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

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.

Key words

guideline - cervical cancer - cervical intraepithelial neoplasia - therapy - follow-up

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).

Guidelines program of the DGGG, OEGGG and SGGG

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

Guideline funding

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

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

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/

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

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
 

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.

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.

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.

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

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.

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/).

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

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].

3  Patient Information

3.1  Informing patients and substance of the information

3.1.1  Informing the patient of the diagnosis

3.1.2  Informing the patient about treatment options

3.1.2.1  Information provided to patients with metastatic or recurrent cervical cancer

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]).

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

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

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.

5.1.2  Staging of cervical cancer

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

5.2  Tissue preparation

5.2.1  Diagnostic biopsies

5.2.2  Conization

5.2.3  Trachelectomy

5.2.4  Specimens after radical hysterectomy

5.2.5  Lymphadenectomy specimens

5.2.6  Sentinel lymph nodes

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.

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].

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).

6.1.1.3  Drainage placement after lymphadenectomy

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

6.3  Adjuvant therapy

6.3.1  Adjuvant therapy after primary surgery

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

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)

6.5.1.2  FIGO stage IB1 and IIA1

6.5.1.3  FIGO stage IB2, IIA2 and IIB

6.5.1.4  FIGO stage III

6.5.1.5  FIGO stage IV

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

7.2  Approach after primary radio(chemo)therapy

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)

8.1.2  Brachytherapy technique in primary combined radiochemotherapy

8.1.3  Indications for primary radiotherapy or radio(chemo)therapy

8.1.4  Adjuvant radio(chemo)therapy

8.1.5  Adjuvant chemotherapy after completing radio(chemo)therapy

8.1.6  Neoadjuvant radio(chemo)therapy

8.1.7  Ovarian preservation and fertility

8.1.8  Anemia during radiochemotherapy

8.1.9  Hyperthermia to treat cervical cancer

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.

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Publication History

Received: 29 September 2021
Received: 14 October 2021

Accepted: 17 October 2021

Article published online:
11 February 2022