about the option of contacting self-help groups.

EC


#

3.1.2  Informing the patient about treatment options

No.

Recommendations/Statements

GoR

LoE

Sources

5.8.

reviewed 2021

Consensus-based recommendation

In accordance with the “Law on Improving Patientsʼ Rights,” the patient must be informed about all of the treatment options described in this guideline that are relevant to her and about their prospects of success and possible effects. In particular, effects on her physical appearance, sexual life, urinary and rectal continence, and aspects of female identity (self-image, fertility) should be mentioned.

EC

5.9.

reviewed 2021

Consensus-based statement

Principles, intended treatment goals, duration and implementation of the individual treatment measures

Surgical treatment measures:

  • Conization; trachelectomy

  • Surgical staging and associated additional measures

  • Forms of lymphadenectomy

  • Forms of radical hysterectomy

  • Exenteration procedures

  • Surgical options in case of recurrence

Radiotherapy:

  • Primary radiotherapy/radio(chemo)therapy

  • Secondary radiotherapy/radio(chemo)therapy

Systemic therapy:

  • Neoadjuvant/adjuvant chemotherapy

  • Combined radio(chemo)therapy

  • Targeted therapy

Side effects of treatment and ways of treating them

Late sequelae of the disease and therapy and ways of treating them

Complementary therapy:

  • Mention of the availability of complementary medicine to reduce side effects

Participation in clinical studies:

  • Principles and intended treatment goals

  • Duration and implementation of therapy

  • Effects and side effects currently known

  • Special aspects (monitoring, additional measures, compliance, data storage and processing)

Other information:

  • Psycho-oncological support and services provided by self-help groups

  • Options for rehabilitation

  • Necessity of follow-up care

  • Aspects of patientʼs own responsibility and compliance (e.g., providing information about symptoms and problems, treatment compliance)

EC

5.10.

reviewed 2021

Consensus-based recommendation

The patient must be informed about the patient guideline on diagnosis, treatment, and follow-up for patients with cervical carcinoma.

EC

5.11.

reviewed 2021

Consensus-based statement

Cervical carcinoma is not an emergency case. The patient can and must be given sufficient time for her own decision-making processes.

EC

3.1.2.1  Information provided to patients with metastatic or recurrent cervical cancer

No.

Recommendations/Statements

GoR

LoE

Sources

5.12.

reviewed 2021

Consensus-based recommendation

The following points can be mentioned as forming the content of a discussion in the palliative situation:

Aims of palliative medical therapy (alleviating suffering, treatment of pain – foremost goal: the patientʼs quality of life)

  • Patientʼs anxieties and fears, with inclusion of her partner and relatives

  • Radio(chemo)therapy – duration and intended effect

  • Palliative drug treatment

  • Palliative surgical treatment

  • Individual treatment decisions, depending on the patientʼs personal life plans

  • If the effectiveness of a treatment is limited, the result of the decision-making process may be to deliberately refrain from palliative tumor treatment

  • Mention of different aspects of palliative care (rehabilitation, psychosocial medicine, psycho-oncology)

  • Side effects and interactions of drugs and complementary medicine

  • Involvement of local hospice group if appropriate

  • Consultation with physicians and nursing services specializing in palliative medicine

Problem situations arising during the course of disease:

  • Pain

  • Ureteral stenosis leading to renal failure

  • Fistulas

  • Fetid discharge

  • Bleeding

  • Paralytic or mechanical ileus

  • Thrombosis, pulmonary embolism

Symptomatic and supportive therapy:

  • Treatment for lymphedema in the lower extremities

  • Pain therapy

  • Dysuria/bladder spasm

  • Psychosocial and religious/spiritual assistance for the patient and her relatives

  • Resources for assistance

EC


#
#
#
#

4  Diagnosis

The new FIGO classification was introduced in 2018. This new classification now also incorporates findings obtained with radiographic imaging or biopsies to determine the stage of disease (s. Table 19 on p. 261 of the long version of the S3 guideline). In addition, paraaortic lymph nodes are now classified as pN1 and no longer as pM1. Previously, the FIGO classification of cervical cancer consisted of purely clinical staging based on bimanual examination of the patient by a gynecologist. Because the (new) FIGO classification is not congruent with that of the (old) TNM, the old FIGO version is still used in this updated version of the guideline. There are currently no data from clinical studies using the new classification.

4.1  Diagnostic workup as the basis for therapeutic decisions

4.1.1  Images agreed upon by the guideline authors on the diagnostic workup and staging as the basis for therapeutic decisions

The guideline authors agreed on two graphs outlining the diagnostic workup and staging of lesions, as this affects the therapeutic decisions regarding lesions classified as FIGO ≤ IIB or > IIB ([Figs. 1] and [2]).

Zoom Image
Abb. 1 Diagnostic workup and staging as the basis for therapeutic decision for lesions which are ≤ FIGO stage IIB (reviewed in 2021). [rerif]
Zoom Image
Abb. 2 Diagnostic workup and staging as the basis for therapeutic decision for lesions which are > FIGO stage IIB (reviewed in 2021). [rerif]

#

4.1.2  Recommendations for the diagnostic workup

No.

Recommendations/Statements

GoR

LoE

Sources

6.1.

modified 2021

Consensus-based recommendation

Vaginal ultrasonography must be used for clinical imaging to establish the extent of local tumor spread, and renal ultrasonography to exclude urinary transport disturbance.

EC

6.2.

modified 2021

Evidence-based recommendation

Patients with histologically confirmed cervical carcinoma from FIGO stage IB2 to III inclusive should undergo pelvic MRI for assessment of locoregional tumor spread. Patients who are unable to undergo pelvic MRI for technical reasons should have a pelvic CT.

B

1+

[5] – [7]

6.3.

modified 2021

Consensus-based recommendation

Starting from FIGO IB2 to III, patients in whom pelvic MRI cannot be carried out for technical reasons should undergo locoregional imaging of the pelvis for staging purposes during staging CT examinations of the chest, abdomen, and pelvis.

EC

6.4.

new 2021

Consensus-based recommendation

Patients in FIGO stage IVA who are unable to undergo pelvic MRI for technical reasons should receive locoregional imaging staging of the pelvis as part of staging CT of the chest/abdomen/pelvis.

EC

6.5.

modified 2021

Consensus-based recommendation

Patients with histologically confirmed cervical carcinoma FIGO stage IB2 or above should undergo chest/abdominal/pelvic CT for assessment of tumor spread.

EC

6.6.

reviewed 2021

Consensus-based recommendation

If a tumor of the vaginal part of the cervix cannot be clearly assessed macroscopically, a differential colposcopy and targeted biopsy must be carried out.

EC

6.7.

reviewed 2021

Consensus-based recommendation

The histologically confirmed tumor stage should be the basis for interdisciplinary treatment decision-making at the tumor conference.

EC

6.8.

modified 2021

Evidence-based recommendation

PET-CT should not be used for treatment planning in primary cervical carcinoma.

B

2+

[6], [8] – [11]

6.9.

modified 2021

Evidence-based recommendation

When a local procedure (radiochemotherapy or exenteration) is being considered for treatment of a recurrence, PET-CT should be carried out to exclude lymph-node metastases and distant metastases.

B

2+

[6], [12] – [14]


#
#
#

5  Pathology

5.1  Classification of invasive cervical cancers

5.1.1  Tumor typing

The majority of invasive cervical cancers are squamous cell carcinomas (~ 80%) and adenocarcinomas (~ 5 – 20%) [15]. Other tumor entities are rare. Neuroendocrine (large or small cell) carcinoma and non-HPV-associated adenocarcinoma with the exception of clear cell adenocarcinoma are tumor types which have a particularly unfavorable prognosis.

No.

Recommendations/Statements

GoR

LoE

Sources

7.1.

reviewed 2021

Consensus-based recommendation

Tumor classification must be carried out on the basis of the currently valid edition of the WHO classification.

EC

7.2.

reviewed 2021

Consensus-based recommendation

In cervical carcinomas with neuroendocrine components, the latter must be reported along with the percentage of the total tumor that they represent.

EC


#

5.1.2  Staging of cervical cancer

Postoperative staging is based on the TNM classification [16]. Lesions are differentiated into micro- and macroinvasive cancers.

No.

Recommendations/Statements

GoR

LoE

Sources

7.3.

modified 2021

Consensus-based recommendation

Staging must be carried out in accordance with the current edition of the TNM classification.

EC

7.4.

reviewed 2021

Consensus-based recommendation

A diagnosis of microinvasive cervical carcinoma must be based on the definitions given in the current editions of both the WHO and TNM classifications.

EC


#
#

5.2  Tissue preparation

5.2.1  Diagnostic biopsies

No.

Recommendations/Statements

GoR

LoE

Sources

7.5.

reviewed 2021

Consensus-based recommendation

The biopsy sample that has been taken must be processed in step sections.

EC

7.6.

modified 2021

Consensus-based recommendation

The report on the findings should mention the evidence and the grade of CIN, ACIS (and its variants in the form of stratified mucin-producing intraepithelial lesions [SMILE]), virus-associated changes, and possible invasion.

EC


#

5.2.2  Conization

No.

Recommendations/Statements

GoR

LoE

Sources

7.7.

reviewed 2021

Consensus-based recommendation

The pathology report must state the size and characteristics of the excised (conization) specimen. The conization specimen must be completely processed and step sections must be prepared from each paraffin block.

EC

7.8.

modified 2021

Consensus-based recommendation

The histological report must note the type of lesion (CIN, ACIS and its variants in the form of stratified mucin-producing intraepithelial lesions [SMILE]), its location (endocervical, ectocervical), and its extent, as well as the presence of invasive tumor. When there is evidence of invasion, details must also be given of its extent and of lymphatic, vascular and perineural sheath invasion, as well as grading. The status of the resection margins must also be noted.

EC

7.9.

new 2021

Consensus-based recommendation

A multifocal microinvasive carcinoma is defined as evidence of invasive foci that are histologically clearly separate from each other at a minimum distance of 0.2 cm.

The size of each invasive tumor focus must be reported separately, with the largest single lesion being relevant for staging.

EC


#

5.2.3  Trachelectomy

No.

Recommendations/Statements

GoR

LoE

Sources

7.10.

reviewed 2021

Consensus-based recommendation

Morphological processing must take place in such a way that all therapeutically and prognostically relevant parameters can be assessed. The report must be produced on the basis of the currently valid WHO classification for tumor type and the current TNM classification for staging, as well as the R classification (UICC).

EC

7.11.

modified 2021

Consensus-based recommendation

The trachelectomy report must include the following details:

  • Histological type (WHO)

  • Grading

  • Presence/absence of lymphatic or venous invasion (L and V status)

  • Presence/absence of perineural sheath infiltration (Pn status)

  • Staging (TNM)

  • Depth of invasion and extent in millimeters in pT1a1 and pT1a2

  • Three-dimensional tumor size in centimeters (from pT1b1)

  • Minimum distance from the resection margins (endocervical stroma in pT1b tumors)

  • R classification (UICC)

EC


#

5.2.4  Specimens after radical hysterectomy

No.

Recommendations/Statements

GoR

LoE

Sources

7.12.

reviewed 2021

Consensus-based recommendation

Morphological processing must take place in such a way that all therapeutically and prognostically relevant parameters can be assessed. The report must be produced on the basis of the currently valid WHO classification for tumor type and the current TNM classification for staging, as well as the R classification (UICC).

EC

7.13.

new 2021

Consensus-based recommendation

To document intratumoral heterogeneity, macroscopically visible tumors ≤ 2 cm in size should be completely processed and at least one block per centimeter at the greatest tumor extension should be embedded from tumors larger than 2 cm.

EC

7.14.

reviewed 2021

Consensus-based statement

Deep stromal infiltration is defined as invasion by the cervical carcinoma into the outer third of the cervical stroma (> 66%).

EC

7.15.

modified 2021

Consensus-based recommendation

The radical hysterectomy report must include the following details:

  • WHO histological type

  • Grading

  • Presence/absence of lymphatic or venous invasion (L and V status)

  • Presence/absence of perineural sheath infiltration (Pn status)

  • Staging (TNM), taking the conization findings into account in patients who have undergone conization

  • Depth of invasion and extension in millimeters in pT1a1 and pT1a2

  • Depth of invasion relative to the cervical wall thickness (measurement or percentage figure)

  • Three-dimensional tumor size in centimeters (from pT1b1)

  • Minimum distance from the resection margins (endocervical stroma in pT1b tumors, vagina in pT2a tumors, and parametrium in pT2b tumors)

  • R classification (UICC)

EC


#

5.2.5  Lymphadenectomy specimens

No.

Recommendations/Statements

GoR

LoE

Sources

7.16.

reviewed 2021

Consensus-based recommendation

Micrometastases are defined as histological evidence of tumor cells in lymph nodes measuring ≥ 0.2 mm, but no larger than 0.2 cm.

EC

7.17.

reviewed 2021

Consensus-based recommendation

In lymphadenectomy specimens obtained during surgical treatment for cervical carcinoma, all removed lymph nodes must be histologically examined.

EC

7.18.

reviewed 2021

Consensus-based recommendation

Lymph nodes up to approx. 0.3 cm in size should be completely paraffin-embedded, and larger lymph nodes should be halved along the long axis and also completely paraffin-embedded.

EC

7.19.

new 2021

Consensus-based recommendation

Evidence of isolated tumor cells or micrometastases should be mentioned in the histological report and included in the TNM classification.

EC

7.20.

reviewed 2021

Consensus-based recommendation

The report on lymph nodes must include the following details: number of affected lymph nodes relative to the number of lymph nodes removed, correlated with the location of removal (pelvic/para-aortic).

EC


#

5.2.6  Sentinel lymph nodes

No.

Recommendations/Statements

GoR

LoE

Sources

7.21.

reviewed 2021

Consensus-based recommendation

Sentinel lymph nodes in cervical carcinoma must be completely paraffin-embedded and examined in step sections.

EC

7.22.

new 2021

Consensus-based recommendation

Sentinel lymph nodes in cervical carcinoma should be processed as follows:

  • Lamellation of the adipose tissue that has been received, with identification of all sentinel lymph nodes

  • Complete removal of all lymph nodes

  • Halving of all lymph nodes ≤ 0.3 cm in size

  • Lamellation of all lymph nodes > 0.3 cm into 0.2-cm thick lamellae

  • Preparation of step sections

  • Immunohistochemical ultrastaging

  • With sentinel lymph nodes that cannot be identified macroscopically, complete embedding of the adipose tissue

EC

7.23.

new 2021

Consensus-based recommendation

Intraoperative rapid frozen-section examination (when clinically indicated) of sentinel lymph nodes in cervical carcinoma should be performed as follows:

  • Standard work-up of the sentinel lymph nodes

  • Examination of ALL sentinel lymph nodes in quick section

  • If there is a macroscopically visible tumor, intraoperative examination of a sample of the involved lymph node is sufficient

  • Macroscopically unremarkable lymph nodes must be examined completely intraoperatively

  • Step sections (three) should be made from the frozen blocks

  • The histological frozen-section examination can be supplemented with intraoperative imprint cytology

EC


#
#

5.3  Morphological prognostic factors

Established prognostic factors for cervical cancer are tumor stage and evidence of pelvic or paraaortic lymph node metastasis [17] – [23]. For more information on resection margins, tumor size, tumor-type histology, HPV status, IECC classification, venous infiltration, perineural sheath infiltration, depth of infiltration, micro- and macrometastasis, immunohistochemical ultrastaging, molecular markers, TCGA classification, mutation load and PD-L1 expression, see Chapter 7.3 of the long version of the guideline.


#
#

6  Basic Principles of Therapy

When this guideline was being updated, the new FIGO classification was already available to the guideline group. The underlying data is based on the previous classification. Therefore, all tumor stages refer to the old FIGO classification.

No.

Recommendations/Statements

GoR

LoE

Sources

8.1.

reviewed 2021

Consensus-based recommendation

The aim of treatment for primary cervical carcinoma should be individualized therapy.

The choice of treatment should take the following factors into account:

  • Patientʼs general condition (with high levels of comorbidity)

  • Patientʼs life situation

  • Clinically/histologically defined stage of the disease

  • Menopausal status

  • Potential wish to have children

  • Short-term and long-term sequelae of the various treatment options

  • Any risk factors

Overtreatment and undertreatment should be avoided.

EC

6.1  Primary therapy

Primary therapy consists of either surgery or radiochemotherapy. Surgical therapy is recommended for patients with FIGO stage IIA disease or lower. Primary radio(chemo)therapy is predominantly used to treat later stages of disease with more extensive infiltration (from stage IIB), disease with lymph node involvement or inoperable disease. Radio(chemo)therapy is also recommended when several preoperatively determined risk factors are present (i.e., lymphangitis [L1], R1, G3 [its importance is dubious and only in combination with two additional risk factors], neuroendocrine carcinoma, tumor > 4 cm [stage], or histology positive for lymph node metastasis). The choice of treatment for stage IV disease should be made on an individual basis. In general, when deciding on the appropriate therapy, no differences are made between the different histological tumor entities (e.g., adenocarcinoma or squamous cell carcinoma). Although the diagnosis of stage IB and II disease is different prior to therapy, surgery and simultaneous radio(chemo)therapy have equivalent long-term outcomes despite the differences in patterns of recurrence and the side-effects profiles of the therapies.

6.1.1  Surgery – hysterectomy and lymphadenectomy

6.1.1.1  Uterine surgery

Different surgical techniques and principles can be used for cervical and uterine surgery (conization, simple or radical trachelectomy, simple or radical hysterectomy) ([Fig. 3]). The Piver-Rutledge classification dating from 1974 is the standard classification to rank radical hysterectomies [24].

Zoom Image
Abb. 3 Surgical therapy techniques and principles (reviewed 2021). [rerif]

#

6.1.1.2  Lymphadenectomy or resection of sentinel lymph nodes to identify tumor stages

In this updated guideline, the use of sentinel lymph nodes as a surgical staging concept for tumors ≤ 2 cm and for pT1a1 and L1 disease was based on new data. It has also been shown that patent blue and radioactive marking are equivalent to intraoperative marking with indocyanine green (ICG).

No.

Recommendations/Statements

GoR

LoE

Sources

8.2.

reviewed 2021

Consensus-based recommendation

Treatment must be administered relative to the histological tumor stage, verified using surgical staging or interventional diagnosis.

EC

8.3.

modified 2021

Consensus-based statement

Sentinel lymphadenectomy alone should be used:

  • For preoperative imaging (patent blue and radioactive)

  • Or intraoperative imaging (indocyanine green)

  • When sentinel lymph nodes are imaged or detected bilaterally

  • In primary tumors in stage T IA 1 L1 and/or FIGO IA 2

  • In primary tumors in stage T IB1 (≤ 2 cm)

  • Removal of all imaged or detected sentinel lymph nodes

EC

8.4.

modified 2021

Evidence-based statement

If the sentinel lymphadenectomy method alone is being carried out, the following staining methods must be used:

  • Staining demonstration or detection using patent blue and radioactive tracer

or

  • Staining demonstration or detection using indocyanine green

  • Primary tumor < 2 cm in size, with no risk factors

  • Removal of all sentinel lymph nodes identified using imaging

A

2++

[25] – [27]


#

6.1.1.3  Drainage placement after lymphadenectomy

No.

Recommendations/Statements

GoR

LoE

Sources

8.5.

reviewed 2021

Evidence-based recommendation

Following pelvic lymphadenectomy, placement of a retroperitoneal drain in the surgical area should be avoided, in order to prevent lymphoceles.

B

1+

[28]


#
#

6.1.2  Radio(chemo)therapy

Radio(chemo)therapy may be administered as neoadjuvant, primary or adjuvant therapy. Standard radio(chemo)therapy is carried out using cisplatin as a radiosensitizer. It is important to differentiate between percutaneous radiotherapy and brachytherapy. Which areas (pelvic/paraaortic) are selected for irradiation depends on histological verification of lymph node involvement and not on any imaging-based presumption of affected lymph nodes. Standard radio(chemo)therapy for stage IIb disease and above as well as lower stages of disease with histologically verified risk factors consists of primary, initially percutaneous, irradiation of the primary tumor and pelvic lymph nodes combined with cisplatin-based chemotherapy followed by brachytherapy.


#
#

6.2  Neoadjuvant drug treatment

No.

Recommendations/Statements

GoR

LoE

Sources

8.6.

reviewed 2021

Evidence-based recommendation

Neoadjuvant drug therapy can be carried out in selected patients who are at high-risk.

0

1−

[29], [30]

8.7.

reviewed 2021

Consensus-based recommendation after systematic research

The significance of tumor-affected lymph nodes after neoadjuvant chemotherapy for further treatment planning is unclear.

EC


#

6.3  Adjuvant therapy

6.3.1  Adjuvant therapy after primary surgery

No.

Recommendations/Statements

GoR

LoE

Sources

8.8.

reviewed 2021

Consensus-based recommendation after systematic research

Adjuvant therapy following primary surgical therapy should be administered on the basis of the postoperative histological tumor stage as follows:

Negative lymph nodes; R0; no risk factors

  • Follow-up

Negative lymph nodes; R0; one or two risk factors (L1, V1, deep stromal invasion, tumor size > 4 cm)

  • Individualized decision

Histologically confirmed lymph-node metastases, pelvic (pN1) or R1 or several (≥ 3) simultaneous risk factors (L1, V1, deep stromal invasion, tumor size > 4 cm, as well as grade G3 if two additional risk factors are present)

  • Adjuvant radio(chemo)therapy including lymphatic drainage areas in the histologically identified area (pelvic)

Histologically confirmed para-aortic lymph-node metastases (pM1)

  • Extended adjuvant radio(chemo)therapy including lymphatic drainage areas in the histologically identified area (pelvic and para-aortic fields)

Distant metastases, M1 (organ metastases, peritoneal carcinosis, ovarian metastases)

  • Systemic chemotherapy; radiotherapy only indicated in case of bleeding problems

EC


#

6.3.2  Adjuvant therapy after primary radiochemotherapy

After primary radio(chemo)therapy has been carried out, the option to perform secondary hysterectomy or expanded chemotherapy may be discussed in specific situations (see Statement).


#
#

6.4  Therapy of locally limited cervical cancer ≤ FIGO stage IIA

No.

Recommendations/Statements

GoR

LoE

Sources

8.9.

reviewed 2021

Consensus-based recommendation after systematic research

In stages ≤ FIGO stage IIA, primary surgical therapy should be carried out if adjuvant therapy is not expected (no preoperative risk factors).

EC


#

6.5  Stage-dependent therapy

6.5.1  Standard therapy for invasive cervical cancer

6.5.1.1  FIGO stage IA (synonyms: early stromal invasion, microcarcinoma or microinvasive carcinoma)

No.

Recommendations/Statements

GoR

LoE

Sources

8.10.

modified 2021

Consensus-based recommendation

In stage IA1 without any risk factors, treatment must be administered as follows:

Surgery:

  • Lymph-node removal is not indicated.

  • If family planning has been completed, or if the patient wishes greater certainty:

    • Simple hysterectomy.

  • If the patient wishes to have children:

    • Conization (within healthy margins) with cervical curettage.

  • If there are positive margins in the conization specimen (R1):

    • Repeat conization, or

    • Trachelectomy (within healthy margins, with prophylactic permanent cerclage).

  • Following successful pregnancy:

    • Secondary hysterectomy is possible, particularly if there is persistent HPV, abnormal Pap findings, if the patient wishes maximum safety, or if the cervix is difficult or impossible to assess.

Radio(chemo)therapy:

  • Not indicated.

EC

8.11.

new 2021

Consensus-based recommendation

In stage IA1 with lymphatic infiltration (L1), treatment must be administered as follows:

Surgery:

  • Sentinel lymphadenectomy is indicated.

  • If family planning has been completed, or if the patient wishes greater certainty:

    • Simple hysterectomy.

  • If the patient wishes to have children:

    • Conization (within healthy margins) with cervical curettage.

  • If there are positive margins in the conization specimen (R1):

    • Repeat conization, or

    • Trachelectomy (within healthy margins, with prophylactic permanent cerclage).

  • Following successful pregnancy:

    • Secondary hysterectomy is possible, particularly if there is persistent HPV, abnormal Pap findings, if the patient wishes maximum safety, or if the cervix is difficult or impossible to assess.

Radio(chemo)therapy:

  • Not indicated.

EC

8.12.

modified 2021

Consensus-based recommendation

In stage IA1 with at least two risk factors,

and stage IA2 with up to one risk factor,

treatment should be administered as follows:

Surgery:

  • If the patient does not wish to have children and if she wants to be particularly safe and has histologically negative lymph nodes (pelvic) after surgical staging with SNB:

    • Hysterectomy (with bilateral adnexectomy if appropriate), without resection of the parametria (Piver I)

  • If the patient wishes to have children and has negative lymph nodes after surgical staging with SNB:

    • Conization with cervical curettage or

    • Radical trachelectomy with prophylactic permanent cerclage.

  • If there are sentinel lymph nodes affected by tumor, or there are pelvic lymph-node metastases:

    • Para-aortic lymphadenectomy (surgical staging).

  • In premenopausal patients:

    • Ovariopexy to maintain intrinsic ovarian function.

  • If there are macroscopically tumor-affected pelvic and/or para-aortic lymph nodes:

    • Surgical removal before radio(chemo)therapy.

  • After successful pregnancy:

    • Secondary hysterectomy, particularly when there is persistent HPV infection, Pap abnormalities, if the patient wants greater safety, and if the cervix can only be assessed to a limited extent or not at all.

Radio(chemo)therapy:

  • If there is histological evidence of pelvic and/or para-aortic lymph-node metastases or there are several risk factors:

    • R(CH)T in the histologically confirmed area of spread.

EC

8.13.

modified 2021

Consensus-based recommendation

In stage IA2 with at least two risk factors, treatment should be administered as follows:

Surgery (preserving fertility is not possible) with SNB:

  • With negative lymph nodes (pelvic) after surgical staging:

    • Radical hysterectomy (with bilateral adnexectomy if appropriate), with resection of the parametria (Piver II)

  • If there are sentinel lymph nodes affected by tumor or if there are pelvic lymph-node metastases:

    • Additional para-aortic lymphadenectomy (surgical staging).

  • In premenopausal patients:

    • Ovariopexy to maintain intrinsic ovarian function.

  • If there are macroscopically tumor-affected pelvic and/or para-aortic lymph nodes:

    • Surgical removal of these before radio(chemo)therapy.

Radio(chemo)therapy:

  • If there is histological evidence of pelvic and/or para-aortic lymph-node metastases or there are several risk factors:

    • R(CH)T in the histologically confirmed area of spread.

EC


#

6.5.1.2  FIGO stage IB1 and IIA1

No.

Recommendations/Statements

GoR

LoE

Sources

8.14.

modified 2021

Consensus-based recommendation

In stages IB1 and IIA1, treatment should be administered as follows:

Surgery:

  • If there are negative lymph nodes (pelvic) after surgical staging:

    • Radical hysterectomy with resection of the medial (near the uterus) half of the parametria, with an adequate safety margin and resection within healthy margins (Piver II).

    • With a tumor-free resection margin at the vaginal cuff (IIA1).

  • If the tumor is < 2 cm, with no risk factors:

    • Surgical staging with SNB and

    • Radical hysterectomy with resection of the medial (near the uterus) half of the parametria, with an adequate safety margin and resection within healthy margins (Piver II).

    • With a tumor-free resection margin at the vaginal cuff (IIA1).

  • If the patient is wishing to have children and the tumor is < 2 cm without risk factors:

    • Surgical staging with SNB and

    • Radical trachelectomy with prophylactic permanent cerclage.

  • If family planning has been completed:

    • Secondary hysterectomy.

  • If there are pelvic lymph-node metastases:

    • Additional para-aortic lymphadenectomy (surgical staging).

  • In postmenopausal patients:

    • Bilateral adnexectomy.

  • In premenopausal patients:

    • Ovariopexy to maintain intrinsic ovarian function.

  • If there are pelvic and/or para-aortic lymph nodes macroscopically affected by tumor:

    • Surgical removal of the nodes, or radio(chemo)therapy.

Radio(chemo)therapy:

  • When there is histological evidence of pelvic and/or para-aortic lymph-node metastases, or several confirmed risk factors:

    • R(CH)T.

  • If the patient is inoperable or requests it:

    • R(CH)T.

  • The radiation volume should be based on the anatomy and histologically confirmed lymph-node involvement.

EC


#

6.5.1.3  FIGO stage IB2, IIA2 and IIB

No.

Recommendations/Statements

GoR

LoE

Sources

8.15.

reviewed 2021

Consensus-based recommendation

In stages IB2, IIA2, and IIB with a maximum of two risk factors, treatment should be administered as follows:

Surgery:

  • With negative lymph nodes (pelvic) after surgical staging:

    • Radical hysterectomy (with bilateral adnexectomy if appropriate), Piver type III.

    • With tumor-free resection margin at the vaginal cuff.

  • When there are pelvic lymph-node metastases:

    • Additional para-aortic lymphadenectomy (surgical staging).

  • When there are pelvic and/or para-aortic lymph-nodes with macroscopic tumor involvement:

    • Surgical removal of these before radio(chemo)therapy.

  • When there is vaginal involvement:

    • (Partial) radical colpectomy, with a tumor-free resection margin.

  • In postmenopausal patients:

    • Bilateral adnexectomy.

  • In premenopausal patients with adenocarcinoma:

    • Bilateral adnexectomy.

  • In premenopausal patients with squamous cell carcinoma:

    • Pre-treatment ovariopexy to preserve intrinsic ovarian function, both before planned R(CH)T and also during surgery with necessary adjuvant therapy.

Radio(chemo)therapy:

  • With histologically confirmed pelvic and/or para-aortic lymph-node metastases, or with several risk factors:

    • R(CH)T.

  • When the patient is inoperable or requests it:

    • R(CH)T.

  • Stage IIB:

    • Preferably R(CH)T.

    • The radiation volume should be based on the anatomy and histologically confirmed lymph-node involvement.

EC

8.16.

modified 2021

Consensus-based statement after systematic research

Radical hysterectomy before planned radio(chemo)therapy offers no benefits for the patient in relation to disease-free survival or overall survival.

EC


#

6.5.1.4  FIGO stage III

No.

Recommendations/Statements

GoR

LoE

Sources

8.17.

reviewed 2021

Consensus-based recommendation

In stage III, the following treatment should be administered:

Surgery:

  • Histological verification of spread

    • Surgical staging or interventional clarification.

  • When there are pelvic and/or para-aortic lymph nodes with macroscopic tumor involvement:

    • Surgical removal before radio(chemo)therapy.

Radio(chemo)therapy:

  • R(CH)T after surgical staging.

EC


#

6.5.1.5  FIGO stage IV

No.

Recommendations/Statements

GoR

LoE

Sources

8.18.

reviewed 2021

Consensus-based recommendation

In stage IVA, treatment should be administered as follows:

Surgery:

  • In selected cases:

    • Primary exenteration.

Radio(chemo)therapy:

  • R(CH)T is the treatment of choice.

EC

8.19.

reviewed 2021

Consensus-based recommendation

In stage IVB, treatment should be administered as follows:

Surgery:

  • Symptom-oriented therapy.

Radiotherapy or radio(chemo)therapy:

  • Symptom-oriented therapy.

Drug therapy:

  • Palliative systemic therapy is the treatment of choice.

Additional measures:

  • Best supportive care.

Palliative medicine:

  • Early palliative medicine intervention.

EC


#
#
#
#

7  Surgical Treatment

Based on new evidence from the LACC trial, the recommendation for the surgical approach to be used for radical hysterectomy in patients with cervical cancer was changed [31]. A clear preference was given to open procedures as opposed to laparoscopic approaches. The relevant recommendation was revised. The guideline authors rated prophylactic salpingectomy carried out in combination with planned hysterectomy as positive. The importance of secondary hysterectomy after radiochemotherapy is still not clear.

7.1  Surgical approach

No.

Recommendations/Statements

GoR

LoE

Sources

9.1.

reviewed 2021

Consensus-based recommendation

In postmenopausal patients with macroinvasive carcinoma, bilateral adnexectomy should be carried out during hysterectomy.

EC

9.2.

new 2021

Evidence-based recommendation

Open radical hysterectomy should be offered to patients up to FIGO stage IB1.

B

1+

[31]


#

7.2  Approach after primary radio(chemo)therapy

No.

Recommendations/Statements

GoR

LoE

Sources

9.3.

reviewed 2021

Consensus-based statement after systematic research

The value of secondary hysterectomy after primary radio(chemo)therapy is unclear in relation to the rate of local recurrence, disease-free survival, metastasis-free survival, and overall survival.

EC

9.4.

reviewed 2021

Consensus-based statement

Hysterectomy after primary radio(chemo)therapy in patients with complete remission on clinical and imaging findings is associated with a higher morbidity rate in comparison with primary radio(chemo)therapy alone.

EC

9.5.

reviewed 2021

Consensus-based statement after systematic research

It is unclear whether secondary hysterectomy should be carried out in the form of simple or radical hysterectomy after primary R(CH)T.

EC


#
#

8  Radiotherapy

After some revision, the recommendations for primary radiochemotherapy including external radiotherapy, simultaneous cisplatin-based chemotherapy and brachytherapy were confirmed. The grading of recommendations on the use of intensity-modulated radiotherapy techniques and for MRI-guided treatment planning for brachytherapy in the context of primary radiochemotherapy was increased as new data is now available which shows the clinical benefits of these techniques.

8.1  Radiochemotherapy

8.1.1  Radiotherapy techniques (percutaneous radiotherapy)

No.

Recommendations/Statements

GoR

LoE

Sources

10.1.

modified 2021

Evidence-based recommendation

Intensity-modulated techniques should be used to achieve optimal sparing of the surrounding tissue during primary radiochemotherapy for cervical carcinoma.

B

1+

[32]


#

8.1.2  Brachytherapy technique in primary combined radiochemotherapy

No.

Recommendations/Statements

GoR

LoE

Sources

10.2.

reviewed 2021

Guideline-adapted recommendation

Brachytherapy should be a component of the curative treatment approach in primary treatment for cervical carcinoma that includes radio(chemo)therapy.

B

4

[6]

10.3.

modified 2021

Consensus-based recommendation

MRI-planned brachytherapy should be used in primary radiochemotherapy for cervical carcinoma, to reduce the rate and severity of gastrointestinal and urogenital toxicities.

EC


#

8.1.3  Indications for primary radiotherapy or radio(chemo)therapy

No.

Recommendations/Statements

GoR

LoE

Sources

10.4.

reviewed 2021

Evidence-based recommendation

In patients with cervical carcinoma in whom there is an indication for primary radiotherapy from stage IB2 onwards, the radiotherapy must be combined with cisplatin-based chemotherapy.

A

1++

[33], [34]


#

8.1.4  Adjuvant radio(chemo)therapy

No.

Recommendations/Statements

GoR

LoE

Sources

10.5.

reviewed 2021

Consensus-based recommendation

Adjuvant cisplatin-containing radiochemotherapy should be used in patients with histologically confirmed postoperative risk factors.

B

1−

[35], [36]


#

8.1.5  Adjuvant chemotherapy after completing radio(chemo)therapy

No.

Recommendations/Statements

GoR

LoE

Sources

10.6.

reviewed 2021

Evidence-based statement

The value of consolidating chemotherapy after the completion of radio(chemo)therapy has not been confirmed.

ST

1−

[37], [38]


#

8.1.6  Neoadjuvant radio(chemo)therapy

No.

Recommendations/Statements

GoR

LoE

Sources

10.7.

reviewed 2021

Consensus-based recommendation

Neoadjuvant radio(chemo)therapy should not be administered outside of research studies.

EC


#

8.1.7  Ovarian preservation and fertility

No.

Recommendations/Statements

GoR

LoE

Sources

10.8.

reviewed 2021

Consensus-based recommendation

Young patients should be offered ovariopexy and high-conformal radiotherapy techniques to preserve ovarian hormone function.

EC


#

8.1.8  Anemia during radiochemotherapy

No.

Recommendations/Statements

GoR

LoE

Sources

10.9.

modified 2021

Guideline-adapted recommendation

During radiotherapy or radio(chemo)therapy for cervical carcinoma, the patientʼs hemoglobin values should be monitored and corrected via transfusion at values below 10 g/dL (6.2 mmol/L).

B

2++

[6]


#

8.1.9  Hyperthermia to treat cervical cancer

No.

Recommendations/Statements

GoR

LoE

Sources

10.10.

reviewed 2021

Evidence-based recommendation

Locoregional hyperthermia can be used in combination with percutaneous radiotherapy to treat locoregional recurrence or primary cervical carcinoma ≥ FIGO stage IIB.

0

1−

[39]

10.11.

modified 2021

Evidence-based statement

No advantage in relation to overall survival or disease-free survival has so far been confirmed in randomized trials, with the addition of locoregional hyperthermia to primary radiochemotherapy for cervical carcinoma.

ST

1−

[40]

10.12.

reviewed 2021

Consensus-based recommendation

Locoregional hyperthermia must be administered in a quality-assured and standardized fashion, preferably in the framework of scientific studies.

EC


#
#
#
#
Zoom Image

#

Conflict of Interest/Interessenkonflikt

The conflicts of interest of all the authors are listed in the long German-language version of the guideline report./Die Interessenkonflikte der Autoren sind im Leitlinienreport aufgelistet.


Correspondence/Korrespondenzadresse

Prof. Dr. med. Matthias Beckmann
Universitätsklinikum Erlangen
Frauenklinik
Universitätsstraße 21 – 23
91054 Erlangen
Germany   

Publication History

Received: 29 September 2021
Received: 14 October 2021

Accepted: 17 October 2021

Article published online:
11 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


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Abb. 1 Diagnostic workup and staging as the basis for therapeutic decision for lesions which are ≤ FIGO stage IIB (reviewed in 2021). [rerif]
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Abb. 2 Diagnostic workup and staging as the basis for therapeutic decision for lesions which are > FIGO stage IIB (reviewed in 2021). [rerif]
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Abb. 3 Surgical therapy techniques and principles (reviewed 2021). [rerif]
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Abb. 1 Diagnosestellung Stadiendefinition als Grundlage der Therapieentscheidung ≤ FIGO-Stadium IIB (geprüft/2021). [rerif]
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Abb. 2 Diagnosestellung und Stadiendefinition als Grundlage der Therapieentscheidung > FIGO-Stadium IIB (geprüft 2021). [rerif]
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Abb. 3 Operative Therapietechniken und -prinzipien (geprüft 2021). [rerif]
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