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Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice
†
Guideline for diagnosis, treatment and follow-up

A. González-Martín, P. Harter, A. Leary, D. Lorusso, R.E. Miller, B. Pothuri, I. Ray-

Coquard, D.S.P. Tan, E. Bellet, A. Oaknin, J.A. Ledermann, on behalf of the ESMO
Guidelines Committee
PII: S0923-7534(23)00797-4
DOI: https://doi.org/10.1016/j.annonc.2023.07.011
Reference: ANNONC 1248

To appear in: Annals of Oncology

Received Date: 26 January 2023

Revised Date: 26 July 2023
Accepted Date: 28 July 2023

Please cite this article as: González-Martín A, Harter P, Leary A, Lorusso D, Miller RE, Pothuri B,
Ray-Coquard I, Tan DSP, Bellet E, Oaknin A, Ledermann JA, on behalf of the ESMO Guidelines
Committee, Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline
†
for diagnosis, treatment and follow-up , Annals of Oncology (2023), doi: https://doi.org/10.1016/
j.annonc.2023.07.011.

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© 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical
Practice Guideline for diagnosis, treatment and follow-up†

A. González-Martín1, P. Harter2, A. Leary3, D. Lorusso4,5, R. E. Miller6,7, B. Pothuri8,

I. Ray-Coquard9, D. S. P. Tan10-13, E. Bellet14, A. Oaknin15 & J. A. Ledermann16, on
behalf of the ESMO Guidelines Committee*

1
Department of Medical Oncology and Program in Solid Tumors Cima-Universidad
de Navarra, Cancer Center Clínica Universidad de Navarra, Madrid and Pamplona,
Spain; 2Department of Gynecology and Gynecologic Oncology, Ev. Kliniken
Essen-Mitte, Essen, Germany; 3Department of Medical Oncology, Gustave Roussy

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Cancer Center, INSERM U981, Université Paris-Saclay, Paris, France; 4Division of
Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli

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IRCSS, Rome; 5Department of Woman, Child and Public Health, Catholic University
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of the Sacred Heart, Rome, Italy; 6Department of Medical Oncology, University
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College Hospital, London; 7Department of Medical Oncology; St Bartholomew's
Hospital, London, UK; 8Department of Obstetrics and Gynecology, Perlmutter Cancer
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Center, NYU Langone Health, New York University School of Medicine, New York,
USA; 9Department of Medical Oncology, Centre Leon Bernard and Université Claude
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Bernard Lyon I, Lyon, France; 10Department of Medicine; 11National University of

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Singapore (NUS) Centre for Cancer Research, Yong Loo Lin School of Medicine,
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National University of Singapore, Singapore; 12Cancer Science Institute, National

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University of Singapore, Singapore; 13Department of Haematology-Oncology,

National University Cancer Institute, National University Hospital, Singapore,
Singapore; 14ACTO - Alleanza contro il tumore ovarico, Milan, Italy; 15Gynaecologic
Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari
Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain;
16
Department of Oncology, UCL Cancer Institute, University College London,
London, UK

*Correspondence to: ESMO Guidelines Committee, ESMO Head Office, Via Ginevra
4, CH-6900 Lugano, Switzerland. E-mail: clinicalguidelines@esmo.org

†
Approved by the ESMO Guidelines Committee: April 2002, last update July 2023.
This publication supersedes the previously published version—Ann Oncol.
2013;24(suppl 6):vi24-vi32.
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Running header: ESMO Clinical Practice Guideline for epithelial ovarian cancer

Word count: 10 279 (excluding title page, acknowledgements, funding and

disclosure sections); References: 105; Tables: 3; Figures: 3; Supplementary
material: 1.

Key words:

epithelial ovarian cancer, guideline, diagnosis, surgery, treatment, follow-up

Highlights:

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• This ESMO Clinical Practice Guideline provides key recommendations for
managing epithelial ovarian cancer.

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• The guideline covers clinical and pathological diagnosis, staging and risk
assessment, treatment and follow-up.
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• Treatment and management algorithms for early and advanced disease, as well
as recurrent disease, are provided.
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• ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for
treatment choices including targeted therapies.
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• The multidisciplinary expert author group stems from different institutions and
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countries in Europe, Asia and the USA.

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INCIDENCE AND EPIDEMIOLOGY

Epithelial ovarian cancer (EOC) represents a heterogeneous spectrum of disease

entities at a clinical, pathological and molecular level. Ovarian cancer is the second
most lethal gynaecological malignancy worldwide behind cervical cancer and the first
in developed countries, with ~200 000 women dying globally in 2020.1 A study of
epidemiological trends from 1990 to 2019 showed that highly developed regions had
the highest burden and mortality.2

Infertility or nulliparity, estrogen hormone treatment and obesity have been reported
as risk factors for EOC and could account for the rising incidence of the disease in

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developed countries.3 Oral contraceptive use, especially over longer periods, and
breastfeeding can reduce incidence.4 A recent large study revealed significant

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heterogeneity of associations for 14 EOC risk factors across histological subtypes.3
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Higher parity, younger age at menopause and tubal ligation were most strongly
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associated with reduced risk in endometrioid carcinomas (ECs) and clear-cell
carcinomas (CCCs), while endometriosis was associated with an increased risk in
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both EOC subtypes.3 Serous and poorly differentiated carcinomas had modest
associations with parity and menopausal hormonal therapy use and stronger
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associations with a family history of ovarian cancer.3 Deleterious germline BRCA1/2

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mutations (gBRCA1/2-mut) are associated with a 16%-65% increased risk of EOC,

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predominantly of high-grade serous histology.5 Women with mutations in mismatch

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repair genes (Lynch syndrome) have a 10%-12% lifetime risk of developing EOC,
which tends to be of either EC or CCC subtype.6

DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

Diagnostic work-up

There is currently no reliable screening method for ovarian cancer. Most women are
diagnosed based on symptoms, with the majority presenting at an advanced stage.
Recognised symptoms include abdominal/pelvic pain, constipation, diarrhoea,
urinary frequency, vaginal bleeding, abdominal distension and fatigue. In advanced
disease, ascites and abdominal masses lead to bloating, nausea, anorexia,
dyspepsia and early satiety. Extension of disease into the pleural cavities can
produce effusions and respiratory symptoms.

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The standard work-up for patients suspected of having EOC should include detailed
history and clinical examination with relevant laboratory and imaging tests (Table 1).
Measurement of serum cancer antigen 125 (CA-125) aids diagnosis and is elevated
in ~85% of patients with advanced disease. CA-125 is less useful in early-stage
disease as it is only elevated in ~50% of International Federation of Gynecology and
Obstetrics (FIGO) stage I cases. Elevated CA-125 is not specific to ovarian cancer
and may be elevated in non-gynaecological malignancies and benign conditions
(e.g. endometriosis and ovarian cysts).7

Measuring serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9

levels in addition to CA-125 alone may help distinguish primary mucinous ovarian

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tumours from a gastrointestinal metastasis. In this scenario, endoscopies should be

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considered, especially if the CA-125/CEA ratio is ≤25/1.8
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Initial imaging should comprise pelvic ultrasound (US; transabdominal and/or
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transvaginal) and computed tomography (CT) of the abdomen, pelvis and thorax to
complete clinical staging and aid surgical planning. US-based diagnostic models
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[International Ovarian Tumor Analysis (IOTA) Simple Rules risk model or IOTA
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Assessment of Different NEoplasias in the adneXa model] are preferable to CA-125,

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the human epididymis protein 4 or the Risk Ovarian Malignancy Algorithm, as they
are superior in distinguishing between benign and malignant ovarian tumours and
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performed better than the Risk of Malignancy Index in a randomised controlled trial
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(RCT).8

A definitive diagnosis of ovarian cancer requires pathological examination by an

expert pathologist of tumour samples from either a diagnostic biopsy or, preferably, a
surgical specimen. An adequate amount of tissue, particularly if neoadjuvant
chemotherapy (ChT) is planned, allows genetic tumour testing for therapeutic
stratification. If a complete pathological response is achieved, sufficient viable
tumour tissue may be unavailable for genetic testing following interval cytoreductive
surgery (ICS). Cytological assessment of ascites (in early-stage disease) and of
pleural fluid (if present and safely assessable) is required to complete staging.

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Pathology and molecular biology

EOC represents the majority (~90%) of ovarian malignancies. The 2020 World
Health Organization (WHO) classification based on histopathology,
immunohistochemistry (IHC) and molecular analysis recognises at least five distinct
subtypes of malignant EOC: high-grade serous carcinoma (HGSC; 70% of cases),
EC (10%), CCC (6%-10%), low-grade serous carcinoma (LGSC; 5%) and mucinous
carcinoma (MC; 3%-4%), along with other rare entities including mesonephric-like
carcinoma, mixed-cell tumour, malignant Brenner tumour, carcinosarcoma and
undifferentiated carcinoma.9 Each subtype represents a distinct disease entity with a
different site of origin, pathogenesis, clinical features and prognosis. The complexity

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of subclassification and its effect on personalised treatment choice underline the

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importance of histological tumour typing by an expert gynaecological pathologist.
Details of the molecular features of HGSC, EC, CCC, LGSC and MC are provided in
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the Supplementary Material Section 1. IHC staining patterns and molecular
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features of the different subtypes are summarised in Table 2. Certain genomic or
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molecular alterations, such as BRCA1/2-mut or homologous recombination

deficiency (HRD), are helpful in predicting the magnitude of benefit of targeted
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therapy with poly (ADP-ribose) polymerase inhibitors (PARPis) in high-grade

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tumours.10
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Recommendations
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• If EOC is suspected, diagnostic work-up should include serum CA-125

measurement, pelvic US by an expert examiner and CT scan of the abdomen,
pelvis and thorax [III, A].
• Pathological diagnosis should be made according to the 2020 WHO
classification by an expert gynaecological pathologist [IV, A].
• All patients with high-grade ovarian cancer should be tested for germline
and/or somatic BRCA1/2-mut at diagnosis [I, A].
• Testing for HRD is recommended in advanced high-grade cancers [I, A].

STAGING AND RISK ASSESSMENT

All patients with ovarian cancer should be surgically staged according to the revised
2014 FIGO staging system for EOC (Table 3).11 The histotype and primary site (i.e.

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ovary, fallopian tube or peritoneum) of the tumour should be established and
recorded as part of routine staging for treatment planning.

There is a strong prognostic link between the degree of post-operative residual

disease and patient survival.12 Preoperative imaging can help predict the likelihood
of suboptimal cytoreductive surgery.13 Extension of tumour from the omentum to
spleen or liver surface (stage IIIC) should be differentiated from isolated liver or
spleen parenchymal metastases (stage IVB). CT and positron emission tomography
(PET)–CT imaging have been shown to underestimate bowel or mesenteric
involvement compared with surgical exploration.14 Diffusion-weighted magnetic
resonance imaging may have better sensitivity than CT for detecting involvement of

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surgically critical tumour sites including mesenteric root infiltration, small bowel and

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colon carcinomatosis.15
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When the disease appears suitable for cytoreduction as assessed by imaging, and
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there are no surgical or medical contraindications, surgical staging (through midline
laparotomy or initial laparoscopy) should be carried out to explore the extent of
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disease in the abdomino-peritoneal cavity and assess the likelihood of

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achieving optimal cytoreduction (no gross visible residual disease or complete

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resection).
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Recommendations
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• The revised 2014 FIGO staging system for EOC should be used [I, A].

MANAGEMENT OF EARLY EOC (FIGO STAGE I-II)

Figure 1 provides a treatment algorithm for the management of FIGO stage I-II
EOC. Supplementary Table S1 provides a summary of benefit of adjuvant systemic
therapy for FIGO stage I-II EOC.

Surgery

The aim of surgery for early EOC is complete resection of the tumour and to
undertake adequate staging, including:

• Midline laparotomy

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 • Inspection and palpation of the whole abdominal cavity
• Peritoneal washing with cytological examination
• Biopsies from all visible lesions and all abdominal fields
• Bilateral salpingo-oophorectomy
• Hysterectomy
• Omentectomy
• Appendicectomy in MC
• Systematic pelvic and para-aortic lymphadenectomy

Whether a laparoscopic approach is a safe alternative to midline laparotomy is being

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debated, but as prospective trials are lacking and the risk of capsule rupture
increases,16 midline laparotomy remains the standard procedure. Surgical staging

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will provide prognostic information and define whether ChT is needed.
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The availability of an intra-operative frozen section to identify a malignant epithelial
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cancer may allow the appropriate surgical staging to be done without the need for a
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second operative procedure. Depending on the histological grade and subtype,

≤60% of patients with apparent early EOC will be upstaged after comprehensive
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surgical staging, which can impact progression-free survival (PFS) and overall
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survival (OS).17,18
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Systematic pelvic and para-aortic lymphadenectomy for staging purposes is

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recommended for high-grade histologies. The rate of lymph node metastases in

patients with low-grade EC or expansile MC is <1%.19 Therefore, lymphadenectomy
could be omitted in patients with these subtypes and with radiologically and clinically
negative nodes. Further information on the role of lymphadenectomy in stage I EOC
is provided in the Supplementary Material Section 2.

Fertility-sparing surgery can be considered in young patients, but always after full
discussion with the patient about potential risks. Patients with any stage IA histotype
or stage IC1-2 with unilateral ovarian involvement and favourable histology (i.e. low-
grade tumours) would be amenable to contralateral ovary and uterus preservation, in
combination with the other recommended surgical staging procedures.20

Systemic therapy

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Adjuvant platinum-based ChT significantly prolongs OS and PFS in patients with
early-stage EOC, as demonstrated in the joint analysis of ACTION and ICON1 trials
and a Cochrane systematic review.21-23 An updated analysis showed the benefit of
adjuvant ChT largely depended on histological subtype (see Figure 1 and
Supplementary Table S1).22 A large Surveillance, Epidemiology and End Results
series of stage I EC demonstrated no improvement in grade 1-2 EC.24 In CCC,
retrospective studies of an Asian population did not identify any benefit with adjuvant
ChT for early-stage disease (stage IA-IC1).25 In stage I MC, adjuvant ChT may be
avoided for either expansile subtype or grade 1 infiltrative based on the excellent
prognosis.26

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The standard adjuvant ChT consists of six cycles of platinum-based ChT. A

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Gynecologic Oncology Group (GOG) trial comparing three versus six cycles of
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adjuvant paclitaxel–carboplatin did not identify a significant reduction in recurrence
risk with longer treatment, but additional toxicity occurred.27 Only serous carcinoma
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seems to benefit from longer adjuvant therapy compared with non-serous tumours.28
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The optimal ChT regimen (platinum alone or platinum-based combination) is not

completely resolved.22
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Recommendations

•
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Surgical staging is recommended in presumed early-stage ovarian cancer for

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classification and recommendation of optimal systemic therapy [III, A].

• Adjuvant ChT in early-stage ovarian cancer is generally recommended for

FIGO stage I-IIB (see exceptions below) [II, A], either paclitaxel–carboplatin [I,
B] or carboplatin (six cycles) alone [I, A].

• For patients receiving paclitaxel–carboplatin, a minimum of three cycles are

recommended except for HGSC/high-grade EC or any stage IC-II histotype,
for which six cycles are suggested [II, B].

• The benefit of adjuvant ChT is uncertain and can be considered as optional

[III, C] for:

o LGSC stage IB-IC

o CCC stage IA-IC1

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 o Low-grade EC stage IB-IC

o Expansile MC stage IC

o Infiltrative MC stage IA

• Adjuvant ChT is not recommended in completely staged patients with LGSC

stage IA, low-grade EC stage IA or expansile MC stage IA-IB [II, E].

MANAGEMENT OF ADVANCED EOC (FIGO STAGE III-IV)

Surgery

In advanced EOC, surgery aims to achieve a complete or optimal cytoreduction,

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defined as total macroscopic tumour clearance with no residual visible disease, since
this has been shown to significantly increase OS and PFS.12 This needs maximal

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surgical effort and may require intestinal resection, diaphragmatic and peritoneal
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stripping, splenectomy and removal of bulky para-aortic lymph nodes and, in some
cases, extra-abdominal disease.29 An increasing body of evidence suggests that
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surgical expertise and specialist training result in improvements in the rate of
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complete cytoreduction. Thus, patients with advanced disease are advised to

undergo surgery in specialised centres with adequate infrastructure and trained
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teams.30 Patients with macroscopic complete resection and clinically negative nodes
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do not benefit from systematic lymphadenectomy, which unnecessarily increases the

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rate of post-operative complications and mortality.31

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The timing of surgical cytoreduction in relation to ChT is still debated. The gold
standard in patients with stage III-IV disease is primary cytoreductive surgery (PCS),
if physically able to undergo surgery and complete resection seems achievable,
followed by systemic treatment (Figure 2). PCS is also recommended in patients
with less chemosensitive subtypes (e.g. MC or LGSC), even if uncertainty about
achieving complete resection exists and a small residual tumour (<1 cm) is likely to
remain.32

Prospective trials have shown that three cycles of platinum-based neoadjuvant ChT
(NACT) followed by ICS and completion of ChT was not inferior to PCS followed by
ChT in patients with advanced bulky stage IIIC or IV disease, for whom complete
resection at primary surgery is unlikely or extensive surgery is not tolerable due to
frailty or other significant comorbidities.33,34 In all neoadjuvant trials, however, the
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PFS and OS were lower than in primary surgery trials. Due to the limitations of
randomised NACT trials, it is not yet determined whether NACT and ICS could be an
option for patients for whom complete resection at primary surgery seems feasible.
This is being addressed in the TRUST/ENGOT-OV33/Arbeitsgemeinschaft
Gynäkologische Onkologie (AGO)-OVAR OP.7 trial (NCT02828618).

Systemic therapy

Systemic ChT after surgery is recommended for all advanced ovarian cancer, and
consideration should be given to the inclusion of antiangiogenic and maintenance
therapies (Figure 2).

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ChT. Standard ChT consists of six cycles of paclitaxel (175 mg/m2)–carboplatin [area

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under the curve (AUC) 5-6] intravenously (i.v.) every 3 weeks.35 Prolonging ChT for
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more than six cycles or adding a third drug does not result in a better outcome.36 For
patients with contraindications to paclitaxel (i.e. allergy, neuropathy or intolerance),
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combining carboplatin with docetaxel or pegylated liposomal doxorubicin (PLD) can
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be considered as an alternative.37,38

The improved PFS and OS seen in the Japanese dose-dense ChT trial39 using
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weekly paclitaxel was not confirmed in a further three randomised trials (GOG-262,40
ICON841 and MITO-742). Outcomes were similar and ICON8 did not show differences
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in quality of life (QoL).43 An improved QoL, however, was seen in MITO-7 using
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weekly carboplatin (AUC 2) and a lower weekly paclitaxel dose (60 mg/m2), making
this regimen a potential alternative for more frail patients.

A meta-analysis of five randomised trials44 using post-operative intraperitoneal (i.p.)

ChT reported a benefit in PFS and OS compared with i.v. ChT regimens in patients
with a small volume (<1 cm) or no residual disease after surgery. Nevertheless, the
negative results of the GOG-252 trial (a large randomised phase III trial comparing
two i.p. platinum regimens, i.p. carboplatin AUC 6 or i.p. cisplatin 75 mg/m2, with i.v.
administration combined with bevacizumab),45 together with the greater toxicity and
complexity of i.p. administration, has led to the decline of this strategy as a standard
of care.

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Hyperthermic i.p. perioperative ChT (HIPEC) in first line has been explored in
OVHIPEC, a randomised phase III trial comparing NACT followed by ICS with or
without HIPEC.46 The trial showed significantly longer PFS and OS without increased
toxicity with HIPEC. Nevertheless, an imbalance of prognostic factors such as
tumour histotype, the lack of stratification based on well-recognised prognostic
factors such as tumour BRCA1/2-mut and HRD status and the limited sample size
made it very difficult to extrapolate these results. In another randomised trial, HIPEC
did not show survival superiority over standard treatment.47 Given these concerns,
HIPEC continues to be an area of research and should not be considered as
standard therapy.

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Antiangiogenic therapy in the first line. Bevacizumab is a monoclonal antibody

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targeting vascular endothelial growth factor (VEGF). Two large RCTs, GOG-21848
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and ICON749, showed that the addition of bevacizumab to paclitaxel–carboplatin
first-line therapy followed by bevacizumab as maintenance resulted in a statistically
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significant increase in PFS versus ChT alone, but without an OS benefit. A post-hoc
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subgroup analysis suggested a greater benefit in PFS and OS in the clinical ‘high-
risk’ population (defined as patients with stage III and macroscopic residual tumour
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>1 cm or stage IV).50 In ICON7 the dose of bevacizumab was 7.5 mg/kg and the
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duration of treatment was shorter (12 months). Although this lower dose is used by
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some, the licensed dose of bevacizumab is 15 mg/kg given for 15 months in

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combination with first-line paclitaxel–carboplatin ChT to patients with stage IIIB-IV

(FIGO 1988 classification) ovarian cancer, regardless of histology. In ENGOT Ov-15
study, a longer duration of bevacizumab administration (30 versus 15 months) did
not improve PFS.51

Bevacizumab in combination with NACT has been explored in two small randomised
trials, ANTHALYA and GEICO 1205/NOVA.52,53 Although no increase in grade 3-4
toxicities compared with ChT alone was reported, the potential benefit of two to three
doses of bevacizumab before ICS is debatable due to its lack of impact on complete
resection rate and PFS.

HRD and PARPis. Up to 50% of HGSCs are detected as HRD-positive with current
tests. Included in these are 15%-20% of gBRCA1/2-mut cases. Somatic BRCA1/2-
mut, epigenetic silencing via hypermethylation of BRCA1 promoter and deficiency in
11
other proteins and pathways involved in the homologous recombination repair of
DNA double-strand breaks contribute to the remainder of positive tests.54 HRD
positivity with or without BRCA1/2-mut is a well-established predictive factor of the
magnitude of response to PARPis. The incorporation of PARPis as maintenance
after first-line ChT has led to a new era in the first-line management of advanced
HGSC/high-grade EC with unprecedented benefit in patients with BRCA1/2-mutated
or BRCA1/2-wild type (wt)/HRD-positive tumours. Supplementary Material Section
3 provides detailed information on the SOLO155, PAOLA-1/ENGOT-OV2556 and
PRIMA/ENGOT-OV26/GOG-301257 trials, which led to the approval of olaparib in
BRCA1/2-mutated tumours, olaparib–bevacizumab in HRD-positive tumours and

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niraparib regardless of biomarker status of the tumour, respectively. The results of
the ATHENA-MONO58 and VELIA59 trials with rucaparib and veliparib, respectively,

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are also described.
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A descriptive OS analysis of SOLO1 at 7-year follow-up60 and the final OS analysis
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of PAOLA-161 have shown a benefit in OS for olaparib in patients with BRCA1/2-
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mutated tumours and olaparib–bevacizumab in patients with HRD-positive tumours

regardless of BRCA1/2-mut status (see Supplementary Material Section 3).
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Non-high grade serous advanced ovarian cancer. Paclitaxel–carboplatin is the

standard systemic ChT used in LGSC, CCC and MC. Multiple retrospective studies,
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however, showed lower response rates in these histotypes compared with HGSC.62-
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Bevacizumab has shown activity in all histotypes including those less
chemoresponsive, e.g. LGSC or CCC.49 The majority of LGSCs have high
expression of estrogen receptor (ER) and progesterone receptor (PgR);
retrospective studies suggest a possible therapeutic value of hormone therapy in the
maintenance of newly-diagnosed advanced LGSC.65 This intervention is currently
under evaluation in a prospective RCT (NCT04095364).

Recommendations

• Patients with advanced EOC should be evaluated for PCS by a specialised

team with the aim of achieving complete cytoreduction (absence of all visible
residual disease) [III, A].

• When complete cytoreductive surgery is feasible, PCS is recommended [III,

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 A]; otherwise, obtaining adequate biopsy tissue for histology and molecular
testing is recommended [III, A].

• When complete cytoreductive surgery is not feasible, NACT for three cycles
followed by ICS and three cycles of paclitaxel–carboplatin are recommended
[I, A].

• Bevacizumab in the neoadjuvant setting, before ICS, can be considered [II, B;

ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: 4].

• When ICS is not possible, and in the absence of overt disease progression,
three additional cycles of paclitaxel–carboplatin alone [I, A] or with

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bevacizumab [II, B; ESMO-MCBS v1.1 score: 4] are recommended.

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• Systemic therapy decisions should be informed by BRCA1/2 (germline and/or
somatic) and HRD status testing carried out at primary diagnosis [I, A].
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• Paclitaxel (175 mg/m2)–carboplatin (AUC 5-6) every 3 weeks for six cycles is
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the standard first-line ChT in advanced ovarian cancer [I, A].
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• The schedule of weekly ChT with paclitaxel (60 mg/m2)–carboplatin (AUC 2)

can be considered as an alternative in frail patients [I, B].
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•
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Bevacizumab improves PFS in patients with stage III-IV ovarian cancer and
should be considered in addition to paclitaxel–carboplatin [I, A; ESMO-MCBS
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v1.1 score: 4].

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• Given the controversy about i.p. ChT [I, E] and HIPEC [II, D], they are not
considered a standard of care in first-line treatment.

• Maintenance treatment with PARPis, with or without bevacizumab, is

recommended for patients with BRCA1/2-mutated or BRCA1/2-wt/HRD-
positive tumours with no evidence of disease at the end of ChT or a complete
or partial response to platinum–paclitaxel first-line ChT [I, A].

o For BRCA1/2-mutated: olaparib for 2 years [ESMO-MCBS v1.1 score:

4; ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
score: I-A], niraparib for 3 years [ESMO-MCBS v1.1 score: 3; ESCAT
score: I-A] or olaparib–bevacizumab for 2 years [ESMO-MCBS v1.1
score: 3; ESCAT score: I-A].

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 o For BRCA1/2-wt/HRD-positive: niraparib for 3 years [ESMO-MCBS
v1.1 score: 3; ESCAT score: I-A] or olaparib–bevacizumab for 2 years
[ESMO-MCBS v1.1 score: 3; ESCAT score: I-A).

• Maintenance treatment with either bevacizumab [I, A; ESMO-MCBS v1.1

score: 3] or niraparib for 3 years [II, B; ESMO-MCBS v1.1 score: 3] can be
recommended for HRD-negative tumours, with the latter following complete or
partial response to platinum–paclitaxel first-line ChT. The choice of treatment
should be based on disease and clinical characteristics of the patient.

• Maintenance with anti-estrogen therapy after first-line platinum-based ChT

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can be considered in LGSC [IV, B].

MANAGEMENT OF RECURRENT EOC

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Patient assessment
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Up to 70% of patients with stage III-IV high-grade ovarian cancer will relapse within 3
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years. Relapse rates for early-stage ovarian cancer are much lower.
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Several factors need to be assessed when selecting a treatment for patients with
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recurrent disease (Figure 3).

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Systemic therapy of recurrent disease is based on platinum or non-platinum-

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containing regimens. There are currently no molecular biomarkers to predict efficacy

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of platinum rechallenge. The definition of platinum-sensitivity based on a 6-month

cut-off of treatment-free interval from last platinum (TFIp) was challenged during the
Fifth Gynecological Cancer InterGroup Ovarian Cancer Consensus Conference and
later discontinued in clinical practice following the 2018 ESMO-European Society of
Gynaecological Oncology Consensus Conference, as many factors may influence
TFIp (e.g. the frequency of follow-up and interval of diagnostic tests) and the
response to platinum (i.e. histotype or BRCA1/2 status).32,66 Not all patients with
TFIp >6 months respond to platinum (objective response rate 47.2%-66%),32 and
conversely, platinum based-combinations have demonstrated activity in patients with
TFIp <6 months.67

Surgery for relapse

14
The role of surgery for patients with a first relapse >6 months after the end of
platinum in the first line was addressed by one non-randomised trial and three
prospective randomised trials.68-71

The DESKTOP series defined the AGO score to identify patients for whom complete
resection is feasible. In patients with a positive AGO score—defined as having
complete resection at primary surgery (alternatively FIGO stage I-II), good
performance status (Eastern Cooperative Oncology Group 0) and absence of ascites
(<500 ml)—the likelihood of achieving a complete resection is 76%.68 Subsequently,
DESKTOP III demonstrated a benefit in OS and PFS for patients with positive AGO
scores randomised into secondary cytoreductive surgery followed by platinum-based

of
ChT versus ChT alone.69

ro
The SOC-1 trial had a similar design, but patients were selected according to the
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iModel. This trial was also positive for PFS, but OS data are still immature.70
re
The GOG-0213 trial did not show a superiority with respect to surgery.71 Although
lP

many explanations have been proposed, the most convincing is the absence of
objective selection criteria for surgery.
a
rn

Systemic therapy when platinum is an option

u

Patients should be considered for platinum therapy at relapse if platinum is not

Jo

contraindicated and there is a reasonable likelihood that the patient may benefit from
platinum rechallenge (no progression during platinum-based therapy or shortly
thereafter) (Figure 3).

ChT options. A meta-analysis of randomised trials comparing carboplatin-based

doublet with carboplatin monotherapy demonstrated a benefit in PFS and OS.72
Current partners for carboplatin combination include paclitaxel, gemcitabine or
PLD,73-75 and the selection should be based on safety profile and patient preference.
Based on safety profile, the combination of carboplatin–PLD could be considered a
preferred option.75 If combination therapy is contraindicated, carboplatin
monotherapy remains an option. Treatment is usually recommended for four to six
cycles.

15
Platinum hypersensitivity reactions (HSRs) affect ~5% of the general cancer
population. Several outpatient-based platinum ‘desensitisation’ protocols exist for
gynaecological oncology patients with HSRs that permit the successful
re-introduction of platinum-based therapy (carboplatin or cisplatin) after patients
have experienced HSRs.76

In the absence of contraindications to platinum, there is no role for a non-platinum-

based combination at first relapse, as was demonstrated by the lack of improvement
in OS in the randomised phase III INOVATYON trial, which compared trabectedin–
PLD with carboplatin–PLD in a subgroup of patients with a TFIp of 6-12 months.77

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Antiangiogenic therapy. Bevacizumab is approved in combination with platinum-

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based combination therapy and then as maintenance therapy in patients with a TFIp
>6 months. Bevacizumab with platinum combinations (either paclitaxel or
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gemcitabine followed by bevacizumab maintenance) leads to a significant benefit in
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objective response rate and PFS.71,78 OS was similar in both arms, partially
explained by the high rate of crossover to bevacizumab in subsequent lines of
lP

therapy.78 PLD–carboplatin–bevacizumab has demonstrated a statistically significant

a

PFS and OS advantage compared with carboplatin–gemcitabine–bevacizumab,

rn

making the former combination the preferred option if a carboplatin-based doublet

with bevacizumab is selected.79
u
Jo

A rechallenge of bevacizumab combined with a carboplatin-based doublet is

associated with a significant improvement in median PFS compared with ChT alone
in patients previously treated with bevacizumab and having relapsed with TFIp >6
months.80 Bevacizumab rechallenge has not been licensed in Europe, however, and
is, therefore, not widely available.

In phase III trials, bevacizumab was administered until progression or unacceptable

toxicity occurred. Treatment should be maintained until clinical or radiological
progression and should not be discontinued based solely on rising CA-125.

Further information is provided in the Supplementary Material Section 4.

PARPis. Three PARPis (olaparib, niraparib and rucaparib) are approved for
maintenance therapy of patients with high-grade tubo-ovarian carcinoma that

16
achieve a response to platinum rechallenge, irrespective of BRCA1/2-mut or HRD
status. Details of the outcome from four randomised trials (Study 19, SOLO2, NOVA
and ARIEL3) are given in Supplementary Material Section 4.

The recommended length of PARPi treatment remains unclear. In NOVA and

ARIEL3 treatment was stopped at progression, but in Study-19 and SOLO2 patients
were allowed to continue olaparib beyond progression, if it was considered
beneficial. From a clinical perspective, treatment beyond disease progression may
have particular value in slow-growing tumours or in the context of oligometastatic
disease (e.g. single site of progression). All trials have shown that there is a small
group of ‘super-responder’ patients (~10%) without progression after 5 years on

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treatment with PARPis.

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Recently, data on OS after maintenance therapy raised concern about a possible
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detrimental effect of PARPis, particularly for non-gBRCA1/2-mut carriers. The OS
re
analyses, however, were secondary and underpowered endpoints. Long-term OS
data from the NOVA trial and interim survival analysis of the NORA study have not
lP

categorically confirmed the initial concern.81,82 Intermediate endpoints such as PFS2

a

(time to second subsequent therapy) or death suggest a continuing benefit from

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PARPis beyond progression. Nevertheless, an exploratory analysis in SOLO2

suggested that gBRCA1/2-mut carriers who received olaparib had a poorer response
u

to platinum-based therapy on subsequent relapse,83 raising the hypothesis that

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PARPis may encourage platinum resistance. The licence for use of PARPis has not
been changed by the European Medicines Agency (EMA), but has been withdrawn
by the Food and Drug Administration (FDA) for niraparib and rucaparib (but not
olaparib) in non-gBRCA1/2-mut carriers. It is advisable, therefore, to have a
discussion with patients without a BRCA1/2-mut about the benefits and risks of
PARPis.

There is currently no approval for pre-treatment with a PARPi. One trial,

OREO/ENGOT-OV38, showed a positive short-lived benefit for some patients
retreated with olaparib.84

Toxicity of PARPis is generally manageable through dose individualisation (for

niraparib), dose reductions and dose interruptions. The rate of acute myeloid

17
leukaemia and myelodysplastic syndromes is higher among gBRCA1/2-mutated
patients and in the recurrent setting compared with first-line. This can probably be
explained by an accumulative exposure to platinum.85

Several factors need to be taken into consideration for the selection of PARPis or
anti-VEGF therapies in relapse including histotype, BRCA1/2 status, prior therapies
(PARPi and/or bevacizumab), expected response to platinum ChT, presence of
symptoms (specifically ascites), persistent toxicities from prior therapies, no
contraindication to bevacizumab and patient preference. Generally, for symptomatic
patients requiring a rapid treatment response, the carboplatin-doublet combination
with bevacizumab would be recommended (Figure 3).

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Further information is provided in the Supplementary Material Section 4.

Systemic therapy when platinum is not an option-p

re
For some patients with recurrent ovarian cancer, platinum rechallenge may not be
considered clinically appropriate. For these patients, alternative systemic treatments
lP

are available. Patients with good performance status should be prioritised for novel
therapies within clinical trials. Integrating early palliative care is particularly crucial.
a
rn

Non-platinum ChT options. Single-agent non-platinum ChT regimens include

u

weekly paclitaxel, topotecan, gemcitabine, PLD and oral metronomic

Jo

cyclophosphamide. These have shown modest activity in patients with relapsed

ovarian cancer for whom platinum is not an option, with 10%-15% objective
response rate and median OS of 10-12 months.86-90 With regards to selecting a
particular regimen, there are no robust randomised data to support one agent over
another, and not all are licensed for this indication. The choice should be guided by
patient preference and toxicity profile. The optimal duration of treatment is unclear; in
clinical trials, ChT with non-platinum agents was planned until tumour progression or
unacceptable toxicity.

Trabectedin–PLD is approved in Europe for patients relapsing >6 months after last
platinum.91 This combination is an option when such patients are ineligible for further
platinum.

18
Data with antibody-drug conjugates have shown encouraging results (see
Supplementary Material Section 4).

Antiangiogenic therapy. The addition of bevacizumab to second- or third-line non-

platinum ChT (paclitaxel, PLD or topotecan) in the AURELIA trial, demonstrated an
improvement in median PFS, tumour response rate and QoL scores compared with
ChT alone.92 Notably, this trial excluded all patients at increased risk of intestinal
fistulae (progression during first-line platinum, history of bowel obstruction or serosal
invasion), and <10% of patients had been previously exposed to bevacizumab.

Systemic therapy for non-high-grade subtypes

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Less common histological subtypes such as CCC, carcinosarcoma or LGSC are

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known to be less responsive to ChT including platinum.93 For these patients, once
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platinum is no longer an option, participation in clinical trials is strongly
recommended.94 For LGSC, one randomised phase III trial demonstrated
re
significantly improved PFS and response rate for the mitogen-activated protein
lP

kinase kinase (MEK) inhibitor trametinib compared with standard of care (single-
agent ChT or hormonal therapy at the choice of the investigator).95 Another phase III
a

trial with binimetinib, however, did not have a positive result.96 These slowly
rn

proliferating tumours frequently express ER and/or PgR, and although objective

u

tumour responses are low, hormonal therapies can be used to control tumour growth
Jo

(e.g. aromatase inhibitors, tamoxifen or luteinizing hormone-releasing hormone

agonists).

Recommendations

• The following should be assessed when selecting treatment for patients with
recurrent disease [I-III, A]:
o Histotype
o BRCA1/2 status
o Number of prior lines of treatment
o Exposure and response to prior treatment
o TFIp
o Possibility of achieving a complete secondary surgical cytoreduction
o Residual ChT toxicity

19
 o Patient‘s general condition and preferences

• Patients with first relapse of ovarian cancer after >6 months of last platinum
administration should be evaluated by a gynaecological oncology centre
experienced in surgery for ovarian cancer to identify potential candidates for
surgical cytoreduction [I, A].

• Patients who have previously responded to platinum without early

symptomatic relapse should be treated with either a platinum doublet (PLD,
gemcitabine or paclitaxel) with bevacizumab [I, A; ESMO-MCBS v1.1 score:
3] or a platinum doublet followed by maintenance with PARPi therapy if a

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response is achieved and the patient has not been previously exposed to
PARPis [I, A; Olaparib for BRCA1/2-mut: ESMO-MCBS v1.1 score: 2;

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niraparib regardless of BRCA1/2 status: ESMO-MCBS v1.1 score: 3;
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rucaparib regardless of BRCA1/2 status: ESMO-MCBS v1.1 score:3].
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• For patients requiring rapid response, the combination of platinum doublet
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with bevacizumab should be preferred [V, A; ESMO-MCBS v1.1 score: 3].

• Bevacizumab should be continued until disease progression (symptomatic) or

a

the next line of treatment is started, as continuation of bevacizumab beyond

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progression has not been evaluated in the recurrent setting [I, A].
u

• PARPi should be continued until disease progression or the next line of

Jo

treatment is started [I, A], as the benefit of continuing treatment beyond

progression has not been demonstrated conclusively to date [III, B].

• Platinum rechallenge following treatment with a non-platinum regimen

(monotherapy or combination) could be considered if the tumour did not
progress during prior platinum therapy [III, B].

• Patients with relapsed EOC for whom platinum is not an option should be
defined by [II-IV, A]:

o Proven resistance (progression during platinum)

o Expected resistance (early symptomatic progression post-platinum,

response to rechallenge unlikely)

o Platinum intolerance

20
 o Patient choice

o QoL issues

• For patients not candidates to receive platinum, integrating palliative care

early in the treatment pathway is strongly recommended [I, A].

• Single-agent non-platinum options that can be recommended include weekly

paclitaxel, PLD, topotecan and gemcitabine (gemcitabine is not EMA
approved) [I, B].

• In patients with platinum intolerance who have relapsed >6 months from
previous platinum, trabectedin–PLD may be recommended [II, C; ESMO-

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MCBS v1.1 score: 2].

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• Bevacizumab should be recommended in combination with weekly paclitaxel,
-p
PLD or topotecan in patients without contraindications to bevacizumab and
not previously exposed to bevacizumab [I, A; ESMO-MCBS v1.1 score: 4].
re
• Hormonal therapy is recommended for relapsed LGSC [II, A].
lP

• For patients with recurrent LGSC, treatment with the MEK inhibitor trametinib
a

should be considered after prior platinum-based ChT and hormone therapy

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(not EMA approved) [I, A].

u

FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

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Surveillance

Although a cure is unlikely after relapse, effective therapies exist for the treatment of
patients with recurrent ovarian cancer. Therefore, surveillance in these patients is
indicated with a combination of thorough symptom review and physical examination.
Studies have noted that 26%-50% of recurrences are in the pelvis97 suggesting a
role for pelvic examination in the follow-up of ovarian cancer. Disease recurrence,
however, may be located outside of the pelvis, e.g. in lymph nodes, liver, lungs or
peritoneal carcinomatosis and may not be detectable by pelvic examination. CT
scans have been noted to have a sensitivity of 79% and specificity of 84% for
detecting relapse in a large pooled meta-analysis.98 CT scans are indicated if
symptoms suggest recurrent disease or the CA-125 is rising.98

21
CA-125 has been evaluated in the surveillance of ovarian cancer and has been
noted to be elevated 2-5 months before radiographic detection of cancer. In a large
prospective phase III Medical Research Council UK OV05 /EORTC 55955 trial, there
was no difference in OS when ChT was initiated based solely on rising CA-125
levels versus when disease recurrence had become clinically evident.99 The benefit
of surveillance with CA-125 in the current era—when more sensitive radiological
detection methods such as PET–CT and complete secondary cytoreduction and
targeted therapy have been shown to improve outcomes—has yet to be defined.

BRCA1/2-mut carriers and survival

Although surveillance is generally undertaken for 5 years after the most recent

of
remission, longer follow-up may be considered in BRCA1/2-mut carriers, given their

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improved long-term survival and need for breast cancer surveillance. Reports have
-p
noted improved survival among BRCA1/2-mut carriers. In a pooled analysis of 1213
EOC cases with pathogenic gBRCA1-mut (n = 909) or gBRCA2-mut (n = 304) and of
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2666 non-carriers, an improved 5-year OS was noted among BRCA1/2-mut carriers
lP

with ovarian cancer.100 A more recent report of 15-year survival data in BRCA1/2-
mut carriers suggests that the survival benefit appears to be within the first 5 years
a

and decreases over time.101

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Recommendations
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Jo

• Surveillance of ovarian cancer patients can include CA-125 determination,

physical examination and CT scan evaluation [IV, B].

• BRCA1/2-mut carriers can be considered for follow-up beyond 5 years [III, B].

• Long-term BRCA1/2-mut survivors should be referred to high-risk breast

cancer clinics for follow-up [I, A].102

METHODOLOGY

This Clinical Practice Guideline (CPG) was developed in accordance with the ESMO
standard operating procedures for CPG development
(https://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology). The relevant
literature has been selected by the expert authors. A table of ESCAT scores is
included in Supplementary Table S2. ESCAT scores have been defined by the
authors and assisted if needed by the ESMO Translational Research and Precision
22
Medicine Working Group.103 A table of ESMO-MCBS scores is included in
Supplementary Table S3. ESMO-MCBS v1.1104 was used to calculate scores for
new therapies/indications approved by the EMA or FDA
(https://www.esmo.org/Guidelines/ESMO-MCBS). The scores have been calculated
by the ESMO-MCBS Working Group and validated by the ESMO Guidelines
Committee. The FDA/EMA or other regulatory body approval status of new
therapies/indications is reported at the time of writing this CPG. Levels of evidence
and grades of recommendation have been applied using the system shown in
Supplementary Table S4.105 Statements without grading were considered justified
standard clinical practice by the authors. For future updates to this CPG, including

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eUpdates and Living Guidelines, please see the ESMO Guidelines website:

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https://www.esmo.org/guidelines/guidelines-by-topic/gynaecological-cancers/newly-
diagnosed-and-relapsed-epithelial-ovarian-carcinoma.

ACKNOWLEDGEMENTS
-p
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Manuscript editing support was provided by Ioanna Ntai, Catherine Evans, Claire
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Bramley and Jennifer Lamarre (ESMO Guidelines staff); this support was funded by
ESMO. Nathan Cherny, Chair of the ESMO-MCBS Working Group, and Urania
a

Dafni, Giota Zygoura, Georgia Dimopoulou and Tereza Dellaporta of Frontier

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Science Foundation Hellas provided review and validation of the ESMO-MCBS

u

scores. Nicola Latino (ESMO Scientific Affairs staff) provided coordination and
Jo

support of the ESMO-MCBS scoring and Angela Corstorphine of Kstorfin Medical

Communications Ltd provided medical writing and editing support in the preparation
of the ESMO-MCBS table; this support was funded by ESMO. Dr Svetlana Jezdic
(ESMO Medical Affairs staff) provided coordination and support of the ESCAT
scoring.

FUNDING

No external funding has been received for the preparation of this guideline.
Production costs have been covered by ESMO from central funds.

DISCLOSURE

AGM reports personal fees for advisory board membership from Alkermes, Amgen,
AstraZeneca, Clovis Oncology, Eisai, Genmab, GSK, HederaDx, Illumina,

23
ImmunoGen, MacroGenics, Mersana, MSD, Novartis, Oncoinvent, PharmaMar,
Regeneron, Roche, SOTIO, Sutro Biopharma and Tubulis; personal fees as an
invited speaker from AstraZeneca, Clovis Oncology, GSK, MSD, Novocure, Roche,
Takeda and Zai Lab; institutional funding as coordinating principal investigator (PI)
from Aravive, GSK, Novartis and Roche; and a non-remunerated role as Steering
Committee Member for MSD.

PH reports personal fees for advisory board membership from AstraZeneca, Clovis
Oncology, GSK, ImmunoGen, Mersana, Miltenyi, MSD, Novartis and Roche;
personal fees as an invited speaker from Amgen, Eisai, Stryker and Zai Lab;
personal fees for lectures from AstraZeneca, GSK, MSD and Roche; personal fees

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as an Independent Data Monitoring Committee (IDMC) member from SOTIO;

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institutional funding as Trial Chair from AstraZeneca, GSK, ImmunoGen and Roche;
-p
institutional funding as local PI from Genmab; institutional funding from Clovis
Oncology and Seagen; and a non-remunerated role as PI from AstraZeneca.
re
AL reports personal fees for advisory board membership from Zentalis
lP

Pharmaceuticals; personal fees as an invited speaker from GSK and Medscape;

a

personal fees for consultancy from GLG; personal fees for writing engagement from
rn

Onko+; fees paid to her institute for advisory board membership from Ability Pharma,
Apmonia, AstraZeneca, Blueprint, Clovis Oncology, GSK, Merck Serono and MSD;
u

fees paid to her institute as an invited speaker from AstraZeneca, Clovis Oncology
Jo

and Kephren Publishing; fees paid to her institute for consultancy from Orion and
Owkin; fees paid to her institute for steering committee membership from MSD;
institutional funding as a PI in clinical trials from Agenus, AstraZeneca, BMS, GSK,
Iovance; MSD and Roche; institutional funding as a Chief Investigator in clinical trials
from AstraZeneca and OSE Immunotherapeutics; institutional research grants as a
PI in translational research from ARCAGY-GINECO, AstraZeneca and Sanofi; a non-
remunerated role as an IDMC member for Clovis Oncology, as an IDMC Chair for
Pfizer (proprietary information) and as a member of the Gynecological Cancer
InterGroup (GCIG); and non-remunerated academic research projects for LXRepair
and Owkin.

DL reports personal fees for advisory board membership from AstraZeneca, Clovis
Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar,
24
Seagen and Sutro Biopharma; personal fees as an invited speaker from
AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar and
Seagen; personal fees for consultancy from AstraZeneca, Clovis Oncology,
Genmab, GSK, ImmunoGen, MSD, Novartis, PharmaMar and Seagen; grants for
travelling from AstraZeneca, Clovis Oncology and GSK; institutional funding as
coordinating PI from Clovis Oncology, Genmab and MSD; institutional funding for a
clinical trial/contracted research from AstraZeneca, Clovis Oncology, Genmab, GSK,
ImmunoGen, Incyte, MSD, Novartis, Roche and Seagen; institutional funding for
founding an academic trial from Clovis Oncology, GSK, MSD and PharmaMar; a
non-remunerated role as a PI in clinical trials for AstraZeneca, Clovis Oncology,

of
Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, PharmaMar, Roche and

ro
Seagen; and a non-remunerated role as a member of the Board of Directors of
GCIG.
-p
REM reports personal fees for advisory board membership from AstraZeneca, GSK
re
and Merck; personal fees as an invited speaker from AstraZeneca, Clovis Oncology
lP

and GSK; and personal fees for expert testimony from Ellipses and Shionogi.
a

BP reports personal fees for advisory board membership from AstraZeneca, Clovis
rn

Oncology, Eisai, GlaxoSmithKline, GOG Foundation, Lily, Merck, Mersana, Seattle

Genetics, Sutro and Tesaro; personal fees for consulting from the Arquer
u

Diagnostics, Atossa, Bioascend, Deciphera, Elevar, Imab, Onclive, Onconova

Jo

Therapeutics, PeerView, Toray and WebMD; institutional funding as local PI from

Acrivon, AstraZeneca, Celgene, Celsion, Clovis Oncology, Eisai, GlaxoSmithKline,
ImmunoGen, Incyte, Karyopharm, Merck, Mersana, Roche Genentech, Seattle
Genetics, Sutro, Takeda, Tesaro, Toray and VBL Therapeutics; membership of the
GOG Partners group at the GOG Foundation; and membership of the Board of
Directors of the Society of Gynecologic Oncology (SGO).

IRC reports personal fees for advisory board membership from Adaptimmune,
Agenus, Amgen, AstraZeneca, BMS, Clovis Oncology, Daiichi Sankyo, Deciphera,
EQRX, Eisai, GSK, MacroGenics, Merck Sereno, Mersana, Novartis, Oxnea, Roche
and Sutro Biopharma; fees paid to her institute for advisory board membership from
MSD; fees paid to her institute for translational research from BMS; a non-

25
remunerated role as President of GINECO; and a non-remunerated role as PI for
PAOLA-1.

DSPT reports personal fees for advisory board membership from AstraZeneca,
Bayer, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD and Roche; personal fees
as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche
and Takeda; ownership of stocks/shares of Asian Microbiome Library (AMiLi);
institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics
and Roche; institutional funding as coordinating PI from AstraZeneca and Bergen
Bio; institutional funding as local PI from Bayer, Byondis B.V. and Zeria
Pharmaceutical Co Ltd; a previous non-renumerated role as Chair of the Asia-Pacific

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Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as

ro
the Society President of the Gynecologic Cancer Group Singapore; non-
-p
renumerated membership of the Board of Directors of the GCIG; and product
samples from AstraZeneca, Cyclacel Pharmaceuticals, Eisai and MSD (non-financial
re
interest).
lP

EB declares no conflicts of interest.

a

AO reports personal fees for advisory board membership from Agenus,

rn

AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals,

u

Eisai, Exelisis, EMD Serono, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen,

Jo

Itheos, Merck Sharps & Dohme de España, SA, Mersana Therapeutics, Novocure,
OncXerna Therapeutics, Inc., PharmaMar, Regeneron, Sattucklabs, Seagen and
Sutro Biopharma; personal fees for travel/accommodation from AstraZeneca,
PharmaMar and Roche; institutional funding from Abbvie Deutschland, Advaxis Inc.,
Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis
Oncology Inc, EISAI limited LTD, F. Hoffmann-La Roche LTD, Immunogen Inc,
Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar
SA, Regeneron Pharmaceuticals and Tesaro Inc.; non-remunerated roles at ESMO
(member, Officer, Co-Chair of the ESMO Gynaecological Cancers Congress 2023-
2025, Chair of the Gynaecological Track ESMO 2019, Scientific Track Member
Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022, member of the
Gynaecological Cancers Faculty and Subject Editor for the Gynaecological Clinical

26
Practice Guidelines); a non-remunerated role at GCIG (member and Cervix Cancer
Chair on behalf of GEICO); and membership of ASCO, GOG and SEOM.

JAL reports personal fees for advisory board membership for Artios Pharma,
AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eisai, Ellipses, GSK,
Immagene, ImmunoGen, Merck/MSD, Miltenyi, Novocure, Nuvation and VBL
Therapeutics; personal fees as an invited speaker from AstraZeneca, Clovis
Oncology, GSK and Neopharm; personal fees as a member for an IDMC from
Mersana and Sutro Bio; a remunerated leadership role as an Associate Editor of
Therapeutic Advances in Medical Oncology (Sage Publishing); institutional research
grants from AstraZeneca and MSD/Merck; non-remunerated roles at ESMO (Officer

of
and Chair for the Gynaecological Clinical Practice Guidelines); and a non-

ro
remunerated leadership role as Vice-President of the European Society of
Gynaecological Oncology (2019-2021). -p
re
a lP
u rn
Jo

27
REFERENCES

1 Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020:

GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers
in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249.
2 Yi M, Li T, Niu M, et al. Epidemiological trends of women's cancers from 1990
to 2019 at the global, regional, and national levels: a population-based study.
Biomarker research. 2021;9(1):55-55.
3 Wentzensen N, Poole EM, Trabert B, et al. Ovarian Cancer Risk Factors by
Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium.
J Clin Oncol. 2016;34(24):2888-2898.

of
4 Karlsson T, Johansson T, Höglund J, et al. Time-Dependent Effects of Oral

ro
Contraceptive Use on Breast, Ovarian, and Endometrial Cancers. Cancer
Res. 2020;81(4):1153-1162. -p
5 Tan DSP, Rothermundt C, Thomas K, et al. “BRCAness” Syndrome in
re
Ovarian Cancer: A Case-Control Study Describing the Clinical Features and
lP

Outcome of Patients With Epithelial Ovarian Cancer Associated With BRCA1

and BRCA2 Mutations. J Clin Oncol. 2008;26(34):5530-5536.
a

6 Ketabi Z, Bartuma K, Bernstein I, et al. Ovarian cancer linked to lynch

rn

syndrome typically presents as early-onset, non-serous epithelial tumors.

Gynecol Oncol. 2011;121(3):462-465.
u
Jo

7 Charkhchi P, Cybulski C, Gronwald J, et al. CA125 and Ovarian Cancer: A

Comprehensive Review. Cancers. 2020;12(12):3730.
8 Timmerman D, Planchamp F, Bourne T, et al. ESGO/ISUOG/IOTA/ESGE
Consensus Statement on pre-operative diagnosis of ovarian tumors. Int J
Gynecol Cancer. 2021;31(7):961-982.
9 WHO Classification of Tumours Editorial Board. Female Genital Tumours:
WHO Classification of Tumours: IARC, Lyon, France, 2020.
10 Miller RE, Leary A, Scott CL, et al. ESMO recommendations on predictive
biomarker testing for homologous recombination deficiency and PARP
inhibitor benefit in ovarian cancer. Ann Oncol. 2020;31(12):1606-1622.
11 Mutch DG, Prat J. 2014 FIGO staging for ovarian, fallopian tube and
peritoneal cancer. Gynecol Oncol. 2014;133(3):401-404.

28
12 du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as
prognostic factor in advanced epithelial ovarian cancer: A combined
exploratory analysis of 3 prospectively randomized phase 3 multicenter trials.
Cancer. 2009;115(6):1234-1244.
13 Jeong SY, Kim TJ, Park BK. Epithelial ovarian cancer: a review of
preoperative imaging features indicating suboptimal surgery. J Gynecol
Oncol. 2020;31(4):e57-e57.
14 Dromain C, Leboulleux S, Auperin A, et al. Staging of peritoneal
carcinomatosis: enhanced CT vs. PET/CT. Abdom Imaging. 2007;33(1):87-
93.

of
15 Michielsen K, Dresen R, Vanslembrouck R, et al. Diagnostic value of whole

ro
body diffusion-weighted MRI compared to computed tomography for pre-
operative assessment of patients suspected for ovarian cancer. Eur J Cancer.
2017;83:88-98.
-p
re
16 Matsuo K, Huang Y, Matsuzaki S, et al. Minimally Invasive Surgery and Risk
of Capsule Rupture for Women With Early-Stage Ovarian Cancer. JAMA
lP

oncology. 2020;6(7):1110-1113.
17 Grabowski JP, Harter P, Buhrmann C, et al. Re-operation outcome in patients
a
rn

referred to a gynecologic oncology center with presumed ovarian cancer

FIGO I-IIIA after sub-standard initial surgery. Surg Oncol. 2012;21(1):31-35.
u

18 Trimbos B, Timmers P, Pecorelli S, et al. Surgical staging and treatment of

Jo

early ovarian cancer: long-term analysis from a randomized trial. J Natl

Cancer Inst. 2010;102(13):982-987.
19 Heitz F, Harter P, Ataseven B, et al. Stage- and Histologic Subtype-
Dependent Frequency of Lymph Node Metastases in Patients with Epithelial
Ovarian Cancer Undergoing Systematic Pelvic and Paraaortic
Lymphadenectomy. Ann Surg Oncol. 2018;25(7):2053-2059.
20 Fruscio R, Corso S, Ceppi L, et al. Conservative management of early-stage
epithelial ovarian cancer: results of a large retrospective series. Ann Oncol.
2013;24(1):138-144.
21 Trimbos JB, Parmar M, Vergote I, et al. International Collaborative Ovarian
Neoplasm Trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm Trial:
Two Parallel Randomized Phase III Trials of Adjuvant Chemotherapy in

29
 Patients With Early-Stage Ovarian Carcinoma. J Natl Cancer Inst.
2003;95(2):105-112.
22 Collinson F, Qian W, Fossati R, et al. Optimal treatment of early-stage ovarian
cancer. Ann Oncol. 2014;25(6):1165-1171.
23 Lawrie TA, Winter-Roach BA, Heus P, et al. Adjuvant (post-surgery)
chemotherapy for early stage epithelial ovarian cancer. The Cochrane
database of systematic reviews. 2015;2015(12):CD004706-CD004706.
24 Oseledchyk A, Leitao MM, Jr., Konner J, et al. Adjuvant chemotherapy in
patients with stage I endometrioid or clear cell ovarian cancer in the platinum
era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000-2013.

of
Ann Oncol. 2017;28(12):2985-2993.

ro
25 Mizuno M, Kajiyama H, Shibata K, et al. Adjuvant Chemotherapy for Stage I
Ovarian Clear Cell Carcinoma: Is it Necessary for Stage IA? Int J Gynecol
Cancer. 2012;22(7):1143-1149.
-p
re
26 Gouy S, Saidani M, Maulard A, et al. Staging surgery in early-stage ovarian
mucinous tumors according to expansile and infiltrative types. Gynecol Oncol
lP

Rep. 2017;22:21-25.
27 Bell J, Brady MF, Young RC, et al. Randomized phase III trial of three versus
a
rn

six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial

ovarian carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol.
u

2006;102(3):432-439.
Jo

28 Chan JK, Tian C, Fleming GF, et al. The potential benefit of 6 vs. 3 cycles of
chemotherapy in subsets of women with early-stage high-risk epithelial
ovarian cancer: An exploratory analysis of a Gynecologic Oncology Group
study. Gynecol Oncol. 2010;116(3):301-306.
29 Ataseven B, Chiva LM, Harter P, et al. FIGO stage IV epithelial ovarian,
fallopian tube and peritoneal cancer revisited. Gynecol Oncol.
2016;142(3):597-607.
30 Fotopoulou C, Concin N, Planchamp F, et al. Quality indicators for advanced
ovarian cancer surgery from the European Society of Gynaecological
Oncology (ESGO): 2020 update. Int J Gynecol Cancer. 2020;30(4):436-440.
31 Harter P, Sehouli J, Lorusso D, et al. A Randomized Trial of
Lymphadenectomy in Patients with Advanced Ovarian Neoplasms. N Engl J
Med. 2019;380(9):822-832.
30
32 Colombo N, Sessa C, du Bois A, et al. ESMO–ESGO consensus conference
recommendations on ovarian cancer: pathology and molecular biology, early
and advanced stages, borderline tumours and recurrent disease. Ann Oncol.
2019;30(5):672-705.
33 Vergote I, Tropé CG, Amant F, et al. Neoadjuvant Chemotherapy or Primary
Surgery in Stage IIIC or IV Ovarian Cancer. N Engl J Med. 2010;363(10):943-
953.
34 Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary
surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-
label, randomised, controlled, non-inferiority trial. Lancet.

of
2015;386(9990):249-257.

ro
35 Stuart GCE, Kitchener H, Bacon M, et al. 2010 Gynecologic Cancer
InterGroup (GCIG) Consensus Statement on Clinical Trials in Ovarian
-p
Cancer: Report From the Fourth Ovarian Cancer Consensus Conference. Int
re
J Gynecol Cancer. 2011;21(4):750-755.
36 Bookman MA. The addition of new drugs to standard therapy in the first-line
lP

treatment of ovarian cancer. Ann Oncol. 2010;21:vii211-vii217.

37 Vasey PA, Jayson GC, Gordon A, et al. Phase III Randomized Trial of
a
rn

Docetaxel-Carboplatin Versus Paclitaxel-Carboplatin as First-line

Chemotherapy for Ovarian Carcinoma. J Natl Cancer Inst. 2004;96(22):1682-
u

1691.
Jo

38 Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus paclitaxel versus

carboplatin plus pegylated liposomal doxorubicin as first-line treatment for
patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin
Oncol. 2011;29(27):3628-3635.
39 Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense
paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for
treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal
cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet
Oncol. 2013;14(10):1020-1026.
40 Chan JK, Brady MF, Penson RT, et al. Weekly vs. Every-3-Week Paclitaxel
and Carboplatin for Ovarian Cancer. N Engl J Med. 2016;374(8):738-748.
41 Clamp AR, McNeish I, Dean A, et al. ICON8: A GCIG phase III randomised
trial evaluating weekly dose- dense chemotherapy integration in first-line
31
 epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC)
treatment: Results of primary progression- free survival (PFS) analysis. Ann
Oncol. 2017;28:v627.
42 Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a
week versus every 3 weeks in patients with advanced ovarian cancer (MITO-
7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol.
2014;15(4):396-405.
43 Blagden SP, Cook AD, Poole C, et al. Weekly platinum-based chemotherapy
versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian
cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled

of
trial. Lancet Oncol. 2020;21(7):969-977.

ro
44 Hess LM, Benham-Hutchins M, Herzog TJ, et al. A meta-analysis of the
efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian
-p
cancer. Int J Gynecol Cancer. 2007;17(3):561-570.
re
45 Walker J, Brady MF, DiSilvestro PA, et al. A phase III trial of bevacizumab
with IV versus IP chemotherapy for ovarian, fallopian tube, and peritoneal
lP

carcinoma: An NRG Oncology Study. Gynecol Oncol. 2016;141:208.

46 van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal
a
rn

Chemotherapy in Ovarian Cancer. N Engl J Med. 2018;378(3):230-240.

47 Lim MC, Chang S-J, Yoo HJ, et al. Randomized trial of hyperthermic
u

intraperitoneal chemotherapy (HIPEC) in women with primary advanced

Jo

peritoneal, ovarian, and tubal cancer. J Clin Oncol. 2017;35(15_suppl):5520-

5520.
48 Burger RA, Brady MF, Bookman MA, et al. Incorporation of Bevacizumab in
the Primary Treatment of Ovarian Cancer. N Engl J Med. 2011;365(26):2473-
2483.
49 Perren TJ, Swart AM, Pfisterer J, et al. A Phase 3 Trial of Bevacizumab in
Ovarian Cancer. N Engl J Med. 2011;365(26):2484-2496.
50 Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without
bevacizumab for women with newly diagnosed ovarian cancer (ICON7):
overall survival results of a phase 3 randomised trial. Lancet Oncol.
2015;16(8):928-936.
51 Pfisterer J, Joly F, Kristensen G, et al. Optimal Treatment Duration of
Bevacizumab as Front-Line Therapy for Advanced Ovarian Cancer: AGO-
32
 OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized
Phase III Trial. J Clin Oncol. 2023;41(4):893-902.
52 Rouzier R, Gouy S, Selle F, et al. Efficacy and safety of bevacizumab-
containing neoadjuvant therapy followed by interval debulking surgery in
advanced ovarian cancer: Results from the ANTHALYA trial. Eur J Cancer.
2017;70:133-142.
53 Garcia Garcia Y, de Juan Ferré A, Mendiola C, et al. Efficacy and safety
results from GEICO 1205, a randomized phase II trial of neoadjuvant
chemotherapy with or without bevacizumab for advanced epithelial ovarian
cancer. Int J Gynecol Cancer. 2019;29(6):1050-1056.

of
54 Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in

ro
BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-
921.
55
-p
Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients
re
with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med.
2018;379(26):2495-2505.
lP

56 Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as

First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019;381(25):2416-
a
rn

2428.
57 González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with
u

Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med.

Jo

2019;381(25):2391-2402.
58 Monk BJ, Parkinson C, Lim MC, et al. A Randomized, Phase III Trial to
Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With
Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-
ov45). J Clin Oncol. 2022;40(34):3952-3964.
59 Coleman RL, Fleming GF, Brady MF, et al. Veliparib with First-Line
Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J
Med. 2019;381(25):2403-2415.
60 DiSilvestro P, Banerjee S, Colombo N, et al. Overall Survival With
Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly
Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The
SOLO1/GOG 3004 Trial. J Clin Oncol. 2022:Jco2201549.

33
61 Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line
maintenance in ovarian cancer: final overall survival results from the PAOLA-
1/ENGOT-ov25 trial. Ann Oncol. 2023;S0923-7534(23)00686-5. doi:
10.1016/j.annonc.2023.05.005.
62 Grabowski JP, Harter P, Heitz F, et al. Operability and chemotherapy
responsiveness in advanced low-grade serous ovarian cancer. An analysis of
the AGO Study Group metadatabase. Gynecol Oncol. 2016;140(3):457-462.
63 Goff BA, Sainz de la Cuesta R, Muntz HG, et al. Clear Cell Carcinoma of the
Ovary: A Distinct Histologic Type with Poor Prognosis and Resistance to
Platinum-Based Chemotherapy in Stage III Disease. Gynecol Oncol.

of
1996;60(3):412-417.

ro
64 Hess V, A'Hern R, Nasiri N, et al. Mucinous Epithelial Ovarian Cancer: A
Separate Entity Requiring Specific Treatment. J Clin Oncol. 2004;22(6):1040-
1044.
-p
re
65 Gershenson DM, Bodurka DC, Coleman RL, et al. Hormonal Maintenance
Therapy for Women With Low-Grade Serous Cancer of the Ovary or
lP

Peritoneum. J Clin Oncol. 2017;35(10):1103-1111.

66 Wilson MK, Pujade-Lauraine E, Aoki D, et al. Fifth Ovarian Cancer
a
rn

Consensus Conference of the Gynecologic Cancer InterGroup: recurrent

disease. Ann Oncol. 2017;28(4):727-732.
u

67 Baert T, Ferrero A, Sehouli J, et al. The systemic treatment of recurrent

Jo

ovarian cancer revisited. Ann Oncol. 2021;32(6):710-725.

68 Harter P, Sehouli J, Reuss A, et al. Prospective Validation Study of a
Predictive Score for Operability of Recurrent Ovarian Cancer: The Multicenter
Intergroup Study DESKTOP II. A Project of the AGO Kommission OVAR,
AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J Gynecol Cancer.
2011;21(2):289-295.
69 Harter P, Sehouli J, Vergote I, et al. Randomized Trial of Cytoreductive
Surgery for Relapsed Ovarian Cancer. N Engl J Med. 2021;385(23):2123-
2131.
70 Shi T, Zhu J, Feng Y, et al. Secondary cytoreduction followed by
chemotherapy versus chemotherapy alone in platinum-sensitive relapsed
ovarian cancer (SOC-1): a multicentre, open-label, randomised, phase 3 trial.
Lancet Oncol. 2021;22(4):439-449.
34
71 Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-
carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-
sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study
GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet
Oncol. 2017;18(6):779-791.
72 Raja FA, Counsell N, Colombo N, et al. Platinum versus platinum-combination
chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis
using individual patient data. Ann Oncol. 2013;24(12):3028-3034.
73 Pfisterer J, Plante M, Vergote I, et al. Gemcitabine Plus Carboplatin
Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent

of
Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and

ro
the EORTC GCG. J Clin Oncol. 2006;24(29):4699-4707.
74 Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based
-p
chemotherapy versus conventional platinum-based chemotherapy in women
re
with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet.
2003;361(9375):2099-2106.
lP

75 Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al. Pegylated Liposomal

Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for
a
rn

Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse. J Clin

Oncol. 2010;28(20):3323-3329.
u

76 Vetter MH, Khan A, Backes FJ, et al. Outpatient desensitization of patients

Jo

with moderate (high-risk) to severe platinum hypersensitivity reactions.

Gynecol Oncol. 2019;152(2):316-321.
77 Colombo N, Gadducci A, Sehouli J, et al. INOVATYON/ ENGOT-ov5 study:
Randomized phase III international study comparing trabectedin/pegylated
liposomal doxorubicin (PLD) followed by platinum at progression vs
carboplatin/PLD in patients with recurrent ovarian cancer progressing within
6-12 months after last platinum line. Br J Cancer. 2023;128(8):1503-1513.
78 Aghajanian C, Goff B, Nycum LR, et al. Final overall survival and safety
analysis of OCEANS, a phase 3 trial of chemotherapy with or without
bevacizumab in patients with platinum-sensitive recurrent ovarian cancer.
Gynecol Oncol. 2015;139(1):10-16.

35
79 Pfisterer J, Shannon CM, Baumann K, et al. Bevacizumab and platinum-
based combinations for recurrent ovarian cancer: a randomised, open-label,
phase 3 trial. Lancet Oncol. 2020;21(5):699-709.
80 Pignata S, Lorusso D, Joly F, et al. Carboplatin-based doublet plus
bevacizumab beyond progression versus carboplatin-based doublet alone in
patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.
Lancet Oncol. 2021;22(2):267-276.
81 Matulonis UA, Herrstedt J, Oza A, et al. Final Overall Survival and Long-Term
Safety in the ENGOT-OV16/NOVA Phase 3 Trial of Niraparib in Patients with
Recurrent Ovarian Cancer. 2023 SGO Annual Meeting on Women's Cancer.

of
Tampa, FL; March 25-28, 2023.

ro
82 Mirza MR, Wu X, Zhu J, et al. VP7-2022: An ad-hoc interim overall survival
results of niraparib with individualized starting dose as maintenance therapy in
-p
patients with platinum-sensitive recurrent ovarian cancer (NORA): A double-
re
blind, randomized, placebo-controlled, phase III trial. Annals of Oncology.
2023;34(1):124-125.
lP

83 Frenel JS, Kim JW, Aryal N, et al. Efficacy of subsequent chemotherapy for
patients with BRCA1/2-mutated recurrent epithelial ovarian cancer
a
rn

progressing on olaparib versus placebo maintenance: post-hoc analyses of

the SOLO2/ENGOT Ov-21 trial. Ann Oncol. 2022;33(10):1021-1028.
u

84 Pujade-Lauraine E, Selle F, Scambia G, et al. LBA33 Maintenance olaparib

Jo

rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated

with a PARP inhibitor (PARPi): Phase IIIb OReO/ENGOT Ov-38 trial. Ann
Oncol. 2021;32(S5):S1308-S1309.
85 Morice PM, Leary A, Dolladille C, et al. Myelodysplastic syndrome and acute
myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-
analysis of randomised controlled trials and a retrospective study of the WHO
pharmacovigilance database. Lancet Haematol. 2021;8(2):e122-e134.
86 Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III Trial of Gemcitabine
Compared With Pegylated Liposomal Doxorubicin in Progressive or Recurrent
Ovarian Cancer. J Clin Oncol. 2008;26(6):890-896.
87 Mutch DG, Orlando M, Goss T, et al. Randomized Phase III Trial of
Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Patients

36
 With Platinum-Resistant Ovarian Cancer. J Clin Oncol. 2007;25(19):2811-
2818.
88 Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel (80
mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal
cancers: A Gynecologic Oncology Group study. Gynecol Oncol.
2006;101(3):436-440.
89 Gordon AN, Tonda M, Sun S, et al. Long-term survival advantage for women
treated with pegylated liposomal doxorubicin compared with topotecan in a
phase 3 randomized study of recurrent and refractory epithelial ovarian
cancer. Gynecol Oncol. 2004;95(1):1-8.

of
90 Spiliopoulou P, Hinsley S, McNeish IA, et al. Metronomic oral

ro
cyclophosphamide in relapsed ovarian cancer. Int J Gynecol Cancer.
2021;31(7):1037-1044.
91
-p
Monk BJ, Herzog TJ, Wang G, et al. A phase 3 randomized, open-label,
re
multicenter trial for safety and efficacy of combined trabectedin and pegylated
liposomal doxorubicin therapy for recurrent ovarian cancer. Gynecol Oncol.
lP

2020;156(3):535-544.
92 Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab Combined With
a
rn

Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The

AURELIA Open-Label Randomized Phase III Trial. J Clin Oncol.
u

2014;32(13):1302-1308.
Jo

93 Mackay HJ, Brady MF, Oza AM, et al. Prognostic Relevance of Uncommon
Ovarian Histology in Women With Stage III/IV Epithelial Ovarian Cancer. Int J
Gynecol Cancer. 2010;20(6):945-952.
94 Leary AF, Quinn M, Fujiwara K, et al. Fifth Ovarian Cancer Consensus
Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design
for rare ovarian tumours. Ann Oncol. 2017;28(4):718-726.
95 Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of
care in patients with recurrent low-grade serous ovarian cancer (GOG
281/LOGS): an international, randomised, open-label, multicentre, phase 2/3
trial. Lancet. 2022;399(10324):541-553.
96 Monk BJ, Grisham RN, Banerjee S, et al. MILO/ENGOT-ov11: Binimetinib
Versus Physician's Choice Chemotherapy in Recurrent or Persistent Low-

37
 Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary
Peritoneum. J Clin Oncol. 2020;38(32):3753-3762.
97 Gadducci A, Cosio S, Zola P, et al. Surveillance procedures for patients
treated for epithelial ovarian cancer: a review of the literature. Int J Gynecol
Cancer. 2007;17(1):21-31.
98 Gu P, Pan L-L, Wu S-Q, et al. CA 125, PET alone, PET–CT, CT and MRI in
diagnosing recurrent ovarian carcinoma. Eur J Radiol. 2009;71(1):164-174.
99 Rustin GJS, van der Burg MEL, Griffin CL, et al. Early versus delayed
treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a
randomised trial. Lancet. 2010;376(9747):1155-1163.

of
100 Bolton KL, Chenevix-Trench G, Goh C, et al. Association between BRCA1

ro
and BRCA2 mutations and survival in women with invasive epithelial ovarian
cancer. JAMA. 2012;307(4):382-390.
101
-p
Lavie O, Chetrit A, Novikov I, et al. Fifteen-year survival of invasive epithelial
re
ovarian cancer in women with BRCA1/2 mutations – the National Israeli Study
of Ovarian Cancer. Gynecol Oncol. 2019;153(2):320-325.
lP

102 Sessa C, Balmaña J, Bober SL, et al. Risk reduction and screening of cancer
in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice
a
rn

Guideline. Ann Oncol. 2023;34(1):33-47.

103 Mateo J, Chakravarty D, Dienstmann R, et al. A framework to rank genomic
u

alterations as targets for cancer precision medicine: the ESMO Scale for
Jo

Clinical Actionability of molecular Targets (ESCAT). Ann Oncol.

2018;29(9):1895-1902.
104 Cherny NI, Dafni U, Bogaerts J, et al. ESMO-Magnitude of Clinical Benefit
Scale version 1.1. Ann Oncol. 2017;28(10):2340-2366.
105 Dykewicz CA. Summary of the Guidelines for Preventing Opportunistic
Infections among Hematopoietic Stem Cell Transplant Recipients. Clin Infect
Dis. 2001;33(2):139-144 [adapted from: Gross PA, Barrett TL, Dellinger EP, et
al. Purpose of quality standards for infectious diseases. Clin Infect Dis.
1994;18(3):421].

38
FIGURES

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-p
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a lP

Figure 1. Management of early EOC (FIGO stage I-II).

rn

See Supplementary Table S1 for a summary of the benefit of adjuvant systemic

u

therapy for early EOC (FIGO I-II stage).

Jo

Purple: general categories or stratification; red: surgery; blue: systemic anticancer

therapy; white: other aspects of management; dashed lines: optional therapy.

CCC, clear-cell carcinoma; ChT, chemotherapy; EC, endometrioid carcinoma; EOC,

epithelial ovarian cancer; FIGO, International Federation of Gynecology and
Obstetrics; HGSC, high-grade serous carcinoma; LGSC, low-grade serous
carcinoma; MC, mucinous carcinoma.

39
 Jo
urn
alP
re
-p
ro
of

40
Figure 2. Management of advanced EOC (FIGO stage III-IV).

Purple: general categories or stratification; red: surgery; blue: systemic anticancer

therapy; turquoise: combination of treatments or other systemic treatments;
white: other aspects of management.

AUC, area under the curve; EMA, European Medicines Agency; EOC, epithelial
ovarian cancer; ESCAT, ESMO Scale for Clinical Actionability of molecular Targets;
FDA, Food and Drug Administration; FIGO, International Federation of Gynecology
and Obstetrics; HRD, homologous recombination deficiency; MCBS, ESMO-
Magnitude of Clinical Benefit Scale; mut, mutation; PARPi, poly (ADP-ribose)
polymerase inhibitor; wt, wild type.

of
a
ESMO-MCBS v1.1104 was used to calculate scores for new therapies/indications

ro
approved by the EMA or FDA. The scores have been calculated by the ESMO-
-p
MCBS Working Group and validated by the ESMO Guidelines Committee
re
(https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms).
b
Weekly chemotherapy with paclitaxel (60 mg/m2)–carboplatin (AUC 2) can be an
lP

alternative in frail patients [I, B].

a

c
ESCAT scores apply to alterations from genomic-driven analyses only. These
rn

scores have been defined by the guideline authors and assisted if needed by the
u

ESMO Translational Research and Precision Medicine Working Group.103 See

Jo

Supplementary Table S3 for more information on ESCAT scores.

d
Only when patients have complete or partial response to platinum or no evidence of
disease. For patients without response to platinum, PARPi is not incdicated; these
patients can be managed with bevacizumab maintenance if appropiate (mainly
stable disease), or with second-line therapy if they have progressive disease (see
Figure 3).
e
Option for patients for whom bevacizumab was added to paclitaxel–carboplatin.

41
 of
ro
-p
re
lP

Figure 3. Management of recurrent EOC.

a

Purple: general categories or stratification; red: surgery; blue: systemic anticancer

rn

therapy; turquoise: combination of treatments or other systemic treatments;

u

white: other aspects of management.

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AGO, Arbeitsgemeinschaft Gynaekologische Onkologie; BSC, best supportive care;

EMA, European Medicines Agency; EOC, epithelial ovarian cancer; FDA, Food and
Drug Administration; MCBS, ESMO-Magnitude of Clinical Benefit Scale; mut,
muation; PARPi, poly (ADP-ribose) polymerase inhibitor; PLD, pegylated liposomal
doxorubicin; TFIp, treatment-free interval from last platinum.
a
Patient choice and quality-of-life issues may also suggest that platinum is not the
best option.
b
In patients with platinum intolerance who have relapsed >6 months from previous
platinum, the combination of trabectedin and PLD may be recommended [II, C;
ESMO-MCBS v1.1 score: 2].
c
Weekly paclitaxel, PLD, topotecan or gemcitabine.

42
d
ESMO-MCBS v1.1104 was used to calculate scores for new therapies/indications
approved by the EMA or FDA. The scores have been calculated by the ESMO-
MCBS Working Group and validated by the ESMO Guidelines Committee
(https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms).
e
Paclitaxel, PLD or gemcitabine.
f
Bevacizumab or PARPi until disease progression or next line of treatment is started
[I, A].
g
Olaparib for BRCA1/2-mut: ESMO-MCBS v1.1 score: 2d; niraparib regardless of
BRCA1/2 status: ESMO-MCBS v1.1 score: 3d; rucaparib regardless of BRCA1/2

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status: ESMO-MCBS v1.1 score:3d.

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Work-up if EOC is suspected

• Detailed history and clinical examination

• Serum CA-125
• Serum CEA and CA 19-9, in the case of MC,
and colonoscopy, if either or both are elevated
• Abdominal and transvaginal US by expert examiner
• CT of thorax, abdomen and pelvis
• Pathological examination of adequate tumour sample from diagnostic
biopsy or surgical specimen
• Cytological assessment of pleural effusion if present

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CA 19-9, carbohydrate antigen 19-9; CA-125, cancer antigen 125;
-p
CEA, carcinoembryonic antigen; CT, computed tomography; EOC, epithelial ovarian
cancer; MC, mucinous carcinoma; US, ultrasound.
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 HGSC EC CCC LGSC MC

IHC staining p53 abnormal abnormal/normal normal normal normal

p16 + - -

WT-1 + - - + -

ER +/- + - + -

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PAX8 + + + -

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Vimentin +

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HNF1β +

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CDX2 +

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Molecular alterations TP53 CTNNB1 ARID1A KRAS CDKN2A
(decreasing prevalence from BRCA1/2
ur ARID1A PI3KCA BRAF KRAS
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top to bottom) HRD PTEN PTEN RAF HER2
KRAS MSI/dMMR
TP53 (high-grade EC)
MSI/dMMR

CCC, clear-cell carcinoma; CDX2, homeobox protein CDX-2; dMMR; mismatch repair deficiency; EC, endometrioid carcinoma;
EOC, epithelial ovarian cancer; ER, estrogen receptor; HGSC, high-grade serous carcinoma; HNF1β, hepatocyte nuclear factor-

1
1beta; HRD, homologous recombination deficiency; IHC, immunohistochemistry; LGSC, low-grade serous carcinoma; MC,
mucinous carcinoma; MSI, microsatellite instability; PAX8, paired box gene 8; WT-1, Wilms tumour 1

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Stage I: Tumour confined to ovaries or fallopian tube(s)

IA Tumour limited to one ovary (capsule intact) or fallopian tube, without

tumour on ovarian or fallopian tube surface and without malignant cells in
the ascites or peritoneal washings

IB Tumour limited to both ovaries (capsules intact) or fallopian tubes, without

tumour on ovarian or fallopian tube surface and without malignant cells in
the ascites or peritoneal washings

IC Tumour limited to one or both ovaries or fallopian tubes, with any of the
following:

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IC1 Surgical spill

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IC2 Capsule ruptured before surgery or tumour on ovarian or fallopian tube
surface -p
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IC3 Malignant cells in the ascites or peritoneal washings

Stage II: Tumour involves one or both ovaries or fallopian tubes with pelvic
lP

extension (below pelvic brim) or primary peritoneal cancer

a

IIA Extension and/or implants on uterus and/or fallopian tubes and/or ovaries
rn

IIB Extension to other pelvic intraperitoneal tissues

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Stage III: Tumour involves one or both ovaries or fallopian tubes or primary
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peritoneal cancer, with cytologically or histologically confirmed spread to the

peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph
nodes

IIIA1 Positive retroperitoneal lymph nodes only (cytologically or histologically

proven):

IIIA1(i) Metastasis ≤10 mm in greatest dimension

IIIA1(ii) Metastasis >10 mm in greatest dimension

IIIA2 Microscopic extra-pelvic (above the pelvic brim) peritoneal involvement

with or without positive retroperitoneal lymph nodes

1
IIIB Macroscopic peritoneal metastasis beyond the pelvis ≤2 cm in greatest
dimension, with or without metastasis to the retroperitoneal lymph nodes

IIIC Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest

dimension, with or without metastasis to the retroperitoneal lymph nodes
(includes extension of tumour to capsule of liver and spleen without
parenchymal involvement of either organ)

Stage IV: Distant metastasis excluding peritoneal metastases

IVA Pleural effusion with positive cytology

IVB Parenchymal metastases and metastases to extra-abdominal organs

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(including inguinal lymph nodes and lymph nodes outside of the abdominal

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cavity)

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EOC, epithelial ovarian cancer; FIGO, International Federation of Gynecology and
Obstetrics
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 Suspected early EOC (FIGO stage I-II)

Surgical staging [III, A]

• LGSC: FIGO stage IB-IC • HGSC/high-grade EC: any FIGO stage

• LGSC: FIGO stage IA • CCC: FIGO stage IA-IC1 • CCC: FIGO stage IC2-IC3
• Low-grade EC: FIGO stage IA • Low-grade EC: FIGO stage IB-IC • Infiltrative MC: FIGO stage IB-IC3
• Expansile MC: FIGO stage IA-IB • Expansile MC: FIGO stage IC • Any histotype FIGO stage II
• Infiltrative MC: FIGO stage IA

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Adjuvant ChT optional [III, C]: Adjuvant ChT [II, A]:
Observation paclitaxel–carboplatin [I, B] paclitaxel–carboplatin [I, B]
(minimum 3 cycles or 6 cycles if FIGO (6 cycles; 3 cycles are acceptable

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stage IC [II, B]) unless HGSC/high-grade EC
or carboplatin alone (6 cycles) [I, A] or FIGO stage IC-II [II, B])
or carboplatin alone (6 cycles) [I, A]

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 Newly diagnosed EOC (FIGO stage III-IV)

Likelihood of complete
Low High
cytoreduction [III, A]

Adequate biopsy tissue for

Primary cytoreductive
histology and molecular
surgery [III, A]
testing [III, A]

3 cycles of neoadjuvant
BRCA1/2 (germline and/ BRCA1/2 (germline and/
paclitaxel–carboplatin alone
or somatic) and HRD status or somatic) and HRD status
[I, A] or with bevacizumab
testing [I, A] testing [I, A]
[II, B; MCBS 4]a

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Interval cytoreductive Interval cytoreductive surgery not
surgery possible possible and no overt disease progression

Interval cytoreductive surgery

[I, A], followed by 3 cycles
3 cycles of paclitaxel–
carboplatin alone [I, A]
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6 cycles of paclitaxel–
carboplatin alone or
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of paclitaxel–carboplatin or with bevacizumab with bevacizumab
alone [I, A] or with [II, B; MCBS 3]a [I, A; MCBS 4]a,b
bevacizumab [II, A; MCBS 3]a
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BRCA1/2-wt/ BRCA1/2-wt/
BRCA1/2-mut
HRD-positive HRD-negative
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Olaparib (2 years)d Bevacizumabe [I, A; MCBS 3]a

[I, A; MCBS 4; ESCAT I-A]a,c Niraparib (3 years)d or niraparib (3 years)d
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or niraparib (3 years)d [I, A; MCBS 3; ESCAT I-A]a,c [II, B; MCBS 3]a maintenance
[I, A; MCBS 3; ESCAT I-A]a,c or olaparib–bevacizumab (2 years)d,e
or olaparib–bevacizumab (2 years)d,e [I, A; MCBS 3; ESCAT I-A]a,c
[I, A; MCBS 3; ESCAT I-A]a,c maintenance maintenance
 Recurrent EOC

Assessment of the following factors [I-II, A]:

• Histotype • TFIp
• BRCA1/2 status • Potential for surgery Unfit or not willing to receive
• Number of prior lines • Residual toxicity BSC
anticancer therapy
• Exposure and response • Patient’s general condition
to prior treatment • Patient preference

Platinum is not the best option Platinum is the best option when:
whena [II-IV, A]: • Prior response to platinum
• Progression during platinum • No contraindication
• Early symptomatic progression
• Platinum intoleranceb

Yes First relapse and positive No

AGO score?

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Early palliative care [I, A]
Single agent (non-platinum)c [I, B] Consider surgery by
+ bevacizumab, if not contraindicated expert team [I, A]
or previously exposed [I, A; MCBS 4]d

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Trabectedin–PLD (if TFIp >6 months
and platinum intolerant) [II, C]

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Priority for symptomatic response
No priority for symptomatic response
and no contraindication to bevacizumab
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Carboplatin-doublete (PLD preferred) + PARPi maintenancef,g,
if responsive and PARPi naïve [I, A] Carboplatin doublete (PLD preferred)–
(preferred option if BRCA1/2-mut) bevacizumabf [V, A; MCBS 3]d
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or carboplatin–doublete (PLD preferred)–bevacizumabf [I, A; MCBS 3]d

(if no contraindication or previous exposure to bevacizumab)
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