2017 ESMO Essentials For Clinicians Gynaecological Tumours

www.esmo.org www.esmo.
org
Andreas du Bois - Marcia Hall - Christina C Fotopoulou

edited by
GYNAECOLOGICAL GYNAECOLOGICAL
Andreas du Bois
Marcia Hall
TUMOURS TUMOURS
Christina C Fotopoulou
E S S E N T I A L S forC L I N I C I A N S E S S E N T I A L S forC L I N I C I A N S
GYNAECOLOGICAL TUMOURS
edited by PA
Andreas du Bois CI
Marcia Hall PS
Christina C Fotopoulou EI
OB
Gynaecological tumours is the 4th edition of the popular “Essentials for
Clinicians” series. Gynaecological tumours: Essentials for Clinicians
is divided into two sections. It starts with the essential information or
“what every oncologist should know”. In this section staging and treatment
strategies for the more common Gynaecological cancers is explained.
The second section builds upon the first by offering more advanced
information on rare tumours, new drugs and novel treatment options.
Progress in oncology is moving quickly and it is becoming an increasingly
complicated speciality, for people interested in specialising or simply
learning about oncology knowing where to start can be difficult,
this is why ESMO has developed the Essential series. These books
E S S E N T I A L S forC L I N I C I A N S
provide the essential information in a visual and interactive format. Endometrioid Mucinous Clear Cell Serous
Complicated concepts in the management of tumours are explained MDM2 • Low-grade
be
• Slow growing
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• Encompass all histologies, including:
in a concise, clear and accessible way, giving the reader a p14ARF
an
opi
- low-grade serous carcinoma
- low-grade endometrioid carcinoma
Fall
Type I Tumours
strong theoretical foundation that can then be built upon.
- mucinous carcinoma
- and some clear cell carcinomas
• They likely evolve through a step-wise
p21, puma, bax, progress from borderline tumours
• Usually chromosomally stable
Mutant p53 MDM2, etc
TP53 • High-grade
• Evolve rapidly
• Include:
Type II Tumours - high-grade serous carcinoma
- high-grade endometrioid carcinoma
Ovary - carcinosarcoma
Fim - undifferentiated carcinomas
HPV-E6 bri
a - and some clear cell carcinomas
• No recognisable precursors in the ovary
• Widespread DNA copy
number changes
Endometrioid Carcinosarcoma Clear Cell Serous

ESMO Press
ISBN 978-88-941795-1-4
ESMO Press · ISBN 978-88-941795-1-4
ESMO Press ESMO Press
9 788894 179514
GynaecoTumours2017.indd 1 14/06/2017 17:52

Gynaecological Tumours
Essentials for Clinicians
Gynaecological Tumours
Essentials for Clinicians
Edited by
Andreas du Bois
Arbeitsgemeinschaft Gynaekologische Onkologie Study Group
Kliniken Essen-Mitte, Department of Gynaecology and
Gynaecologic Oncology, Essen, Germany
Marcia Hall
Mount Vernon Cancer Centre
Northwood, UK
Ovarian Cancer Action Research Centre
Department of Surgery and Cancer
Imperial College London, UK
Series editor
Michele Ghielmini
Oncology Institute of Southern Switzerland, Ospedale San Giovanni
Bellinzona, Switzerland
ESMO Press
First published in 2017 by ESMO Press
© 2017 European Society for Medical Oncology
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Contents
Preface vi
Contributors vii
Abbreviations viii
Acknowledgements ix
A. What every oncologist should know

1. Histopathology of gynaecological cancers 1
GD Aletti & S Carinelli
2. Staging and surgical treatment of ovarian cancer 7
S Mahner & L Woelber
3. Systemic treatment of ovarian cancer 13
D Krell & M Hall
4. Staging and surgical treatment of endometrial cancer 19
MJ Halaska & L Rob
5. Non-surgical treatment of endometrial cancer 25
M Mirza
6. Staging and surgical treatment of cervical cancer 31
D Cibula
7. Non-surgical treatment of cervical cancer 38
S Marnitz & CC Fotopoulou
B. More advanced knowledge

8. Epidemiology and risk factors for ovarian, uterine and cervical cancers 47
A Gonzalez Martin
9. Diagnosis and treatment of vulvar cancer 51
L Rob & P Skapa
10. Rare gynaecological cancers 55
I Ray-Coquard & H Vanacker
11. Hereditary ovarian and uterine cancer syndromes 59
C Marth
12. New drugs and novel treatment strategies for gynaecological cancers 63
M Zweifel & C Sessa
Appendices
1. WHO Classification 69
2. FIGO Ovarian, Fallopian Tube, and Peritoneal Cancer Staging System and Corresponding TNM 74
3. Selected treatment schedules 76
Image sources 83
Declarations of interest 84
Index 85
v
Contents
Preface
After decades of stagnation, the new millennium has seen a greater understanding of gynaecological
cancers. With this new knowledge, significant advances have been made in preventive medicine
(vaccination in HPV-related diseases and surgery in high-risk disease based on genetic mutations,
e.g. BRCA, Lynch) and the introduction of personalised targeted medicine in ovarian cancer has been
possible. This volume of the Essentials for Clinicians series provides clinicians with an easily accessible and
up-to-date overview of the latest developments and studies, including new consensus guidelines, within
gynaecological oncology.
Under the excellent supervision of Drs Christina Fotopoulou and Marcia Hall, the chapters have been
developed by European experts in gynaecological oncology. This publication includes specialists from
disciplines involved in diagnostics and the management of gynaecological tumours such as gynaecological
oncology, radio-oncology, pathology and medical oncology. The editors have been mindful to ensure
that this publication covers the broad spectrum of gynaecological oncology ranging from pathology, early
diagnosis and prevention to the current therapeutic options for gynaecological tumours including treatment
options for recurrent disease and rare tumours.
The book uses concise text paired with informative illustrations. It is aimed at gynaecological oncologists-in-
training; however, it is also informative and useful for medical oncologists and radio-oncologists who have a
focus on gynaecological oncology.
Andreas du Bois, MD, PhD

Essen, Germany
vi
Preface
Contributors
GD Aletti
Department of Gynaecologic Oncology, European Institute of Oncology, Milan, Italy
S Carinelli
Department of Pathology, European Institute of Oncology, Milan, Italy
D Cibula
Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Charles University in Prague and
General University Hospital in Prague, Czech Republic
CC Fotopoulou
Department of Gynecological Oncology, Imperial College London, London, UK
A Gonzalez Martin
MD Anderson Cancer Center, Madrid, Spain
MJ Halaska
Gynecologic Oncology Center, Department of Obstetrics and Gynecology, University Hospital Kralovske Vinohrady,
Third Medical Faculty, Charles University, Prague, Czech Republic
M Hall
Mount Vernon Cancer Centre, Northwood, UK
D Krell
Mount Vernon Cancer Centre, Northwood, UK
S Mahner
Department of Gynecology and Obstetrics, University of Munich, Munich, Germany
S Marnitz
Department of Radiation Oncology, Charité University Medicine, Berlin, Germany
C Marth
Department of Obstetrics and Gynecology, Medical University, Innsbruck, Austria
M Mirza
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
I Ray-Coquard
Medical Oncology, Centre Léon Bérard, Lyon, France
L Rob
Gynecologic Oncology Center, Department of Obstetrics and Gynecology, University Hospital Kralovske Vinohrady,
Third Medical Faculty, Charles University, Prague, Czech Republic
C Sessa
Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland
P Skapa
Department of Pathology and Molecular Biology, Second Medical Faculty, Charles University, Prague, Czech Republic
H Vanacker
Medical Oncology, Centre Léon Bérard, Lyon, France
L Woelber
University Medical Center Hamburg-Eppendorf, Department of Gynecology, Hamburg, Germany
M Zweifel
Department of Medical Oncology, University Hospital Bern, Switzerland
vii
Contributors
Abbreviations
AIN Anal intraepithelial neoplasia PCNA Proliferation cell nuclear antigen

BEP Bleomycin, etoposide, platinum PCOS Polycystic ovary syndrome
BER Base-excision repair PD-1 Programmed death-1
BMI Body mass index PE Pelvic exenteration
BV Bevacizumab PET Positron emission tomography
CC Cervical cancer PFS Progression-free survival
CCC Clear cell carcinoma PLD Pegylated liposomal doxorubicin
CDDP Cisplatin PLN Pelvic lymphadenectomy
ChT Chemotherapy PLND Pelvic lymph node dissection
CI Confidence interval pPS Partially platinum sensitive
CIN Cervical intraepithelial neoplasia pRef Platinum refractory
CT Computed tomography PS Platinum sensitive
D&C Dilatation and curettage PT Cisplatin and paclitaxel
DSB Double-strand break QOL Quality of life
d-VIN Differentiated-type vulvar intraepithelial neoplasia RFC Replication factor C
EBRT External beam radiotherapy RGC Rare gynaecological cancer
EC Endometrial cancer RH Radical hysterectomy
EFRT Extended field radiation therapy ROC Relapsed ovarian cancer
ER/PR Oestrogen receptor/progesterone receptor RR Relative risk
ET Epithelial tumour RT Radiotherapy
FDA Food and Drug Administration SCST Sex cord–stromal tumours
FIGO International Federation of Gynecology and Obstetrics SEER Surveillance, Epidemiology, and End Results Program
GC Carboplatin and gemcitabine SERM Selective oestrogen receptor modulator
GCIG Gynecologic Cancer InterGroup SLN Sentinel lymph node
GCT Germ cell tumour SSB Single-strand break
GnRH Gonadotrophin releasing hormone STIC Serous intraepithelial carcinoma
HBOC Hereditary breast and ovarian cancer TC Carboplatin and paclitaxel
hCG Human chorionic gonadotrophin TKI Tyrosine kinase inhibitor
HGSC High-grade serous carcinoma u-VIN Vulvar intraepithelial neoplasia of usual type
HGSOC High-grade serous ovarian cancer VaiN Vaginal intraepithelial neoplasia
HNPCC Hereditary non-polyposis colorectal cancer VC Vulvar cancer
HPV Human papillomavirus VDA Vascular disrupting agent
HR CTV High risk clinical target volume VEGF Vascular endothelial growth factor
HR HPV High-risk human papillomavirus VMAT Volumetric modulated arc therapy
HR Hazard ratio WHO World Health Organization
HRT Hormone replacement therapy
i.p. Intraperitoneal
i.v. intravenous
IDL Insertion-deletion loop
IDS Interval debulking surgery
IHC Immunohistochemistry
IMRT Intensity-modulated radiation therapy
IVF In-vitro fertilisation
LEER Laterally extended endopelvic resection
LGSC Low-grade serous carcinoma
LGSOC Low-grade serous ovarian cancer
LMPT Low malignant potential tumours
LMS Leiomyosarcoma
LN Lymph node
LND Lymph node dissection
LVSI Lymphovascular space invasion
MMR Mismatch repair
MRI Magnetic resonance imaging
MSI Microsatellite instability
NAC Neoadjuvant chemotherapy
NHEJ Non-homologous end-joining
OC Ovarian cancer
OR Odds ratio
ORR Overall response rate
OS Overall survival
PA Para-aortic
PARP Poly(ADP-ribose) polymerase
PARPi PARP inhibitor
viii
Abbreviations
Acknowledgements
The editors would like to thank the members of the ESMO Publishing Working Group and the Educational
Steering Committee for their support in this initiative. The editors wish to thank Dr Keith McGregor,
Claire Bramley and Matthew Wallace of ESMO for their support in the preparation of this publication.
Andreas du Bois
Marcia Hall
ix
Acknowledgements
A
What every oncologist should know

1 Histopathology of gynaecological cancers
Ovarian tumours
Ovarian tumours are classified based on cell types, Classification of Tumours of the Ovary
patterns of growth and, whenever possible, on Epithelial tumours (ET)
histogenesis (WHO Classification 2014). Sex cord–stromal tumours (SCST)
Germ cell tumours (GCT)
There are 3 major categories of primary ovarian tumour:
epithelial tumours (ETs), sex cord–stromal tumours Monodermal teratoma and somatic type tumours arising from dermoid cyst
(SCSTs) and germ cell tumours (GCTs). Secondary Germ cell–sex cord stromal tumours
tumours are not infrequent. Mesenchymal and mixed epithelial and mesenchymal tumours
The incidence of malignant forms varies with age. Other rare tumours, tumour-like conditions
Carcinomas, accounting for over 80%, peak at the 6th Lymphoid and myeloid tumours
decade; SCSTs peak in the perimenopausal period; GCTs Secondary tumours
peak in the first three decades. Prognosis is worse for WHO, 2014
carcinomas.
Stage I: Tumour confined to ovaries or Fallopian tube(s)

IA: Tumour limited to 1 ovary (capsule intact) or Fallopian tube; no tumour on
ovarian or Fallopian tube surface; no malignant cells in the ascites or peritoneal The staging classification has been recently revised
washings (FIGO 2013 Classification) and ovarian, Fallopian tube
IB: Tumour limited to both ovaries (capsules intact) or Fallopian tubes; no and peritoneal cancer are classified together.
tumour on ovarian or Fallopian tube surface; no malignant cells in the ascites or
peritoneal washings
Stage I cancer is confined to the ovaries or Fallopian
IC: Tumour limited to 1 or both ovaries or Fallopian tubes, with any of the following:
• IC1: Surgical spill tubes. Peritoneal cytology/washing, tumour rupture or
• IC2: Capsule ruptured before surgery or tumour on ovarian or Fallopian tube
surface
surface involvement warrants a Stage IC.
• IC3: Malignant cells in the ascites or peritoneal washings
Stage II: Tumour involves 1 or both ovaries or Fallopian tubes with pelvic
In Stage II, the disease involves one or both ovaries/
extension (below pelvic brim) or primary peritoneal cancer Fallopian tubes with extension to the pelvis below the
IIA: Extension and/or implants on uterus and/or Fallopian tubes and/or ovaries
pelvic brim (note: peritoneal cancer has no FIGO Stage I).
IIB: Extension to other pelvic intraperitoneal tissues
FIGO, 2013
Stage III: Tumour involves 1 or both ovaries or Fallopian tubes, or primary

peritoneal cancer, with cytologically or histologically confirmed spread to
the peritoneum outside the pelvis and/or metastasis to the retroperitoneal
Most patients with ETs present at high stage (III-IV). lymph nodes
In Stage III, the disease involves one or both adnexae
IIIA1: Positive retroperitoneal lymph nodes only
and spread to the pelvic and abdominal peritoneum • IIIA1(i) Metastasis up to 10 mm
• IIIA1(ii) Metastasis more than 10 mm
and/or retroperitoneal lymph nodes.
IIIA2: Microscopic extrapelvic peritoneal involvement with or without positive
lymph nodes
Stage IV includes patients with pleural diffusion and
intraparenchymal liver/spleen or extra-abdominal IIIB: Macroscopic extrapelvic peritoneal metastasis up to 2 cm, with or without
metastasis to the retroperitoneal lymph nodes
metastases or extra-abdominal lymph nodes (LNs).
IIIC: Extrapelvic peritoneal metastasis more than 2 cm in greatest dimension, with or
without metastasis to the retroperitoneal lymph nodes
The revised FIGO staging system better reflects the
prognosis of patients with ovarian cancer and LN Stage IV: Distant metastasis excluding peritoneal metastases
metastases. IVA: Pleural effusion with positive cytology
IVB: Parenchymal metastases and metastases to extra-abdominal organs
(including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)
FIGO, 2013
REVISION QUESTIONS
1. How many categories of ovarian tumour can be classified?
2. If the disease is on the bladder peritoneum, is the patient staged as Stage IIA or IIB?
3. If the disease involves the abdominal peritoneum and mediastinal LNs, is the patient staged as Stage IIIC or IVB?
1
Aletti & Carinelli
Epithelial ovarian tumours
Primary ETs are classified based on histological type

Site of origin (+ immunohistochemical markers) and histological type
and into benign, borderline (atypical, non-invasive) and (+ genetic association) of ovarian carcinomas
malignant. Carcinomas represent a heterogeneous group
Fallopian tube (PAX8, WT1)
of different diseases. High-grade serous (p53, BRCA1, BRCA2 )
Endosalpingiosis, serous borderline tumours (PAX8, WT1)
Some carcinomas follow a benign–adenoma– Low-grade serous (BRAF, Kras, PIK3CA, MSI )
carcinoma morphological and molecular pathway in the Endometriosis (PAX8, ER, PR)
ovary: they are frequently unilateral, low grade (in most Clear cell (ARID1a)
Endometrioid (ARID1a, b-catenin, PTEN, MSI )
cases), and show lower levels of genetic anomalies.
Not known, tubal peritoneal-junction? (-)
Staging is prognostically relevant. Mucinous (Kras, HER2 )
Brenner
High-grade serous carcinomas are usually detected at
high stage and no macroscopic residual disease after
debulking is the main prognostic variable. All show
p53 mutations and genetic instability; BRCA genes are
involved in hereditary and in some sporadic cases.
Endometrioid and clear cell carcinomas may arise in

endometriosis. Borderline tumours are rare and clinically
Endometrioid Serous intraepithelia carcinoma
cyst benign, but can be found associated with carcinomas.
Grading is relevant in endometrioid carcinomas.
Small (early) serous carcinoma
Mucinous carcinomas usually develop within borderline
Endometrioid carcinoma tumours (otherwise clinically benign) and behaviour is
dependent on the presence of invasion and high grade
of atypia.
Serous borderline tumours can develop from inclusion

Fimbria of the Fallopian tube
cysts. They can present as Stage >1 and may recur.
Invasive peritoneal implants are markers for progression
and represent evolution into low-grade serous carcinoma,
which may also develop in the ovary and peritoneum.
Ovarian Carcinomas
High-grade serous carcinomas are the most frequent
Type % Stage 1 % Survival %
carcinomas. Unlike previously thought, they often do
Type 1
not arise in the ovary. The distal Fallopian tube is the
site of origin in BRCA patients and it is commonly Endometrioid 10 >60 78
Clear cell 10 >60 80
involved in sporadic cases. Serous intraepithelial
Mucinous 3 80 80
carcinoma (STIC) is considered the precursor lesion; Low-grade serous <5 >85
however, it can already metastasise. Type 2
High-grade serous 70 <5 40
REVISION QUESTIONS
1. What is the most frequent and more frequently disseminated type of ovarian carcinoma?
2. What are the most important prognostic variables in serous carcinomas?
3. What is considered the main precursor of clear cell carcinoma of the ovary?
2
Histopathology of gynaecological cancers
Non-epithelial ovarian tumours
Non-epithelial tumours are typically unilateral. Those

Granulosa cells (“sex cords”)
that contain granulosa cells and Sertoli cells (“sex
cords”), theca cells, fibroblasts, Leydig cells and
steroid cells not otherwise specified form a broad
category of rare tumours characterised by endocrine
manifestations (SCSTs).
Granulosa cell tumours are low-grade malignant tumours Germ cells

with late recurrence. Most occur in adults; the rare
juvenile type is aggressive when ruptured. Grading has
value in Sertoli cell tumours. Stroma cells
Steroid cell tumours can be malignant. Staging is Foetal ovary

prognostically relevant for all of these. The other tumours
are benign.
Most GCTs are benign mature teratomas (dermoid

cysts); only rarely may a malignant tumour arise
from somatic-type teratomatous tissues. Primitive
SALL4, OCT3/4 (Dysgerminoma)
Steroid hormones (malignant) GCTs are similar to those occurring in
males; a few occur in subjects with disorders of sexual
development (most phenotypically females with Y
chromosome) from a mixed germ cell–sex cord stromal
tumour (gonadoblastoma).
Beta-hCG (Syncytiotrophoblastic cells)
Primitive GCTs include dysgerminoma (similar to seminoma),
yolk sac tumour and rarer types (embryonal carcinoma and
Alpha-foetoprotein (Yolk sac tumour)
choriocarcinoma) alone or in combination (10%). Immature
(embryonal) teratomas also are in this group. Tumour cell
markers and chemosensitivity are typical.
Among undifferentiated cancers, some mimic Metastatic carcinoma

(bilateral and multinodular)
undifferentiated carcinomas of other organs (lung);
one aggressive type associated with hypercalcaemia
typically arises in the first decades.
Metastatic tumours from the gastrointestinal tract may

simulate primary mucinous carcinomas. Those from the
stomach and breast show typical features, bilaterally and
single-cell growth alone or with other features.
Tumour-like lesions may simulate malignant tumours.
REVISION QUESTIONS
1. What is the most important prognostic histological feature in malignant SCSTs?
2. Why is the prognosis of malignant primitive germ cell tumours favourable in most cases?
3. Are bilateral mucinous (intestinal-type) carcinomas most likely to be primary or metastatic?
3
Aletti & Carinelli
Uterine corpus tumours
In the uterine corpus there are three major categories

Cytological atypia Spindle-shaped cells
of cancer: (1) epithelial, (2) mesenchymal and (3) mixed
epithelial and mesenchymal.
Uterine leiomyosarcoma (LMS) is the most common

type of mesenchymal malignant tumour; microscopic
features of LMS include cytological atypia, mitotic
activity and necrosis. They are aggressive also when
Stage 1.
Endometrial stromal sarcoma is less frequent than

LMS. Most are low-grade tumours and the stage is
prognostically relevant; few are high grade. They show
typical genetic anomalies.
Mitotic activity Necrosis
Grade 1 Grade 3 FIGO staging of endometrial carcinoma: Stage I:

limited to the corpus; Stage II: infiltration of the cervical
stroma; Stage III: metastases to adnexa, vagina and
retroperitoneum; and Stage IV: metastases to bladder,
rectum and distant organs.
There are two stereotypes of endometrial carcinoma.

Type 1 (75%), or low-grade endometrioid carcinomas,
present at low stage in perimenopause and are associated
with unopposed oestrogen stimulation, obesity and
infertility. Prognosis depends on depth of myometrial
invasion and stage. Grading is mixed, architectural and
nuclear. Molecular changes include microsatellite
instability, mutations of p-TEN, k-RAS, and β-catenin.
Type 2 (10%), or serous carcinoma, arises in atrophic

endometrium in postmenopausal women and is more
aggressive. p53 mutations and genetic instability are
characteristic.
A third minor type, clear cell carcinoma, shows

intermediate features.
An integrated genomic characterisation of endometrial

carcinoma identified four different prognostic
subgroups: POLE ultramutated, microsatellite instability
hypermutated, copy number low and copy number high.
This may impact postsurgical treatments for aggressive
tumours. Uterine serous carcinoma
REVISION QUESTIONS
1. What are the diagnostic histological features of uterine LMS?
2. What are the clinical features of Type 1 and Type 2 endometrial carcinomas?
3. What are the molecular features of Type 1 and Type 2 endometrial carcinomas?
4
Uterine cervical tumours
Cervical cancer is the most serious complication of

HPV INFECTION
human papillomavirus (HPV) infection, particularly from
some HPV types designated as “high-risk HPV” (mostly
Types 16 and 18).
Two viral reading frames, E6/E7, deregulate reparative

proteins, p53 and Rb, at cell cycle check points
favouring genetic errors and malignant transformation.
The declining incidence of cervical cancer over the last

decades is related to screening programmes that detect
early cancers or precursor lesions. Vaccination is a new
horizon for prevention.
Low grade (infection) High grade (progression)
HPV, Human papillomavirus.
FIGO staging: Stage I: limited to the cervix; Stage II: initial

parametria/vagina; Stage III: deep infiltration parametria/
vagina; Stage IV: bladder/rectum/distant metastasis.
Squamous cell carcinoma accounts for 70% of

cervical cancers. Pre-invasive lesion (cervical
intraepithelial neoplasia, CIN) features include well-
known condylomatous changes or low-grade CINs
(multinucleation and perinuclear halos) and features
suggestive of malignancy or high-grade CINs (marked
cell atypia, and p16 positivity).
Invasive carcinoma is usually of the non-keratinising type.

Squamous cell carcinoma
Adenocarcinomas account for 20%–25% of cervical

cancers and are difficult to detect by screening. Most
are HPV cancers and HPV18 is frequent. Histological
types include endocervical and mucinous; mixed
adenosquamous carcinomas may occur.
Small cell undifferentiated carcinoma is the least frequent,

but a highly aggressive, HPV cancer.
A few adenocarcinomas are not HPV related; they include
gastric type mucinous and clear cell adenocarcinoma and
adenocarcinoma arising from mesonephric remnants.
Cervical adenocarcinoma
REVISION QUESTIONS
1. Why is the incidence of cervical cancer in developed countries decreasing? What is a promising discovery for reducing cervical
cancer incidence even in developing countries?
2. What are the most common, high-risk HPVs related to invasive cervical cancer? What is the molecular pathogenesis?
3. What HPV-related features can be identified at cytology/histology?
5
Aletti & Carinelli
Summary: Histopathology of gynaecological cancers
• Ovarian tumours:
• Epithelial ovarian tumours
• Sex cord ovarian tumours
• Germ cell ovarian carcinomas
• Ovarian cancer is not a homogeneous disease, but rather a group of diseases—each with different morphology
and biological behaviour. Reproducible histopathological diagnosis of tumour cell type is a conditio sine qua non for
successful treatment. FIGO staging has recently been revised and reflects the tumour dissemination and subsequent
prognosis
• Uterine corpus tumours:
• Sarcomas
• Type 1: Endometrioid carcinomas
• Type 2: Serous carcinomas
• In uterine corpus cancers, three major types can be identified according to their intrinsic biology and subsequent
treatments: (1) epithelial, (2) mesenchymal and (3) mixed epithelial and mesenchymal
• Uterine cervical tumours:
• HPV and pre-invasive lesions
• Squamous carcinoma
• Adenocarcinomas
• Cervical cancers mainly derive from high-risk HPV infections (mostly by HPV16/18). Here we describe the pathological
features of the two principal subtypes: (1) squamous cell carcinoma, (2) adenocarcinomas
Further Reading
Bennett JA, Oliva E. Pathology of the adnexal mass. Clin Obstet Gynecol 2015; 58:3–27.
Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during
the platinum era: a meta-analysis. J Clin Oncol 2002; 20:1248–1259.
Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of
endometrial carcinoma. Nature 2013; 497:67–73.
Gilks CB, Prat J. Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol 2009; 40:1213–1223.
Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010;
34:433–443.
Oliva E, Young RH. Endocrine pathology of the ovary: in tribute to Robert E Scully, MD. Endocr Pathol 2014; 25:102–119.
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009; 105:103–104.
Prat J; FIGO Committee on Gynecologic Oncology. Staging Classification for Cancer of the Ovary, Fallopian Tube, and Peritoneum:
Abridged Republication of Guidelines From the International Federation of Gynecology and Obstetrics (FIGO). Obstet Gynecol 2015;
126:171–174.
6
2 Staging and surgical treatment of ovarian cancer
Assumed early stage
Complete surgical staging and tumour removal is a

central prognostic factor for patients with ovarian
cancer.
In assumed early-stage ovarian cancer, only thorough

staging surgery can confirm an early stage of disease. No
radiological workup is equally effective.
In advanced ovarian cancer, complete resection of
all visible disease is the most important first step of
treatment and potential cure of the patient.
Complete staging in assumed early-stage ovarian cancer

100 Lymphadenectomy consists of: systematic assessment of the abdominal
cavity, hysterectomy with bilateral salpingo-oophorectomy,
75 No lymphadenectomy omentectomy, appendectomy (in mucinous histology),
Survival (%)
peritoneal mapping, peritoneal washing and systematic

50
pelvic and para-aortic lymphadenectomy.
25
P <0.001
Performance of lymphadenectomy itself is likely
0 to be an individual prognostic factor. Systematic
0 50 100 150 lymphadenectomy results in detection of metastasis
Time (months) in 22% of patients, compared to 9% with lymph-node
Number at risk
No lymphadenectomy 3824 2194 1055 207
sampling only.
Lymphadenectomy 2862 1414 546 97
It is difficult to assess the individual effect of each 1.0

staging procedure. However, several analyses have been .9
published showing potential prognostic effects. Group A Optimal
.8
.7
Performance of systematic peritoneal biopsies, for
example, was shown to be prognostically relevant. .6
.5
Group C No biopsies
In the end, performance of individual surgical steps .4
may just be surrogate parameters for thorough general .3
surgical quality. .2
p=0.003
.1
0.0
12 24 36 48 60 72 84 96 108 120
Overall survival (months)
REVISION QUESTIONS
1. Why should surgical staging be performed in assumed early-stage ovarian cancer?
2. What are the steps of surgical staging in assumed early-stage ovarian cancer?
3. Why is systematic lymphadenectomy especially important?
7
Mahner & Woelber
Fertility-sparing surgery and surgical approach
In case of ovarian cancer confined to one of the ovaries,

Literature review of results of conservative management in
fertility-sparing surgery should be discussed with women epithelial ovarian cancer (7 series reported including >10 cases)
with childbearing potential. Stage l A Grade I Stage l A Grade 2 Stage l A Grade 3 Stage l C Grade I Stage l C Grade 2 Stage l C Grade 3
Italian series 1 recurrence among 3 recurrences among 1 recurrence among No recurrence among 1 recurrence among No recurrence among
Since the overall recurrence rate is higher in fertility- Zanetta el al

Colombo et al
24 patients 8 patients 4 patients 10 patients 6 patients 3 patients
sparing surgery, all patients need to be counselled American series

Schilder et al
2 recurrences among
33 patients
2 recurrences among
6 patients
No recurrence among
3 patients
No recurrence among
5 patients
1 recurrence among
3 patients
No recurrence among
2 patients
accordingly. French series
Morice et al
1 recurrence among
13 patients
4 recurrences among
14 patients
1 recurrence among
3 patients
2 recurrences in
2 patients
No patient 1 recurrence in
1 patient
Bogfeldt et al No recurrence among No recurrence in No patient No patient No patient 1 recurrence in
8 patients 1 patient 1 patient
Several small series have been published on fertility- Park et al 1 recurrence among No recurrence in 4 recurrences in 1 recurrence in 1 recurrence in 2 recurrences in
sparing surgery, suggesting that it might be considered Anchezar et al 1 recurrence among No patient 1 recurrence in No recurrence in No recurrence in No recurrence in
10 patients 1 patient* 3 patients 1 patient 1 patient
an option. Satoh et al 5 recurrences among No recurrence in 2 recurrences in 5 recurrences among No recurrence in 1 recurrence in
Total 11 (5%) recurrences 9 (20%) recurrences 8 (45%) recurrences 8 (8%) recurrences 4 (29%) recurrences 5 (3%) recurrences
among 207 patients among 45 patients among 18 patients among 100 patients among 14 patients among 15 patients
*Patient considered as having a Stage IA Grade 3 tumour after pathological review of the initial tumour at the time of the recurrence.
Open incision surgery is the standard approach for

surgery in presumed early- as well as advanced-stage
ovarian cancer.
Laparoscopy as well as robotic surgery has been

assessed in several smaller series, regarding their
potential to replace open incision surgery, especially for
staging presumed early-stage ovarian cancer.
Methodological limitations prohibit definitive conclusions

regarding the utility of minimal access surgery in this setting.
Given the biology and tumour spread of ovarian cancer,

complete tactile and visual exploration of the abdomen
can only be performed through open surgery.
To avoid under-diagnosis of peritoneal and retroperitoneal

spread and subsequent under-therapy, laparoscopic or
robotic surgical staging of presumed early-stage ovarian
cancer cannot be recommended.
REVISION QUESTIONS
1. In which setting is fertility-sparing surgery an option and should be discussed with the patient?
2. What are the risks of fertility-sparing surgery?
3. What are the potential problems of laparoscopic or robotic staging surgery in presumed early-stage ovarian cancer?
8
Staging and surgical treatment of ovarian cancer
Advanced stages
For optimal surgical assessment and resection of

advanced ovarian cancer, open incision surgery and an
effective retractor system are key prerequisites.
Specialisation of the surgical team, as well as all the other

specialities involved with perioperative patient care, is an
important factor for successful treatment.
Surgery for patients with ovarian cancer, therefore, should
only be performed in specialised centres.
Numerous, mostly retrospective, studies have evaluated

the use of diagnostic laparoscopy to estimate operability.
In some patients it may be possible to predict that they

might not be able to undergo complete cytoreduction.
However, since patients also benefit from suboptimal

debulking, with individual residual disease <1 cm, this
assessment can hardly ever influence therapy decisions.
Diagnostic laparoscopy can be useful in patients with

equivocal findings on initial gynaecological or radiological
workup, as well as history of other malignancies; however, it
may not always predict operability.
This picture shows findings of a premenopausal

woman, with a history of gastric cancer 10 years ago
as well as a strong family history of breast and ovarian
cancer. Histology after diagnostic laparoscopy revealed
metastases of the gastric cancer.
REVISION QUESTIONS
1. Why should patients with ovarian cancer receive surgery in specialised centres?
2. What is the aim of cytoreductive surgery in advanced ovarian cancer?
3. How can a laparoscopy be useful in the workup of patients with suspected ovarian cancer?
9
Mahner & Woelber
Surgical principles in advanced disease
The central aim of all surgical effort in patients with

100%
advanced ovarian cancer should always be complete
HR (95%CI)
gross resection of all visible tumour. This aim can 1-10 mm vs 0 mm: 2.70 (2.37; 3.07)
>10 mm vs 1-10 mm: 1.34 (1.21; 1.49)
be achieved in approximately 2 out of 3 patients in 75%
specialised centres.
% overall survival
50% 0 mm
Patients without residual disease after surgery have

a 5-year survival rate of >60%, whereas those with 25%
1-10 mm
residual tumour have only about a 25% rate of survival.
>10 mm
It is important to note that patients with small residuals log-rank: p <0.0001
0%
(1–10 mm) do have a significantly better survival than 0 12 24 36 48 60 72
Months
84 96 108 120 132 144
those with larger residuals >1 cm. 0 mm N=1046 996 900 773 566 333 147 70 36 19 8 0 0 E=369
1-10 mm N=975 886 689 451 293 157 73 36 18 12 5 0 0 E=653
>10 mm N=1105 933 650 435 247 116 40 15 6 2 0 0 0 E=829
CI, Confidence interval; HR, hazard ratio.
Colon sigmoideum, Mesosigmoideum

Lig. ovarii proprium dextrum
Tuba uterine dextra
Plica epigastrica
(Plica umbilicalis lateralis) Advanced ovarian cancer usually spreads over the
Lig. teres uteri sinistrum
Infundibulum tubae Plica chordae a
umbilicalis (Plica
peritoneum of the pelvis, as well as throughout the
Ovarium sinistrum
Ampulla tubae
uterinae
umbilicalis medialis)
Lig. teres
abdomen.
Plica ureterica uteri dextrum
Plica Chordae urachi

A major principal of surgery in advanced ovarian cancer
recto-uterina
Incisura
Sptium
praeperitoneale
is the extraperitoneal en-bloc resection of the peritoneum
transversalis
recti Cavitas uteri
together with the tumour.
Fornix
vaginae Excavatio
Excavatio
vesico-uterina
Spatium
This figure highlights the peritoneum in green and
recto-uterina
retropubicum
M. levator ani sin.
shows access for the retroperitoneal approach.
Ureter dexter, (M. puborectalis et
Vesica urinaria Fibrae praerectales)
Spatium (septum) Clitoris
rectovaginale
M. levator ani dex.
Spatium (septum)
vesicovaginale
Vagina
Urethra
Diaphragma urogenitale
M. levator ani dex. Labium minus

(M. puborectalis et
Fibrae praerectales)
The respective surgical picture shows an en-bloc

specimen of the uterus, pelvic peritoneum and sigmoid
colon.
At primary surgery for advanced ovarian cancer, the

pelvis can almost always be cleared of tumour with this
approach.
Resection of the sigmoid colon is necessary in about
60%–70% of patients and a continent anastomosis can
usually be placed without a stoma.
REVISION QUESTIONS
1. What is the primary aim of cytoreductive surgery in advanced ovarian cancer?
2. How often can complete cytoreduction be achieved with upfront debulking surgery?
3. What is the major principle of pelvic surgery in advanced ovarian cancer?
10
Surgical principles in advanced disease
Tumour cells and subsequent peritoneal

Recessus subphrenicus
carcinomatosis can spread throughout the abdomen Recessus subphrenicus
dexter superior
sinister superior
with the peritoneal fluid stream. Recessus subphrenicus

sinister inferior
Recessus subphrenicus
All the areas highlighted in green need to be checked dexter inferior
for tumour involvement during surgery and removed if Bursa omentalis
affected. Recessus duodenalis superior
Recessus duodenalis inferior

This again illustrates why open access surgery is the only
Right parietocolic gutter
adequate way to approach ovarian cancer. Recessus paracolici
Recessus ileocaecalis superior

Recessus intersigmoideus
Recessus ileocaecalis inferior
Recessus retrocaecalis
Recessus of pelvic cavity
Large areas of peritoneum are usually resected during

debulking surgery.
The picture shows peritoneal stripping of the left

diaphragm after the liver has been mobilised and
turned over to the right.
In some cases the spleen will also be removed, together

with the omentum. Splenectomy is necessary in about
20% of patients at primary surgery.
Neoadjuvant chemotherapy with interval debulking 100 women with advanced ovarian cancer
surgery (IDS) has been proposed to reduce surgical
morbidity, compared to upfront debulking followed
by adjuvant chemotherapy. However, this comparison
was hampered by the rate of dropouts before IDS.
Neoadjuvant chemotherapy and IDS have been

compared to mainly non-radical upfront debulking in two
prospective randomised trials. Both trials showed no
difference in overall survival between the two approaches.
Since the rate of complete resection in both of these
studies was below 20%, and so far less than can be
achieved with adequate surgical radicality, these results
cannot be used to define routine clinical practice.
Additional trials are needed.
REVISION QUESTIONS
1. What are the abdominal regions that have to be explored during surgery, due to their likelihood of being affected by ovarian cancer?
2. How often is a splenectomy necessary in tumour debulking for advanced ovarian cancer?
3. What are the potential advantages/disadvantages of neoadjuvant chemotherapy in advanced ovarian cancer?
11
Mahner & Woelber
Summary: Staging and surgical treatment of ovarian cancer
• Adequate surgical staging is most important in assumed early-stage ovarian cancer
• Fertility-sparing surgery can be offered under specific circumstances in young patients
• Laparoscopy and robotic surgery have no role in surgical staging of assumed early-stage ovarian cancer
• Complete gross resection is the main objective of surgery in advanced ovarian cancer
• In experienced centres, complete resection can be achieved in the majority of patients
• Multivisceral surgery is often necessary to achieve complete gross resection
• Patients with complete resection in advanced ovarian cancer have a 5-year survival rate of >60%
• Neoadjuvant chemotherapy and IDS currently have no role in ovarian cancer. A possible exception might be
patients with acute medical conditions (i.e. fresh fulminant embolism, heart attack, etc.) who are not fit for extensive
multivisceral surgery
• To assess a possible role of neoadjuvant chemotherapy, trials with adequate surgical radicality are needed
Further Reading
Chan JK, Munro EG, Cheung MK, et al. Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstet Gynecol
2007; 109:12–19.
du Bois A, Reuss A, Harter P, et al; Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom; Groupe
d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. Potential role of lymphadenectomy in advanced ovarian cancer: a
combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin Oncol 2010; 28:1733–1739.
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: by the Arbeitsgemeinschaft Gynaekologische
Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de
l’Ovaire (GINECO). Cancer 2009; 115:1234–1244.
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 2015; 386:249–257.
Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft Dkg, Awmf). S3-Leitlinie Diagnostik, Therapie und Nachsorge maligner
Ovarialtumoren, Langversion 1.1, AWMF-Registernummer: 032/035OL; 2013 (In German). Available at: http://www.awmf.org/uploads/
tx_szleitlinien/032-035m_S3_Maligne_Ovarialtumoren_Diagnostik_Therapie_Nachsorge_2013-06.pdf. Accessed 2 June 2016.
Maggioni A, Benedetti Panici P, Dell’Anna T, et al. Randomised study of systematic lymphadenectomy in patients with epithelial ovarian
cancer macroscopically confined to the pelvis. Br J Cancer 2006; 95:699–704.
Mahner S, Eulenburg C, Staehle A, et al. Prognostic impact of the time interval between surgery and chemotherapy in advanced ovarian
cancer: analysis of prospective randomised phase III trials. Eur J Cancer 2013; 49:142–149.
Morice P, Denschlag D, Rodolakis A, et al; Fertility Task Force of the European Society of Gynecologic Oncology. Recommendations
of the Fertility Task Force of the European Society of Gynecologic Oncology about the conservative management of ovarian malignant
tumors. Int J Gynecol Cancer 2011; 21:951–963.
Rutten MJ, Leeflang MM, Kenter GG, et al. Laparoscopy for diagnosing resectability of disease in patients with advanced ovarian
cancer. Cochrane Database Syst Rev 2014; 2:CD009786.
Timmers PJ, Zwinderman K, Coens C, et al. Lymph node sampling and taking of blind biopsies are important elements of the surgical
staging of early ovarian cancer. Int J Gynecol Cancer 2010; 20:1142–1147.
Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC
Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in Stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363:943–
953.
12
3 Systemic treatment of ovarian cancer
Early- and late-stage disease
In optimally surgically staged patients, there is no significant

Review: Adjuvant (post-surgery) chemotherapy for early-stage epithelial ovarian cancer
overall survival (OS) benefit for adjuvant chemotherapy Comparison: 1 Adjuvant chemotherapy vs. observation
(ChT) (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: Outcome: 6 Progression-free 10-yr survival (sub-grouped by risk)
0.63–2.37), but a subgroup analysis suggests there is for Study or subgroup Log (hazard ratio) Hazard ratio Hazard ratio
those suboptimally staged (HR: 0.63; 95% CI: 0.46–0.85). (SE) IV, Random, 95% CI IV, Random, 95% CI
1 Low/medium
ICON 2003 -0.0408 (0.259) 0.96 (0.58, 1.59)
Adjuvant platinum-based ChT confers an OS benefit
compared to observation for patients with FIGO Stage 1 2 High
ovarian cancer (OC) (HR: 0.74; 95% CI: 0.58–0.95), ICON 2003 -0.6539 (0.2322) 0.52 (0.33, 0.82)
especially in those with higher grade stage early cancers,
i.e. G2/3 Stage 1b/c.
0.1 0.2 0.5 1 2 5 10
Favours chemotherapy Favours observation
There is no good evidence to suggest that addition of
paclitaxel has any benefit in this setting. CI, Confidence interval.
100% res. tum. = 0, FIGO IIB-IIIB

res. tum. >0, FIGO IIB-IIIB
Optimal surgical debulking was defined as ≤1
res. tum. = 0, FIGO IIIC cm residual disease until 10 years ago, when the
res. tum. >0, FIGO IIIC
res. tum. = 0, FIGO IV Gynecologic Cancer InterGroup (GCIG) changed
75%
res. tum. >0, FIGO IV criteria on the basis of compelling retrospective data
which suggested there are incremental benefits in OS
% Overall survival
50% in relation to residual disease <1 cm – so NO residual

disease is the new gold standard.
25% Retrospective analysis of phase III trials has shown that

surgically removing OC, prior to any ChT, to achieve no
log-rank: p < 0.0001 residual disease optimises OS.
0%
0 12 24 36 48 60 72 84 96 108 120 132 144
Phase III randomised studies comparing neoadjuvant chemotherapy

with primary surgery plus adjuvant chemotherapy
Study group EORTC CTU-MRC JCOG All India Institute
Carboplatin plus paclitaxel (TC) is (Vergote) (Kehoe) (Yoshikawa) Medical Sciences
EORTC 55971 CHORUS JGOG0602 (Kumar)
recommended for women with FIGO Stage ID 1473
II-IV OC. TC is non-inferior to cisplatin and Stage Stage IIIC/IV Stage III/IV Stage III/IV Stage IIIC + IVa
Necessity for biopsy/ FNA cytology allowed, Neither biopsy nor cytology Cytology necessary, Either biopsy or
paclitaxel (PT) and associated with better cytology biopsy if possible necessary biopsy allowed cytology is allowed
quality of life (progression-free survival [PFS] Tumour marker CA125/CEA ratio >25 CA125/CEA ratio >25 CA125 >200 U/ml; Normal CEA
CEA <20 ng/ml
~20 months, OS ~48.7–57.4 months). Regimen Platinum + taxane Platinum-based Platinum and taxane Platinum and taxane
Chemotherapy cycles (n) NAC3 total 6 NAC 3 total 6 NAC 4 total 8 NAC 3 total 6
Not every patient is suitable for primary Planned number of 704 150 (Phase II) + 400 (III) 300 180
patients
surgery, due to comorbidities, poor Start date September 1998 March 2004 (Phase III part) November 2006 November 2001
medical condition at presentation or Accrual period 4 years 4 years 3 years 5 years
disease that cannot be entirely surgically Study status Closed 2006 Closed 2011 Open Open
removed. Neoadjuvant ChT and interval Study design Noninferiority Noninferiority Noninferiority Noninferiority
debulking is non-inferior where complete Outcomes

Residual disease <1 cm residual disease: No residual disease: N/A (trial still open) N/A (trial still open)
primary debulking is not possible. PS vs NAC 48% vs 83% 15% vs 35%
Survival at 12 months 89.85% vs 92.51% 70% vs 76% N/A (trial still open) N/A (trial still open)
PS vs NAC
FNA, Fine needle aspiration; NAC, neoadjuvant chemotherapy; PS, primary surgery.
REVISION QUESTIONS
1. How should patients with early FIGO Stage I OC be managed after surgery?
2. How important is surgery in patients with Stage II-IIIC OC?
3. What is the current “gold standard” ChT for Stage II-IV patients?
13
Krell & Hall
Adjuvant options
Weekly paclitaxel with 3-weekly carboplatin is better

100
tolerated and improved OS in a Japanese population. Weekly
Although smaller, different studies (MITO7 and GOG262) Every 3 weeks
have not confirmed this, data from the larger ICON8 trial 75
are awaited.
Overall survival (%)

50
It is not clear whether this is simply due to a slightly
higher overall dose (80 mg/m2 d1, d8, d15 versus 175
mg/m2 d1 every 3 weeks) or because of a theoretical 25
angiogenic action that relates to the weekly scheduling.

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
Time (months from randomisation)
Number at risk
Conventional regimen 319 305 285 266 241 217 199 189 172 161 148 132 108 76 44 21 10 1 0
Dose-dense regimen 312 300 286 272 255 230 213 198 186 171 155 143 118 80 53 21 6 1 0
After primary surgery, the addition of bevacizumab to TC,

ICON7: Overall survival by risk groups and increasing maintenance to 12 months, improves PFS
and OS in those with residual disease (ICON7; HR: 0.64;
1.00
Interaction: p=0.011 95% CI: 0.48–0.85; P=0.002).
0.75 Control, low risk
Questions remain over the role of bevacizumab in OC.
Proportion alive
Research, low risk

Control, high risk
0.50
Research, high risk It is possible that rescheduling paclitaxel to weekly
Low-risk CPP CPB7.5 (from 3-weekly) adds similar antiangiogenic protection
0.25
subgroup
Deaths, n (%)
(n=530)
91 (17)
(n=532)
99 (19)
and is less expensive. The ICON8B trial will hopefully
Median, months
Log-rank test
Not yet reached
p=0.64
answer this question.
HR (95% CI) 1.07 (0.81-1.42)
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Time (months)
CI, Confidence interval; CPB7.5, carboplatin, paclitaxel and bevacizumab 7.5 mg/kg;
CPP, carboplatin, paclitaxel and placebo; HR, hazard ratio.
Tunnelled catheters and ports have improved the ability

to deliver ChT intraperitoneally. These can be placed
surgically or radiologically over the costal margin or
superior anterior iliac crest.
In a meta-analysis of 5 clinical trials, intraperitoneal (i.p.)

administration of ChT offered an OS benefit, particularly in
women with <1 cm or no residual disease postoperatively.
However, these trials did not incorporate current standard
intravenous (i.v.) ChT schedules. Therefore, i.p. ChT is
currently recommended in the clinical trial setting only.
REVISION QUESTIONS
1. How does different scheduling of paclitaxel help in the adjuvant treatment of OC?
2. Which population of patients has an OS benefit for the addition of bevacizumab to carboplatin and paclitaxel?
3. What is the value of i.p. ChT compared to i.v. adjuvant ChT in Stage II-IIIC OC?
14
Systemic treatment of ovarian cancer
Follow-up
Follow-up should include a careful history (35% have

symptoms). Only ~4% have abnormal physical findings; Overall survival - no difference
however, patients find examination reassuring. if treatment delayed until symptomatic
1·00 Median:
61% of patients relapse with rising CA125, but treating Early 25·7 months (95% CI 23·0–27·9)
Proportion surviving
Delayed 27·1 months (95% CI 22·8–30·9)
relapsed OC (ROC) with ChT, where relapse is only 0·75
HR 0·98 (95% CI 0·80–1·20), p=0·85
evident by a rising CA125, has no impact on OS.
0·50
Any benefit of debulking surgery in ROC should be 0·25

considered only where complete cytoreduction can be
0
achieved. The DESKTOP III trial will inform on the value of
0 6 12 18 24 30 36 42 48 54 60
this approach in a subset of good-risk patients. Months since randomisation
Number at risk
Early 265 247 211 165 131 94 72 39 27 22 15
Delayed 264 236 203 167 129 103 69 46 31 25 16
Reasons for follow-up:

Recently abandoned GCIG Classification of Platinum Responsiveness
• Detect curative disease
Classification Definition
• Identify relapse without unnecessary investigations
Progress with an interval of >12 months • Reassure and deal with ongoing toxicity
Platinum Sensitive (PS) after completion of ChT
• Collect research data
Progress with an interval of between 6-12 months
Partially PS (pPS) after completion of ChT • Educate and help patients plan for the future
Progress with an interval of less than 6 months
Platinum Resistant (PR) after completion of ChT 70% of Stage III/IV patients will relapse despite optimal
Progress during, or within 4 weeks surgery and ChT. Response to second-line ChT is
Platinum Refractory (PRef) after completion of ChT dependent on the progression-free interval following
ChT, Chemotherapy. first-line treatment.
Currently the Gynecologic
Cancer InterGroup (GCIG)
categorises patients based on the
length of remission following
platinum-based ChT
The platinum-free interval is, however, somewhat Rechallenge with platinum-based therapy
theoretical and in real life exists as a spectrum.
Extending the platinum-free interval by treating with

maintenance non-platinum therapy, e.g. bevacizumab,
taxanes, hormones, helps improve the patients’ chances
of having a subsequent response to platinum.
Platinum sensitivity is a reasonable “marker” of
homologous recombination defects such as BRCA
mutations.
OS, Overall survival; PFS, progression-free survival.
REVISION QUESTIONS
1. How important is the platinum-free interval and what does it predict?
2. What is the role of follow-up after first treatments for OC patients?
3. Define partially platinum-sensitive recurrent OC.
15
Krell & Hall
Treatment of platinum-sensitive relapsed ovarian cancer
Platinum-sensitive (PS) (52%–61% overall response rate GC + PL GC + BV

[ORR]) and partially platinum-sensitive (pPS) (27%–33% 1.0 (n = 242) (n = 242)
Events, n (%) 187 (77) 151 (62)
Progression-Free Survival
ORR) ROC patients should be re-treated with platinum- Median PFS, months 8.4 12.4
0.8 (95% CI) (8.3 to 9.7) (11.4 to 12.7)
based ChT. Substitute carboplatin with cisplatin to Stratified analysis HR 0.484
(95% CI) (0.388 to 0.605)
mitigate hypersensitivity or offer desensitisation regimen.
(proportion)
0.6 Log-rank P < .0001
Combinations of carboplatin with gemcitabine, pegylated

0.4
liposomal doxorubicin (PLD) or paclitaxel improve PFS
versus carboplatin alone in PS patients. 0.2
In the OCEANS trial, 484 ROC patients (PS and pPS)

0 6 12 18 24 30
received carboplatin and gemcitabine (GC) plus
bevacizumab or placebo. Bevacizumab improved PFS Time (months)
but not OS. No. at risk
GC + PL 242 177 45 11 3 0
GC + BV 242 203 92 33 11 0
BV, Bevacizumab; CI, confidence interval; GC, gemcitabine and carboplatin; HR, hazard ratio;
PL, placebo.
Effect of subsequent treatment on OS in ROC

Comparison of OS between the OCEANS trial,
published in 2012, and the original AGO study of GC in
ROC published in 2006 shows that OS is related to the
number of further lines of treatment beyond relapse.
If patients are fit, efforts should be made to identify or

repeat lines of ChT. Clinical trials of new agents should be
sought for such patients.
BV, Bevacizumab; CI, confidence interval; GC, gemcitabine and carboplatin; HR, hazard ratio;
OS, overall survival; PL, placebo; ROC, relapsed ovarian cancer.
Maintenance olaparib improves PFS among PS ROC 1.0 Hazard ratio, 0.35 (95% CI, 0.25–0.49)
Probability of Progression-free
patients (8.4 vs 4.8 months; HR for progression or 0.9 P<0.001

death: 0.35; 95% CI: 0.25–0.49; P <0.001). Phase III 0.8
trials of PARP inhibitors (PARPi) in this setting are 0.7 Olaparib
currently underway (SOLO, ARIEL). 0.6
Survival
0.5
A preplanned subgroup analysis suggested that olaparib 0.4

0.3
offered greater benefit in patients with a known germline
0.2 Placebo
BRCA mutation (gBRCA).
0.1
No OS benefit was seen with olaparib in either BRCA 0.0
0 3 6 9 12 15
wild-type (HR: 0.99; 95% CI: 0.63–1.55; P=0.96) or BRCA
Months since Randomization
mutation patients (HR 0.73; 95% CI: 0.45–1.17; P=0.19).
Crossover to PARPi occurred in 22%.
REVISION QUESTIONS
1. How do subsequent lines of therapy impact on OS in patients with ROC?
2. What can be offered to patients who have had a hypersensitivity reaction to carboplatin?
3. What is the current indication for PARPi in ROC?
16
Treatment of platinum-resistant ROC
This patient group has a poor prognosis (<1 year);

symptom control and quality of life (QOL) remain the 100
PLD
primary focus. Hormonal therapies such as tamoxifen are 80
GEM
a good treatment option, being active and well tolerated.
OS (%)
60
Single agents such as PLD, gemcitabine or topotecan 40

or combinations of non-platinum therapy such as
20
treosulfan/gemcitabine are advised, as combination P = .048
platinum therapy increases toxicity and offers no OS
0 24 48 72 96 120 144
advantage over single agents.
Time (weeks)
No. of patients at risk
Different scheduling, e.g. weekly paclitaxel, has PLD 50 31 17 11 7 4
been shown to increase PFS. Continuous low doses GEM 51 29 13 3 2 1
(metronomic ChT, e.g. cyclophosphamide) can be
GEM; Gemcitabine; OS, overall survival; PLD, liposomal doxorubicin.
effective in the platinum-resistant setting.
AURELIA investigated the benefit of bevacizumab in

CT BEV + ChT
1.0 (n = 182) (n = 179) patients with platinum-resistant recurrent OC.
Events, n (%) 166 (91%) 135 (75%)
0.8 Median PFS, months 3.4 6.7
95% CI 2.2 to 3.7 5.7 to 7.9 361 patients with platinum-resistant disease received
PFS (probability)
HR (unstratified) 0.48
95% CI 0.38 to 0.60 weekly paclitaxel, PLD or topotecan either alone (ChT)
0.6 Log-rank P value
(2-sided, unstratified)
< .001
or in combination with bevacizumab (BEV+ChT) until
0.4
progression.
0.2 Bevacizumab improved ORR (11.8% vs 27.3%, P = 0.001)

and PFS (HR: 0.48; 95% CI: 0.38–0.60; P <0.001) but no
3.4 6.7
significant OS benefit was seen.
0 3 6 9 12 15 18 21 24
No. at risk
Time (months)
CT 182 93 37 20 8 1 1 0 0
BEV + CT 179 140 88 49 18 4 1 1 0
BEV, Bevacizumab; ChT, chemotherapy; CI, confidence interval; PFS, progression-free survival.
Please circle one number for each line to best show how much that aspect troubled you on
average during the last 3-4 weeks
The aims of therapy in the platinum-resistant setting are: No trouble Mild Moderate Severe Worst I can
at all imagine
• Improvement in QOL and symptoms 1 Pain (all and anywhere) 0 1 2 3 4 5 6 7 8 9 10
• Reduction in tumour burden with possible OS benefit 2 Fatigue (tiredness) 0 1 2 3 4 5 6 7 8 9 10
• Evaluation of potentially active new drugs by 3 Poor appetite (or feeling full quickly) 0 1 2 3 4 5 6 7 8 9 10
participation in clinical trials – current ambitions to 4 Abdominal pain, discomfort 0 1 2 3 4 5 6 7 8 9 10

and/or cramps
include targeted agents alone or in combination (e.g. 5 Abdominal swelling, bloating 0 1 2 3 4 5 6 7 8 9 10
ICON 9, cediranib/olaparib) rather than ChT are exciting. and/or fullness
6 Trouble eating 0 1 2 3 4 5 6 7 8 9 10
The patients’ own assessment of their QOL is vital. 7 Indigestion 0 1 2 3 4 5 6 7 8 9 10
The MOST 10-point symptom benefit scale, specific 8 Nausea 0 1 2 3 4 5 6 7 8 9 10
for OC, is currently being validated to understand the 9 Vomiting 0 1 2 3 4 5 6 7 8 9 10
impact of ChT on symptom control and QOL. 10 Diarrhoea 0 1 2 3 4 5 6 7 8 9 10
REVISION QUESTIONS
1. What are the aims of treatment in patients with platinum-resistant OC?
2. Does bevacizumab improve survival in platinum-resistant recurrent OC?
3. How can changing the scheduling of ChT help those with platinum-resistant ROC?
17
Krell & Hall
Summary: Systemic treatment of ovarian cancer
• Adjuvant single-agent carboplatin should be offered to all women with early-stage (Ib/c) OC
• Primary surgery should be undertaken in preference to neoadjuvant ChT in all patients where complete resection
(leaving no residual disease) can be achieved
• Neoadjuvant ChT and interval surgery can safely be offered to patients when it is not possible to have residual-free
disease after primary surgery
• Adjuvant carboplatin/paclitaxel is the standard of care following surgery (or neoadjuvant therapy)
• Improvements on 3-weekly scheduling have been shown with bevacizumab, dose-dense (weekly) paclitaxel regimens
and i.p. therapy in certain settings
• Patients with platinum-sensitive and partially platinum-sensitive ROC should be offered further platinum-based doublet ChT
• Maintenance PARPi improve PFS in women with platinum-sensitive high-grade serous ROC who have responded to
ChT, particularly in BRCA mutant patients
• Patients with platinum-resistant or platinum-refractory disease should be offered single-agent ChT, such as paclitaxel
or PLD
• Bevacizumab improves PFS in platinum-resistant ROC
• Hormonal therapies could be considered in platinum-resistant ROC
Further Reading
Collinson F, Qian W, Fossati R, et al; ICON1 collaborators. Optimal treatment of early-stage ovarian cancer. Ann Oncol 2014;
25:1165–1171.
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: by the Arbeitsgemeinschaft Gynaekologische
Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de
l’Ovaire (GINECO). Cancer 2009; 115:1234–1244.
Friedlander ML, King MT. Patient-reported outcomes in ovarian cancer clinical trials. Annals Oncol 2013; 24(Suppl 10):x64–x68.
Hall M, Rustin G. Recurrent ovarian cancer; when and how to treat. Curr Oncol Rep 2011; 13:459–471.
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 cancer. Int J Gynecol Cancer 2007; 17:561–570.
Katsumata N, Yasuda M, Isonishi S, et al; Japanese Gynecologic Oncology Group. 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; 14:1020–1026.
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med
2012; 366:1382–1392.
Ozols RF, Bundy BN, Greer BE, et al; Gynecologic Oncology Group. Phase III trial of carboplatin and paclitaxel compared with cisplatin
and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;
21:3194–3200.
Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;
365:2484–2496.
Rustin G, van der Burg M, Griffin CL, et al; MRC OV05; EORTC 55955 investigators. Early versus delayed treatment of relapsed ovarian
cancer (MRC OV05/ EORTC55955): a randomized trial. Lancet 2010; 376:1155–1163.
Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC
Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363:943–953.
18
4 Staging and surgical treatment of
endometrial cancer
Pathology and biology
Endometrial cancer (EC) is one of the most common Breast

cancers worldwide. In Europe it represents the most Colorectum
common gynaecological malignancy. Lung

Corpus uteri
Cervix uteri
The incidence of EC in Europe varies from Ovary
13.5–43.8/100 000, with a mortality rate of Melanoma of skin
2.5–12.4/100 000. Thyroid
Stomach
Non-Hodgkin lymphoma
Kidney
Leukaemia
Pancreas
Brain, nervous system Incidence
Mortality
Bladder
0 20 40 60 80
ASR (W) rate per 100,000
ASR, Age-standardised rate (weighted).

Type I: endometrioid carcinoma
Based on pathogenesis, there are two types of EC.
Type I is related to hyperoestrogenism and is usually

endometrioid with PI3K/AKT and Bcl-2 pathways
involved together with K-RAS mutations and
microsatellite instability.
Type II is non-oestrogen-related, most commonly

represented by serous or a clear cell histopathological
type with high-grade characteristics. Mutations of p53
and HER2/neu are often expressed.
Type II: serous carcinoma
There are several known risk factors for Type I EC:

obesity, diabetes mellitus, nulliparity, polycystic ovary
syndrome and tamoxifen administration. Lynch syndrome
and hereditary non-polyposis colon cancer are other
confirmed risk factors.
Protective factors include the use of oral contraception,
increasing age at menarche, number of delivered children
and smoking.
In Type II cancer, a recent review found similar risk
factors, except for body mass index (BMI: lower), slightly
increased age and hereditary predisposition.
REVISION QUESTIONS
1. Is EC a common cancer in Europe?
2. What is the pathogenesis of EC?
3. Which risk factors play a role in development of EC?
19
Halaska & Rob
Prognostic factors
Several prognostic factors that have an impact on survival Stage I Tumour confined to the corpus uteri
outcome have been described: IA NO or less than half myometrial invasion
• Myometrial invasion IB Invasion equal to or more than half of the myometrium
• Lymph node (LN) involvement Stage II Tumour invades cervical stroma, but does not extend beyond the uterus
• Histological type Stage IIILocal and/or regional spread of the tumour
• Histological grade III A Tumour invades the serosa of the corpus uteri and/or adnexae
• Lymphovascular space invasion status III B Vaginal and/or parametrial involvement
III C Metastasis to pelvic and/or para-aortic lymph nodes
• Tumour diameter over 2 cm
III C1 Positive pelvic nodes
III C2 Positive para-aortic lymph nodes with or without positive pelvic
The updated FIGO staging system from 2009 is lymph nodes
currently used. Stage IV Tumour invades bladder and/or bowel mucosa, and/or distant
metastases
IV A Tumour invasion of bladder and/or bowel mucosa
A categorisation of patients by ESMO-ESGO-ESTRO IV B Distant metastases, including intra-abdominal metastases and/or
2016 guidelines based on the risk of LN metastasis is lymph nodes
a
used for the indication of surgical staging and also for
the indication of adjuvant treatment.
Discordance between pre- and postoperative risk

IA IB II
assessment (low/intermediate/high-risk groups) is about
G1 Low Intermediate High 10% towards upgrading and 29% towards downgrading.
G2 Low Intermediate High Reclassification is more common in Type II cancer.
G3 High-intermediate High High Serous and clear cell cancers are high grade with
different behaviour for metastasising and have a
worse prognosis.
Pre- and intraoperative assessment of depth of invasion
has low sensitivity and specificity. Approximately
20% of Grade 1 tumours have a higher grade on final
histopathological examination.
The actual risks of LN metastasis based on stage and Stage Pelvic metastasis Para-aortic metastasis
grade are presented using Surveillance, Epidemiology,
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3
and End Results (SEER) data from 4052 patients.
Para-aortic metastases in Stage I patients are rare and 15/988 34/1165 16/526 1/988 5/1165 10/526
IA
(1.5%) (2.9%) (3.0%) (0.1%) (0.4%) (1.9%)
usually present together with positive pelvic LNs.
20/288 43/483 36/312 9/288 22/483 24/312
IB
Exact numbers of only para-aortic metastasis are difficult (6.9%) (8.9%) (11.5%) (3.1%) (4.5%) (7.7%)
to find as there are discrepancies in nomenclature of 6/78 17/131 15/81 3/78 11/131 10/81
II
the LN regions and/or the studies do not differentiate (7.7%) (13.0%) (18.5%) (3.8%) (8.4%) (12.3%)
between Type I and Type II cancers.
REVISION QUESTIONS
1. What are the independent prognostic factors for EC?
2. Is preoperative and final risk assessment similar?
3. How high is the risk of positive pelvic LNs in G3 tumours?
20
Staging and surgical treatment of endometrial cancer
Presentation, examination and staging: I
Invasion into outer
half of myometrium
Most cases, especially Type I EC, present as abnormal
vaginal bleeding or discharge. Advanced cases can have
symptoms such as abdominal pain, bowel obstruction or
abdominal bloating.
After suspicion of EC, an ultrasonographic evaluation of

the uterus should be performed.
A cutoff value for endometrial thickness of 3 mm was

found to be most precise to detect carcinoma.
Atypical perfusion
in the tumour
Histopathological confirmation is best performed by dilatation and

curettage (D&C) with hysteroscopic guidance, followed by D&C
alone and then Pipelle aspiration.
Preoperative evaluation of myometrial invasion is important to

assess the risk of nodal involvement. It is usually performed by
ultrasonography and/or magnetic resonance imaging of the pelvis.
Staging of EC is surgical. Most data come from the pivotal

GOG 33 study, which evaluated 1180 women undergoing
complete surgical staging (hysterectomy, bilateral salpingo-
oophorectomy, washings, pelvic and para-aortic LN).
In serous cancers, surgical staging is similar to that of Clinical Stage I Endometrial Cancer
serous epithelial ovarian cancer, including omentectomy
and peritoneal biopsies. BSOH & surgical staging in “high risk” only (serious complications: 13%)
25 patients
Currently, several contradictory algorithms are used to
assess the extent of surgical staging.
No extrauterine disease, n=17 Extrauterine disease, n=8
• No surgical staging: intermediate/high-risk patients have
external beam radiotherapy (EBRT) to the pelvis
• Staging for all: EBRT or chemotherapy in LN-positive 11 low risk 6 high risk 5 pelvic nodes only 3 PA nodes
/other sites
patients 11 no RT
• Staging only for high-risk patients (currently most widely 11 pelvic RT ± ChT Tailor treatment:
± ChT/RT
accepted)
BSOH, Bilateral salpingo-oophorectomy and hysterectomy; ChT, chemotherapy; PA, para-aortic;
RT, radiotherapy.
REVISION QUESTIONS
1. Which method is preferred for diagnosis and evaluation of myometrial invasion?
2. Which method should be used for histopathological confirmation of EC?
3. Name one of the most important studies in EC staging.
21
Halaska & Rob
Staging: II
No consensus with high level of evidence exists regarding

surgical staging. 1·0
Overall survival
HR=1·16 (95% CI 0·87–1·54); p=0·31
0·9
A randomised trial with 1408 patients (ASTEC study) 0·8
found no difference in survival; however, several 0·7
flaws in the study have been reported, including
Proportion alive
0·6
an insufficient number of LNs harvested and 0·5
discrepancies in the randomised groups. Moreover, 0·4
adjuvant treatment (AT) was not directed by the results 0·3
of LN status. 0·2
Events Totals
0·1 Standard 88 704
Lymphadenectomy 103 704
Similar results have been confirmed in the Italian LINCE 0
study with 514 patients. 0 1 2 3 4
Years from randomisation
5 6

Number at risk
Standard 704 614 488 317 214 119 33
Contrary
Lymphadenectomy 704
to these
620
studies,
489
the
327
SEER 211
analysis116of 69
56 360 patients showed improvement of prognosis in

low-risk patients with pelvic lymph node dissection
(LND). However, no information on the influence of
comorbidities was recorded and changes of treatment
over the time were found.
A randomised trial (LYTEC) will evaluate the real value

of lymphadenectomy and, by merging with other trials
(AFTER 4, ENGOT EN2 and GOG 0258 and 0249), will
combine the results with AT.
The frequently cited Japanese SEPAL study (671

patients) reported significant improvement in
overall survival in the para-aortic LND group, but its
retrospective design, different population and AT bias
LND, Lymph node dissection. are obvious, making this trial unusable.
Detection of sentinel lymph node (SLN) involvement in

EC is not yet standardised and the detection rate varies
greatly between 45% and 100%. Nevertheless, it does 100
attract extensive research interest, as it could replace the

need for systematic LND. 80
Several SLN mapping techniques have been described:

Survival (%)
60
(a) cervical injection, (b) subserosal injection,
(c) combination of cervical and subserosal injection, 40
and (d) hysteroscopic subendometrial injection. Pelvic lymphadenectomy in low-risk patients

20 Pelvic and para-aortic lymphadenectomy in low-risk patients
Ultrastaging can detect micrometastases undiagnosed by Pelvic lymphadenectomy in intermediate-risk and high-risk patients
Pelvic and para-aortic lymphadenectomy in intermediate-risk and high-risk patients
regular histology in approximately 41% of all positive LN. 0
The clinical relevance of micrometastatic disease is under 0 1 2 3 4 5 6 7 8 9 10
Time (years)
investigation, but some reports found a worse prognosis
in the case of micrometastasis.
REVISION QUESTIONS
1. Are there prospective studies on staging and what are the major findings?
2. Is SLN mapping standardised and which techniques are used?
3. Can ultrastaging help in the staging of the disease?
22
Staging: III
The choice of optimal surgical approach (open,

laparoscopic, robotic) is currently under intense debate. Age < 65
(Recur/Patients) Rel Haz Var[ln(HR)]
(118/1,449) 1.321 0.041
Laparoscopy Better Laparotomy Better
One of the issues is the age of the patients and especially Age > 65 (188/1,067) 1.056 0.024
FIGO-09 Stage 1A (102/1,732) 1.492 0.050
their BMI, which is typically extremely high and poses a FIGO-09 Stage 1B (44/314) 1.374 0.115
FIGO-09 Stage 2 (18/99) 0.836 0.235
significant obstacle to surgery. FIGO-09 Stage 3A (14/64) 0.660 0.293
FIGO-09 Stage 3C1 (34/117) 1.529 0.151
FIGO-09 Stage 3C2 (41/109) 0.996 0.103
A prospective, randomised study (LAP2) of 1696 FIGO-09 Stage 4B (48/67) 1.593 0.092
Endometrioid (152/2,023) 1.248 0.031
patients evaluated complications and survival outcome Clear Cell (12/42) 0.360 0.348
of EC patients who underwent laparoscopic surgery Mixed Epithelial

Sarcoma
(19/74)
(40/87)
0.857
1.063
0.226
0.110
versus those who had a laparotomy. Serous

No Myo Inv
(82/289)
(59/971)
1.087
1.307
0.058
0.098
< 50% Myo Inv (97/934) 1.507 0.052
> 50% Myo Inv (154/594) 1.003 0.028
Less postoperative complications (14% vs 21%, No Lymph Inv

Lymph Inv
(162/1,993)
(138/486)
1.014
1.343
0.027
0.035
P <0.0001) but longer operating time (204 vs 130 min, 0.20 0.5 0.67 1.0 1.5 2.0 2.5
P <0.001) were observed in the laparoscopic group. Relative Hazard
No difference in progression-free survival and overall
survival was seen at 59 month follow-up, making Inv, Invasion; Myo, myometrial; Recur, recurrence; Rel Haz, relative hazard; Var[In(HR)], variance
of the log treatment hazard ratio estimate.
laparoscopy a preferable approach.
Robotic surgery has rapidly evolved in recent years and

has shown similar results to laparoscopic approaches
with respect to complications and hospital stay, but these
techniques have not been compared in prospective studies.
The advantage of robotic surgery seems to be a shorter
learning curve and it is more effective in obese patients.
In a large retrospective study (3947 patients) evaluating

BMI and outcome, 38% of patients had a normal
BMI, 38% were obese and 24% were morbidly obese.
48% of patients underwent laparoscopy and 52%
laparotomy.
Morbidly obese patients were more likely to develop

postoperative complications: 16%, vs 13% normal BMI
vs 11% obese (P = 0.001). This significant difference
was seen after laparotomy but not after laparoscopy.
ASA, American Society of Anesthesiology Classification; BMI, body mass index;
WBC, white blood cell.
The impact on pre- and postoperative morbidity of the Hysterectomy with bilateral salpingo-oophorectomy +
combination of surgery and AT should be taken into Staging No
account in future trials. Staging RT
+ RT staging
Number 100 12 100 25
Complication (%) 6 13 <1 3
RT, Radiotherapy.
REVISION QUESTIONS
1. Describe the results in the LAP2 study.
2. Does BMI influence the complication rate?
3. Is there a role for robotic surgery?
23
Halaska & Rob
Summary: Staging and surgical treatment of endometrial cancer
•E
C is one of the most common cancers in developed countries
•P
reoperative work-up includes imaging and histopathological diagnosis (ideally via D&C) to determine the extent of
surgical staging
•P
lanning for surgery uses preoperative histopathological type, grade and assessment of myometrial invasion
•N
o consensus has been reached regarding the impact of staging on AT, while the potential therapeutic role of LND has
never been proven
•L
ow-risk patients do not benefit from pelvic and para-aortic LND
• In intermediate- and high-risk patients with higher risk of LN involvement, pelvic (and para-aortic) LND will help to guide
the necessity for and tailor the type of AT
•P
rospective randomised data show that laparoscopic surgical staging for uterine cancer results in fewer complications
and shorter hospital stay with equivalent oncological outcome
•S
LN techniques have shown promising results in various prospective and retrospective trials and appear to be the
future approach. The exact method and technique remains to be defined
Further Reading
Barton DP, Naik R, Herod J. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC Trial): a randomized
study. Int J Gynecol Cancer 2009; 19:1465.
Chino JP, Jones E, Berchuck A, et al. The influence of radiation modality and lymph node dissection on survival in early-stage
endometrial cancer. Int J Radiat Oncol Biol Phys 2012; 82:1872–1879.
Colombo N, Creutzberg C, Amant F, et al: ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment
and follow-up. Ann Oncol 2016; 27:16–41.
GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available at: http://globocan.iarc.fr/Default.
aspx. Accessed 4 June 2016.
Katsoulakis E, Mattes MD, Rineer JM, et al. Contemporary analysis of pelvic and para-aortic metastasis in endometrial cancer using the
SEER registry. Int J Gynaecol Obstet 2014; 127:293–296.
Lewin SN, Herzog TJ, Barrena Medel NI, et al. Comparative performance of the 2009 International Federation of Gynecology and
Obstetrics’ staging system for uterine corpus cancer. Obstet Gynecol 2010; 116:1141–1149.
Mahdi H, Jernigan AM, Aljebori Q, et al. The impact of obesity on the 30-day morbidity and mortality after surgery for endometrial
cancer. J Minim Invasive Gynecol 2015; 22:94–102.
Morrow CP, Bundy BN, Kurman RJ, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II
carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991; 40:55–65.
Naoura I, Canlorbe G, Bendifallah S, et al. Relevance of sentinel lymph node procedure for patients with high-risk endometrial cancer.
Gynecol Oncol 2015; 136:60–64.
Robova H, Rob L, Halaska MJ, et al. Current status of sentinel lymph node mapping in the management of endometrial cancer. Expert
Rev Anticancer Ther 2013; 13:55–61.
Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for
comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 2012; 30:695–700.
24
5 Non-surgical treatment of endometrial cancer
Adjuvant radiation therapy
New risk groups to guide adjuvant therapy use

A definition of risk groups to identify postoperative
patients with uterine cancer at risk of recurrence who Risk group Description LOE
may benefit from adjuvant therapy has been devised by Low Stage I endometrioid, grade 1-2, <50% myometrial I
an ESMO-ESGO-ESTRO consensus panel (2015). invasion, LVSI negative
Intermediate Stage I endometrioid, grade 1-2, ≥50% myometrial I
invasion, LVSI negative
External beam radiotherapy (EBRT, ± brachytherapy) High-intermediate Stage I endometrioid, grade 3, <50% myometrial I
may be an option for high-risk patients with endometrioid invasion, regardless of LVSI status
histology to maximise local control. In patients with Stage I endometrioid, grade 1-2, LVSI unequivocally II
non-endometrioid histology, consider adjuvant platinum positive, regardless of depth of invasion
High Stage I endometrioid, grade 3, ≥50% myometrial I
chemotherapy. Vaginal brachytherapy may be offered for invasion, regardless of LVSI status
Stage 1A. Stage II I
Patients who relapse locally and have never had pelvic Stage III endometrioid, no residual disease I
radiotherapy (RT) can be salvaged by using RT. Thus the Non-endometrioid (serous or clear-cell or I
undifferentiated carcinoma, or carcinosarcoma)
majority of patients (who do not relapse locally) can be
Advanced Stage III residual disease and Stage IVA I
spared the toxicity of pelvic RT. Metastatic Stage IVB I
LOE, Level of evidence; LVSI, lymphovascular space invasion.
Cochrane Meta-analysis of 8 clinical trials (n = 3628) A Cochrane meta-analysis of 8 clinical trials (n=3628)
Overall Survival Locoregional Control confirmed that adjuvant pelvic RT has no benefit on
overall survival.
All trials of adjuvant pelvic RT included in the Cochrane

review confirmed that RT confers (statistically)
significantly better local control (hazard ratio: 0.36).
Overall trial populations are representative of prevalence

of uterine cancer, including low- and high-risk early stage
patients, with and without surgical lymphadenectomy.
Long Term Outcomes after External Beam Radiation (EBRT)

for Early Stage Endometrial Cancer Oslo Trial – revisited!
40-year follow-up of younger patients (<60 years at Overall survival <60 years of age at treatment
100
Cumulative percentage (%)
time of diagnosis) in the Oslo trial was performed as a 75

logrank p=0.013
post-hoc analysis. Data suggest significantly inferior 50 Control
survival in the patients who received RT. 25
EBRT
0
The risk of developing a second malignancy doubled in 0 10 20 30 40
Number at risk Analysis time (years)
the patients who received RT. Control 140
EBRT 155
122
130
103
102
70
55
13
7
Currently there is no evidence that intensity-modulated Risk of secondary cancer <60 years of age at treatment
1-cumulative incidence (%)
100
radiation therapy (IMRT) is better than standard conformal logrank p=0.002
75
EBRT, but the TIME-C clinical trial is set to evaluate
50
the differences in toxicity and outcome between both Control
EBRT
25
techniques.
0
0 10 20 30 40
Number at risk Analysis time (years)
Control 130 118 94 62 11
EBRT 134 111 80 42 5
EBRT, External beam radiation therapy.
REVISION QUESTIONS
1. Does adjuvant pelvic RT improve survival?
2. What are the benefits of adjuvant pelvic radiation in patients with early endometrial cancer (EC)?
3. Can radiation-naïve patients be salvaged with RT at the time of relapse?
25
Mirza
Adjuvant radiation and chemotherapy
Several trials comparing RT alone versus RT plus Phase III trials of adjuvant radiotherapy with chemotherapy
chemotherapy (ChT) have been unable to show any GOG 34 Finnish Study GOG 184 NSGO9501/ILAIDE
benefit for the addition of ChT. Morrow et al Kuoppala et al Honeslay et al Hogberg et al
Population 1A-B, G3
1-3 3-4 1-3
(Stage) 1C-3A
These trials are criticised for having either good
n 181 157 586 534
prognosis patients or insufficient ChT, or both. RT (split)
RT RT/AP6 RT
Regimen CEP/RT/CEP/
RT/Doxo8 RT/TAP6 RT+ChT
NSGO9501 demonstrated an improved progression RT/CEP
free-survival (PFS). The study was not powered to show 69
PFS – NS NS 78
an overall survival (OS) difference. HR 0.63
HR 0.69
OS NS NS –
NS
Cancer-
HR 0.55
specific – – –
Ad hoc
survival
ChT, Chemotherapy; HR, hazard ratio; NS, not significant; OS, overall survival;
PFS, progression-free survival; RT, radiation therapy.
Randomised Trial of Radiation Therapy With or Without

Chemotherapy for Endometrial Cancer PORTEC-3 recruited patients with Stage IB-IIIC EC,
PORTEC-3 randomised to pelvic RT alone versus chemoradiation plus
NCT00411138 ChT. Follow-up is ongoing and final results are awaited.
Enrollment completed
n=670
Preliminary toxicity results have revealed that RT + ChT
Stage IA with invasion, grade 3 with Radiation + Chemotherapy is feasible; the only persistent toxicity is taxane-related
documented LVSI Pelvic radiation plus 2 concurrent
Stage IB grade 3 cycles cisplatin followed by 4 adjuvant peripheral neuropathy.
Stage II cycles carboplatin and paclitaxel
Stage IIIA or IIIC; or IIIB if parametrial +/- Brachytherapy
invasion only Neither this trial nor NSGO9501 included women who
Stage IV (with invasion), IB, II or III with
serous or clear cell histology
Pelvic Radiation alone had surgical lymphadenectomy, which will make it difficult
+/- Brachytherapy
to extrapolate results to this group.
LVSI, Lymphovascular space invasion.
1.0
Type 2 (serous and carcinosarcomas) uterine cancers
have a tendency to early distant spread. EBRT may be
ChT +/- RT
considered to improve local control, though it does not 0.8
influence OS.
Cumulative survival
RT alone
0.6
Survival benefits have been shown for adjuvant ChT
(and RT) in patients with serous uterine cancers, but OBS
the evidence is controversial as this improvement 0.4
was not seen in meta-analysis. Results of the GOG
phase III trial comparing cisplatin–ifosfamide versus
0.2
carboplatin–paclitaxel are awaited.
p=0.001
Although small, the differences in rates of recurrence 0.0
of serous uterine cancer are important, as 88% are
0.0 20.0 40.0 60.0 80.0 100.0
incurable and the majority die within a year. Progression-free survival
ChT, Chemotherapy; OBS, observation; RT, radiation therapy.
REVISION QUESTIONS
1. What are the explanations for the lack of benefit in patients treated with adjuvant ChT in the management of uterine cancer?
2. Define a relevant population of patients with uterine cancer where adjuvant ChT should be evaluated in a randomised trial.
3. How do you treat high-risk early stage disease?
26
Non-surgical treatment of endometrial cancer
Chemotherapy for metastatic disease
A phase III randomised trial has proven both improved Phase III trials in advanced/metastatic disease
PFS and OS where patients with relapsed Stage III and Radiotherapy vs doublet
Single agent vs doublet
IV uterine cancer are treated with ChT. chemotherapy
GOG EORTC55872 GOG 107
Combination (doublet) ChT is superior to single-agent Randall et al Van Wijk Thigpen
Population Stage 3-4 Stage 3-4
treatment, but toxicity is greater. (Stage)
III-IV
& relapsed & relapsed
n 396 177 299
Surgery for recurrent Stage III/IV uterine cancer can WART Dox vs Dox vs
Regimen
be advantageous if resection is complete (no residual A60 P50 X 8 Dox-Cisplat Dox-Cisplat
disease). PFS
Signif
NS
Signif
HR 0.71 HR 0.73
Signif
OS NS NS
HR 0.68
Cisplat, Cisplatin; Dox, doxorubicin; HR, hazard ratio; NS, not significant; OS, overall survival;
PFS, progression-free survival.
Phase III trials in advanced/metastatic disease

Doublet vs doublet Doublet vs triplet
GOG GOG
Fleming (Ann Onc ’04) Fleming (JCO ’03)
Comparison of two different doublets (doxorubicin–
Population cisplatin versus doxorubicin–paclitaxel) demonstrated
Stage 3-4 & relapsed Stage 3-4 & relapsed
(Stage) equal efficacy.
n 317 273
Dox-Cisplat Dox-Cisplat Although triplet therapy (doxorubicin–cisplatin–taxol)
Regimen vs vs
Dox-Paclitax Dox-Cisplat-Tax
improved PFS and OS compared to carboplatin–
Signif paclitaxel alone, it was too toxic and resulted in
PFS NS
P <0.01 excess mortality.
Signif
OS NS
P <0.037
Ann Onc, Annals of Oncology; Cisplat, cisplatin; Dox, doxorubicin; JCO, Journal of Clinical
Oncology; NS, not significant; OS, overall survival; Paclitax; paclitaxel; PFS, progression-free
survival.
Phase III trials in advanced/metastatic disease

TAP vs TC
GOG 209 compared triplet versus doublet therapy and GOG 209
confirmed non-inferiority for carboplatin and paclitaxel Miller
with distinct toxicity advantages, establishing it as Population
Stage 3-4
(Stage)
standard first-line therapy.
n 1312
Carbo-Tax
Further benefit is unlikely to arise from conventional ChT. Regimen vs
Evaluation of different therapeutic strategies (e.g. targeted Dox-Cisplat-Tax
therapy) will be needed to improve patient outcomes. PFS Equal
OS Equal
Cisplat, Cisplatin; Dox, doxorubicin; OS, overall survival; PFS, progression-free survival;
TAP, doxorubicin/cisplatin/paclitaxel; Tax, paclitaxel; TC, carboplatin/paclitaxel.
REVISION QUESTIONS
1. How would you treat a patient with disseminated serous adenocarcinoma of the uterus?
2. Considering treatment-related toxicity and efficacy, which regimens are available and which would you choose for your patient?
3. Suggest a clinical trial to improve the outcome of EC patients
27
Mirza
Endocrine therapy for Type 1 (endometrioid) endometrial cancer
Multiple clinical trials and a meta-analysis exploring the

Adjuvant hormonal therapy
potential benefits of hormone treatments adjuvantly
in high-risk EC do not show any benefit. Endocrine • Systematic review of 9 randomised trials
therapy is not recommended as postoperative adjuvant
treatment. • The available evidence does not demonstrate any benefit for
adjuvant hormonal therapy
Likewise hormone replacement therapy (HRT) is
NOT recommended in patients with endometrioid • The use of hormonal therapy is not recommended as
adenocarcinoma of the uterus, although it may adjuvant treatment
be considered if the patient is oestrogen receptor/
progesterone receptor (ER/PR) negative.
Hormone studies by treatment type grouping Endocrine therapy is recommended in advanced/

Hormone Studies Number RR mean PFS mean recurrent disease.
Progestogens 8 1303 23 7.5
Progestogens are most commonly used, e.g. megestrol
SERMs 7 319 29.8 4.9 acetate (Megace 160 mg day) or medroxyprogesterone
Combinations 3 136 25 4.6
acetate (Provera 200 mg day). Approximately 30% of
patients will respond, some for many years.
Aromatase inhibitors 2 55 10 8.8
GnRH analogues 5 143 28.8 NS There is a greater likelihood of response if the tumour
is ER/PR positive. Other hormonal agents such as
Others 1 25 0 NS
aromatase inhibitors, tamoxifen, and gonadotrophin-
GnRH, Gonadotrophin-releasing hormone; PFS, progression-free survival; RR, relative risk;
SERM, selective oestrogen receptor modulator.
releasing hormone (GnRH) analogues are also active.
A randomised, double-blind, placebo-controlled, phase III trial of palbociclib

in combination with letrozole versus placebo with letrozole for patients with
oestrogen receptor positive recurrent endometrial cancer.
Clinical trials are needed to incorporate emerging
ENGOT-EN3-NSGO/PALEO
knowledge from molecular genetics to endocrine therapy. NCT02730429
Randomisation: 1:1 ARM A
The ENGOT-EN3/PALEO double-blind, placebo- Endometrial cancer N=190 Letrozole 2.5 mg d1-28 every 28 days
Placebo d1-21 every 28 days
controlled, phase III randomised trial is evaluating the Primary Stage 4
or relapsed Until progression
efficacy of letrozole with or without palbociclib. disease Randomise
ER-positive ARM B
Preclinical data indicate that high expression of cyclin endometrioid Letrozole 2.5 mg d1-28 every 28 days
adenocarcinoma Palbociclib 125 mg d1-21 every 28 days
A is associated with poor prognosis in endometrial Until progression
endometrioid adenocarcinomas. CDK4/6 inhibitors in
Stratification:
combination with endocrine therapy may be a promising • Number of prior lines of therapy (primary advanced disease vs 1st relapse vs ≥2 relapses)
• Measurable vs evaluable disease
therapy. • Prior use of MPA/Megace (prior MPA/Megace use capped to a maximum of 50%)
ER, Oestrogen receptor; MPA, medroxyprogesterone acetate.
REVISION QUESTIONS
1. Which patient population at early-stage disease would you treat with adjuvant hormonal therapy?
2. What is your first choice of hormonal therapy for ER-positive metastatic disease?
3. Does hormonal therapy improve survival in metastatic EC?
28
Targeted therapy and future directions
The Cancer Genome Atlas has identified four molecular

subtypes of EC: microsatellite unstable, ultra-mutated
(POLE), high copy number, and others without any of
these features.
In EC, mutations frequently alter the PI3K/AKT and

the RAS-RAF-ERK-MERK signalling pathways.
Homologous recombination and mismatch repair
deficiencies are associated with Lynch syndrome.
Although there are multiple targets in EC, the frequency

of each abnormality is small, presenting a significant
challenge in evaluating novel therapies.
MITO END-2 trial

Primary PFS analysis
Antiangiogenic therapy is a promising area for clinical trials
Standard Exp in EC, and is being evaluated in recurrent disease.
100
ChT ChT-B
(N=54) (N=54)
80 The MITO END-2 phase II randomised trial
Events, n 34 32
60 Median PFS, 8.7 13
demonstrated a statistical improvement in median PFS
PFS (%)
months (95% CI) (6.3-11.2) (9.2-16.8) (13 vs 8.7 months) for the addition of bevacizumab.
40 HR (stratified)
0.59
(95% CI)
(0.35-0.98)
20 2-sided log-rank
0.036 The ENGOT-EN1 randomised trial is evaluating the
p-value
0 efficacy of nintedanib (anti-vascular endothelial growth
0 3 6 9 12 15 18 21 24
Months
factor [VEGF] tyrosine kinase inhibitor) in this population.
ChT, Chemotherapy; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
Clinical trials with biopsies for biomarkers are needed to 1.0 CD8+/FoxP3+ ratio
explore the benefit of genetic findings. PI3 kinase and High ratio
mTOR inhibitors are worthy of further evaluation in EC. 0.8 Low ratio
Basket studies – with patients divided into cohorts on
Cumulative survival
the basis of histological / molecular features – may 0.6

be warranted, e.g. checkpoint inhibitors, active in
microsatellite instability (MSI)-associated colorectal 0.4
cancers, may be useful in MSI-related EC.
0.2
The immune system is important in EC. Relapsed EC
patients had a longer survival when the CD8+/FoxP3+
0.0 P=0.007
ratio was high.
0.0 1.0 2.0 3.0 4.0 5.0
Disease-free interval (years)
REVISION QUESTIONS
1. How would you interpret the recent preclinical advances?
2. Would you use bevacizumab as standard of care?
3. What have you learned from this chapter?
29
Mirza
Summary: Non-surgical treatment of endometrial cancer
• Adjuvant EBRT/vaginal brachytherapy does not improve survival and improvements in local control are at the cost
of toxicity
• Adjuvant EBRT with chemotherapy may improve PFS, although trials are needed in a correctly defined high-risk
population
• Adjuvant ChT does not improve survival in endometrioid uterine cancer, although trials are ongoing in the high-risk
population
• Adjuvant endocrine therapy does not improve survival
• ChT does improve survival in metastatic disease
• Endocrine therapy may be beneficial in a subgroup of patients with metastatic endometrioid uterine cancer
• Clinical trials are required to fully evaluate targeted and biological therapies
Further Reading
Bradford LS, Rauh-Hain JA, Schorge J, et al. Advances in the management of recurrent endometrial cancer. Am J Clin Oncol 2015;
38:206–212.
Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497:67–73.
Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment
and follow-up. Ann Oncol 2016; 27:16–41.
Kong A, Johnson N, Kitchener HC, Lawrie TA. Adjuvant radiotherapy for stage I endometrial cancer: an updated Cochrane systematic
review & meta-analysis. J Natl Cancer Inst 2012; 104:1625–1634.
Onsrud M, Cvancarova M, Hellebust TP, et al. Long-term outcomes after pelvic radiation for early-stage endometrial cancer. J Clin Oncol
2013; 31:3951–3956.
30
6 Staging and surgical treatment of cervical cancer
Pathological staging
Stage IA (category T1a) is an invasive carcinoma which is

diagnosed only by microscopy with a maximal depth of stromal
invasion of 5.0 mm and a maximal horizontal spread of 7.0 mm. IA2 IA1
5 mm
3 mm
There are two substages according to the depth of stromal invasion:
less than 3.0 mm (Stage IA1) and between 3.0 and 5.0 mm (Stage IA2).
Stage IB is a clinically visible tumour confined to the cervix or greater
than IA2. It has two substages, according to the greatest dimension:
less than 4.0 cm (Stage IB1) or bigger (Stage IB2).
Stage II tumour invades either the proximal two-thirds of the

vagina, with the greatest dimension of 4.0 cm (Stage IIA1) or larger
(Stage IIA2), or to the parametria (Stage IIB).
IIB
Stage T3a tumour invades the lower one-third of the vagina.
Stage T3b either reaches the pelvic wall or causes hydronephrosis or
a non-functioning kidney.
IIA
Stage T4 tumour invades either the full wall thickness of the bladder
or rectum or it extends beyond the pelvis.
Regional lymph nodes (LNs) for cervical cancer are pelvic nodes
including the: paracervical, parametrial, internal iliac (II), obturator
(OB), common iliac (CI), external iliac (EI) and presacral (PS). FIGO stages TNM categories
Involvement of para-aortic (PA) or inguinal LNs is considered distant Stage IIIB T1, T2, T3 N1 M0
metastasis.
Stage IVA T4 Any N M0
Involvement of regional LN is classified as FIGO Stage IIIB-IVB. Stage IVB Any T Any N M1
FIGO, International Federation of Gynecology and Obstetrics;
TNM, tumour node metastasis.
REVISION QUESTIONS
1. What is the maximal depth of cervical stromal invasion in Stage IA2?
2. How is Stage IB2 characterised?
3. Are inguinal nodes regional LN in cervical cancer?
31
Cibula
Clinical staging
In pre-treatment (clinical) staging, obligatory examinations

Obligatory examinations Facultative examinations
should include a gynaecological examination, an
ultrasound of pelvis and upper abdomen and a chest X-ray. Gynaecological examination Chest and abdominal CT scan
In local staging, cystoscopy, rectoscopy and intravenous Chest X-ray Whole-body MRI
urography should be replaced by one of the accurate
modern imaging modalities, such as pelvic magnetic Pelvic MRI or transvaginal / PET scan
transrectal ultrasound
resonance imaging (MRI) or ultrasound.
CT, Computed tomography; MRI, magnetic resonance imaging;
PET positron emission tomography.
In locally advanced stages, a computed tomography
(CT) scan, whole-body MRI or positron emission
tomography (PET) scan should be performed to
exclude distant metastasis. However, in evaluation
of LN involvement, CT, MRI and PET-CT have
demonstrated disappointing accuracies.
LN involvement is the most significant prognostic

parameter in the early stages of cervical cancer.
Oncological outcome is related to the number of
positive pelvic LNs.
The size of the tumour and its stage are closely related
prognostic parameters, together with the depth of cervical
stromal invasion.
Although FIGO IB substaging is based on the size of
4 cm, a better criterion for oncological outcome after
surgical treatment seems to be a tumour dimension of
2 cm or a deep ( >two-thirds) stromal invasion.
Overall survival and

event-free survival
according to FIGO stage LN status (N=645)
and LN status combining results from
SLN ultrastaging and pelvic
non-SLN staging
The prevalence of LN involvement increases with the Stages IA IB1 IB2 IIAB P value
stage of the disease. N° of patients 55 477 58 55
Involvement of para-aortic LNs significantly worsens Macrometastasis 9% 20% 24% 44%

prognosis.
Micrometastasis 4% 6% 12% 13% <0.0001
Additional prognostic parameters include: parametrial
involvement, lymphovascular space invasion (LVSI) Isolated tumour cells 4% 4% 5% 6%
and histological type (a better prognosis for squamous LN, Lymph node; SLN, sentinel lymph node.
cell cancer).
REVISION QUESTIONS
1. Which two modern imaging methods should be used for local preoperative staging?
2. What is the most significant prognostic parameter in the early stages?
3. Is the grading of a tumour an important prognostic parameter in cervical cancer?
32
Staging and surgical treatment of cervical cancer
Surgical procedures
The principle of radical hysterectomy (RH) is removal of

tissue surrounding the cervix (parametrium) ± the
upper part of the vagina in addition to the uterus with
or without adnexa.
If the aim is to preserve fertility, the distal part of the

cervix, with the upper part of the vagina, is removed either
with the parametrium (radical trachelectomy) or without it
Simple hysterectomy
(simple trachelectomy). Radical hysterectomy
Simple trachelectomy
Radical parametrectomy combined with upper
Radical trachelectomy
vaginectomy can be performed in women after a simple Radical parametrectomy
hysterectomy, aiming at completion of the extent of
standard surgical procedure.
1.0 Postoperative morbidity is caused mostly by the

resection of the parametria and upper vagina.
One minus cumulative survival
0.8 Morbidity prevalence and severity correspond to

log-rank p-value <<0.05 the radicality of parametrial resection (RH).
0.6
III + nerve sparing
+ censored Voiding dysfunctions, such as incomplete bladder
0.4
II emptying, loss of bladder sensation, incontinence and a
+ censored
0.2
need to use straining to void, are side effects that affect
III 10%–50% of patients.
+ censored
0.0
0 10 20 30 Anorectal dysfunctions, mostly constipation and flatal
Immediate postoperative periods (days) incontinence, occur in 10%–30%. Lymphoedema
Event = resuming bladder function = ability to void and pelvic lymphocoeles occur in up to 30%, as a
spontaneously and post-voiding residual > 100 cc consequence of pelvic lymphadenectomy (PLN).
Postoperative recovery
of spontaneous voiding
according to the extent
of parametrial resection
The standard procedure for LN staging is a

systematic PLN.
PLN should include the removal of lymphatic tissue

from the following regions: EI, CI, II, OB, and PS.
Para-aortic lymphadenectomy can be performed for
staging purposes, before pelvic radiotherapy, but its
prognostic significance has not yet been confirmed.
REVISION QUESTIONS
1. What is the principle of RH?
2. What is the most prevalent type of morbidity after RH?
3. Which LN should be removed for LN staging?
33
Cibula
Treatment of early stages
A sentinel lymph node (SLN) biopsy followed by

Overall survival
pathological ultrastaging allows the detection of small ITC
metastases and micrometastases in about 10%–15% of 1.0
Neg
patients with early stages.
Proportion of surviving
0.9 MIC
In a retrospective study, it was shown that the detection MAC

0.8
of any micrometastases (0.2–2.0 mm) is associated with p<0.001
a decreased overall survival. 0.7
SLN ultrastaging (complete SLN processing in 150–250 μm) 0.6

0 20 40 60 80 100 120
attains 96%–100% sensitivity for the staging of pelvic LN, Time (months)
if SLN are detected on both pelvic sides. Mutual comparison of categories (p values):
ITC
ITC Micro-met. Macro-met. Negative
Negative 0.549 <0.001 <0.001 Micro-metastases
ITC 0.036 0.009
Micro-met. 0.886 Macro-metastases
ITC, Isolated tumour cells; MAC, macro; Macro-met, macrometastases; MIC, micro;
Micro-met, micrometastases; neg, negative.
Simple hysterectomy or conisation is considered a

sufficient procedure for Stage IA cervical cancer, due
to the very low risk of parametrial involvement and an
excellent prognosis.
Stage No. of cases LN involvement
IA1 383 1.2% Clinical practice for LN staging in Stage IA is not

uniform, but it is mostly not required in Stage IA1
IA2 487 3.4% without LVSI due to low risk of LN involvement.
LN staging is mostly recommended in Stage IA2, due to

a higher risk of LN involvement. These cases are good
candidates for SLN biopsy and ultrastaging.
Overview of studies of
conservative surgical treatment
(simple hysterectomy) for early-
stage cervical cancer Author/year No. of IB1 Follow-up Relapses Deaths
cases time (months)
Rob/2008 27 47 1 0
RH combined with pelvic LN staging is considered a Pluta/2009 46 47 0 0

standard surgical procedure for Stage IB1 cervical cancer. Maneo/2011 36 66 1 1
Nerve-sparing modification of RH should be preferred, Fagotti/2011 13 16 0 0
especially in small tumours due to the lower prevalence of
Palaia/2012 9 38 0 0
urinary and anorectal dysfunction.
Raju/2012 10 96 0 0
Simple hysterectomy seems to be a safe alternative for Biliatis/2012 62 56 0 0
patients with small tumours (≤2 cm), but a satisfactory
oncological outcome needs to be confirmed by Plante/2011 6 27 0 0
ongoing prospective trials (SHAPE trial). Total 209 2 1
REVISION QUESTIONS
1. How prevalent are micrometastases in SLN in early stages?
2. What is a standard surgical procedure(s) in the treatment of Stage IA2?
3. What is a standard surgical procedure(s) in the treatment of Stage IB1?
34
Fertility-sparing procedures and treatment of locally advanced disease
The key limit for fertility-sparing treatment in Stage IB1 is a cranial

extension of the tumour in the cervix, since its proximal part must
be preserved for future pregnancy.
Simple conisation, simple trachelectomy (partial cervix removal), isthmus

radical vaginal or abdominal trachelectomy are procedures of choice
in LN-negative patients with small tumours (≤2 cm) localised in a
distal part of the cervix.
The recurrence rate has been reported to be 2%–3% in large
series. Pregnancy outcome is directly related to the size of Key condition for
fertility-sparing surgery
remaining cervix, thus less radical procedures are better. (isthmus–cranial tumour
margin distance)
Survival of patients
treated by surgery or
radiotherapy based on
tumour size
In large cervical tumours (Stage IB2) and selected

Stage IIB cases (initial parametrial infiltration), surgical
treatment is an alternative to primary chemoradiation.
Oncological outcome of surgery seems to be equal

or superior to chemoradiation but evidence from the
literature is limited.
5-year survival rates after surgical treatment are

reported to range between 60%–80%, according to the
proportion of IIB stages, LN positivity, use of adjuvant
radiotherapy and radicality of surgery.
Overall survival
1.0
0.9
0.8
0.7
0.6 HR 1.07 (95% CI 0.54–2.12); two-sided P =0.85*
0.5
0.4
0.3
0.2 Neoadjuvant chemotherapy (NACT)
Patients with large tumours and without LN involvement 0.1
0.0
Radical surgery (RS)
may benefit from surgical treatment most if they do not 0 1 2 3 4 5

6 7
receive adjuvant radiotherapy, since single-modality Number at risk

NACT 67 63 55 43 26 14 4
RS 67 59 52 47 30 14 1
treatment carries a lower risk of morbidity.
Progression-free survival
1.0
0.9
Neoadjuvant chemotherapy before surgery is reported
0.8
0.7
to improve morbidity and decrease the use of adjuvant 0.6
radiotherapy, but data on oncological outcome are 0.5

0.4
HR 1.06 (95% CI 0.60–1.88); two-sided P =0.85*
controversial. 0.3
0.2 Neoadjuvant chemotherapy (NACT)
0.1 Radical surgery (RS)
Due to the high risk of parametrial and LN 0.0
0 1 2 3 4 5 6 7
involvement in large tumours, a type of RH Number at risk

with complete removal of the parametria Survival of patients NACT

RS
67
67
51
47
45
43
36
39
20
26
10
12
4
1
randomised to neoadjuvant
and systematic lymphadenectomy should chemotherapy or upfront *Stratified Cox regression analysis and stratified log-rank test
be performed in these large tumours. radical surgery CI, Confidence interval; HR, hazard ratio.
REVISION QUESTIONS
1. What is a key limit for fertility-sparing treatment locally in the cervix?
2. What recurrence rate has so far been reported after fertility-sparing treatment?
3. Could surgical treatment be offered to a patient with Stage IIB tumour?
35
Cibula
Pelvic exenteration
1=anterior;
Pelvic exenteration (PE) is a treatment of choice in cases with 2=posterior; 3=total
central pelvic recurrence or tumour progression, with or without
previous radiotherapy.
Rarely, RH can be performed for recurrence or progression in
the cervix after radiotherapy. Such treatment is associated with
a higher risk of fistulae.
PE can be performed as an anterior (preserving rectum), posterior

(preserving urinary bladder and urethra) or total procedure, with
consequent creation of a colostomy and/or urostomy (continent
or incontinent).
Overall survival after

pelvic exenteration
according to LN status
PE is associated with high postoperative morbidity

(50%–90%), mortality (up to 10%) and in some cases a
long-term deterioration in quality of life, depending on the
indication and stage of the disease.
The 5-year overall survival after PE for central pelvic

cervical cancer recurrence is about 50%. The most
important prognostic parameter is involvement of the
para-aortic LNs.
Distant spread of the disease should always be excluded

before PE.
OS, Overall survival. Overall survival for

patients after LEER
according to LN status
PE can be performed in selected cases as a primary

treatment or for palliative reasons.
In recurrent tumours with attachment to the pelvic side

wall, a laterally extended endopelvic resection (LEER)
procedure is an alternative management that offers up
to 50% long-term survival.
In selected cases with recurrent tumours attaching to

pelvic bones, the composite procedure combined with
bone resection can be considered to achieve complete
resection.
LEER, Laterally extended endopelvic resection; LN, lymph node.
REVISION QUESTIONS
1. Which type of exenteration should be indicated if the tumour involves uterus, vagina and urinary bladder?
2. What is the chance of long-term survival in patients with central pelvic recurrence after primary radiotherapy if they receive PE?
3. Is there a chance of curative surgery if a recurrent tumour is fixed to the pelvic side wall?
36
Summary: Staging and surgical treatment of cervical cancer
• Pre-treatment staging: gynaecological examination, chest X-ray, pelvic MRI or ultrasound
• Prognostic factors: LN involvement, tumour size, depth of stromal invasion, parametrial involvement, LVSI, stage and
histological type
• The main principle of RH is removal of the parametrium and upper vagina together with the uterus
• Postoperative morbidity: (a) related to RH: voiding dysfunction, anorectal dysfunction; (b) related to lymphadenectomy:
lymphoedema
• Micrometastases: detected in SLNs in about 10%–15% of patients with early stages; may be associated with a
decreased overall survival in cervical cancer
• Simple hysterectomy or conisation combined with pelvic LN staging is a standard treatment for Stage IA2
• RH combined with pelvic LN staging is a standard treatment for Stage IB1
• In large tumours (IB2, selected IIB), radical hysterectomy with more extensive removal of parametria, combined with
pelvic LN staging, is an alternative to primary chemoradiation
• Fertility-sparing treatments: the key limit is cranial extension of the tumour in the cervix; conisation, simple
trachelectomy (partial cervix removal) or radical trachelectomy (including parametria) are surgical options to be
considered in combination with LN staging
• In cases with pelvic recurrence and in selected cases with locally advanced tumours, pelvic exenteration or laterally
extended endopelvic resection should be considered
Further Reading
Cao DY, Yang JX, Wu XH, et al. Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary
results of a multi-center research in China. Br J Cancer 2013; 109:2778–2782.
Cibula D, Abu-Rustum NR, Dusek L, et al. Prognostic significance of low volume sentinel lymph node disease in early-stage cervical
cancer. Gynecol Oncol 2012; 124:496–501.
Cibula D, Velechovska P, Sláma J, et al. Late morbidity following nerve-sparing radical hysterectomy. Gynecol Oncol 2010; 116:506–511.
Höckel M, Horn LC, Einenkel J. (Laterally) extended endopelvic resection: surgical treatment of locally advanced and recurrent cancer of
the uterine cervix and vagina based on ontogenetic anatomy. Gynecol Oncol 2012; 127:297–302.
Hou J, Goldberg GL, Qualls CR, et al. Risk factors for poor prognosis in microinvasive adenocarcinoma of the uterine cervix (IA1 and
IA2): a pooled analysis. Gynecol Oncol 2011; 121:135–142.
Ramirez PT, Pareja R, Rendón GJ, et al. Management of low-risk early-stage cervical cancer: should conization, simple trachelectomy,
or simple hysterectomy replace radical surgery as the new standard of care? Gynecol Oncol 2014; 132:254–259.
Raspagliesi F, Ditto A, Fontanelli R, et al. Type II versus Type III nerve-sparing radical hysterectomy: comparison of lower urinary tract
dysfunctions. Gynecol Oncol 2006; 102:256–262.
Schmidt AM, Imesch P, Fink D, Egger H. Indications and long-term clinical outcomes in 282 patients with pelvic exenteration for
advanced or recurrent cervical cancer. Gynecol Oncol 2012; 125:604–609.
Wethington SL, Cibula D, Duska LR, et al. An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies.
Int J Gynecol Cancer 2012; 22:1251–1257.
Zikan M, Fischerova D, Pinkavova I, et al. A prospective study examining the incidence of asymptomatic and symptomatic lymphoceles
following lymphadenectomy in patients with gynecological cancer. Gynecol Oncol 2015; 137:291–298.
37
Cibula
Non-surgical treatment of cervical cancer 7
Staging and treatment strategy
FIGO staging is of limited utility for cervical cancer (CC) as it

100
does not consider lymph node (LN) involvement, the most
important factor for prognosis and treatment decisions in
80
this disease.
As combined-modality treatment with radio- (RT) 60
% surviving
and chemotherapy (ChT) is needed to adequately treat
Stage ≥I/IIA, an accurate evaluation of LN involvement is 40
necessary. Imaging modalities are inadequate and the
Surgery ≤4 cm
gold standard is surgical lymphadenectomy. 20 Radiotherapy ≤4 cm
Surgery >4 cm
Although surgical lymphadenectomy is associated with Radiotherapy >4 cm
higher morbidity (such as lymphoedema), it has not been 0
0 20 40 60
shown to alter outcome. RT had the same
overall survival (OS) Time since treatment (months)
as surgery, but with half
the morbidity
1.0
Treatment Alive Dead Total A randomised study of RT vs radical surgery (+ adjuvant
0.9 CIS
CIS + FU + HU
96
99
80
74
176
173
RT if: surgical stage ≥pT2b, <3 mm clear tumour
0.8 margins, R1 resection, or N1 status) in Stage Ib/IIA gave
Proportion Surviving
HU 60 117 177
0.7 the same progression-free survival (PFS) and overall
0.6 survival (OS) (but 64% had postoperative RT).
0.5
0.4 Trimodality treatment (surgery plus chemoradiation)
0.3 doubles the risk of significant long-term toxicity, so
0.2 that for patients with a high probability of resulting LN+
0.1
after surgery, i.e. Stage ≥I/IIA confined to the pelvis,
0 12 24 36 48 60 72 84 96 108 120
chemoradiation alone should be preferred.
Time on Study (months)
Randomised trials demonstrated a statistically
No. at risk (for death)
Regimen 60 months 120 months significant benefit on local control, PFS and OS for
RT + CIS
RT + CIS + FU + HU
106
109
98
100
platinum-based chemoradiation compared to RT alone.
RT + HU 75 61
CIS, Cisplatin; FU, fluorouracil; HU, hydroxyurea.

OS by treatment
Stage Treatment Issue

IA1 Conisation or simple Conservative surgery
hysterectomy +/-
salpingo-oophorectomy
and PLND if LVSI
Palliative therapy utilising systemic ChT ± RT is instead
IA2 Conisation/radical Adjuvant ChT/RT if risk factors
the first choice for patients with distant metastases. trachelectomy or modified (LVSI, G3, positive resection
radical hysterectomy and PLND margins, multiple nodes)
CC treatment according to stage is detailed in the IB1, IIA Radical hysterectomy and Adjuvant ChT/RT if risk factors
ESMO Clinical Practice Guidelines. PLND (LVSI, G3, positive resection
margins, multiple nodes)
IB2, IIB-IV Combination ChT/RT with NACT to large bulky tumours
cisplatin prior ChT/RT
ChT, Chemotherapy; LVSI, lymphovascular space invasion; NACT, neoadjuvant chemotherapy;
PLND, pelvic lymphadenectomy; RT, radiation therapy.
REVISION QUESTIONS
1. What is the inherent problem of the FIGO classification for treatment decisions in CC?
2. What is the evidence regarding the toxicity profile of multimodal combined treatment approaches in locally advanced CC?
3. What is the standard of care for locally advanced and/or LN-positive CC patients?
38
Non-surgical treatment of cervical cancer
Radiotherapy treatment
CC is a highly radioresponsive tumour

with considerable tumour shrinkage
during treatment.
Chemoradiation is the standard treatment

option for ≥FIGO Stage IIA and/or LN-positive
patients. For FIGO Stage IVA, individual
decisions should be taken.
Treatment includes external beam
FIGO Stage IIB CC
radiotherapy (EBRT), concomitant ChT before and 3 months after
with cisplatin (40 mg/m2) weekly, 5-6× and chemoradiation
intracervical brachytherapy.
1 There is a clear relationship between the dose given to

0.9 the tumour, the volume, the treatment duration and the
local control rate.
Local control probability
0.8
0.7
The recommended dose (biologically equivalent dose
0.6
for 2 Gy fractionation = EQD2) should not be <85 Gy to
0.5
the macroscopic tumour, which can only be achieved
0.4
through the addition of brachytherapy.
0.3 OTT ≤55 days & HR-CTV <30 cm3
OTT ≥56 days & HR-CTV <30 cm3
0.2 p=0.001 OTT ≤55 days & HR-CTV ≥30 cm3
Treatment prolongation >56 days leads to higher local
OTT ≥56 days & HR-CTV ≥30 cm3
0.1 recurrence rate (thought to be due to repopulation) and
0 lower survival.
0 10 20 30 40 50 60 70 80 90 100 110 120
D90 HR-CTV (Gy) Dose–response
relationships between D90
OTT, Overall treatment time. high-risk clinical target volume
(HR-CTV) and local control
according to treatment time
and tumour volume
Intensity modulated radiation therapy

(IMRT) and other new techniques –
tomotherapy, volumetric modulated arc
therapy (VMAT), RapidArc – significantly
decrease treatment toxicity in the short
term. Long-term toxicity remains under
evaluation.
Sophisticated radiation techniques should

increasingly be the standard of care in
preference to 3D techniques. 3D technique
Conformal
treatment with
with high dose
The oncological outcome can be further to the bowel
tomotherapy and lower
improved by using real-time magnetic dose to the bowel
resonance imaging-guided brachytherapy.
REVISION QUESTIONS
1. For which patients is chemoradiation the standard of care?
2. Why is dose and treatment duration a critical issue for your patients?
3. What is the role of intracervical brachytherapy?
39
Marnitz & Fotopoulou
Para-aortic disease
Between 15% and 30% of patients with locally advanced

CC present with para-aortic disease.
The ESMO Clinical Practice Guidelines recommend

cisplatin-based ChT for patients with positive para-aortic
nodes plus extended field radiation therapy (EFRT).
The 3–5 year OS rate ranges from 11%–47%, and
correlates with the size and number of involved LNs.
18-FDG-PET-CT in
a patient with pelvic
and para-aortic LN
metastases
CT, Computed tomography; FDG, fluorodeoxyglucose;

LN, lymph node; PET, positron emission tomography.
Radiation volume should include the para-aortic LN

region up to the level of the renal vessels.
EFRT should be given simultaneously with pelvic

chemoradiation.
Because of the large bowel volumes, EFRT should be

done with modern (e.g. IMRT) techniques, minimising the
dose to the small bowel.
EFRT:
EFRT, Extended field radiation therapy. 95% isodose Excellent locoregional
(red) control rate (left) but lower
OS rate (right)
Locoregional recurrence-free survival Overall survival

With modern IMRT techniques, treatment is well tolerated 1.0 Event
Censored
1.0 Event
Censored
with low rates of high-grade gastrointestinal toxicity.

0.8 0.8
Cumulative survival
Cumulative survival
Although EFRT provides good local control to the 0.6 0.6
para-aortic nodes, these patients are at high risk for 0.4 0.4
distant metastases. This is likely to be the reason for the
disappointing OS despite EFRT in this group. 0.2 0.2
0.0 0.0
0 20 40 60 80 0 20 40 60 80
Follow-up (months) Follow-up (months)
REVISION QUESTIONS
1. Para-aortic metastases are considered distant metastases. Why do we use a radical treatment (with curative intent)?
2. How can you decrease treatment-related toxicity?
3. What is the greatest risk in patients with para-aortic metastases? How could the outcomes for this group be improved?
40
Fertility and organ preservation
Preservation of ovarian function is an emerging medical,

emotional and quality of life issue for pre-menopausal
women affected by CC.
Successful deliveries after in-vitro fertilisation (IVF)-
stimulated oocyte retrieval from the ovary and transfer to
surrogate mothers have been described in CC patients,
but this delays the start of radical chemoradiation.
Ovarian function can be preserved either by cryo-

conservation and retransplantation of ovarian tissue
after oncological treatment or more commonly by
ovarian transposition.
Fixation of the ovaries
with mobilised omentum and
identification mark for planning
computed tomography (CT) using
titanium clips (orange)
Isodoses of the prescribed

dose (47.8 Gy) in the target volume
decreasing to the periphery and to the
ovaries (in black circles) to <2 Gy between Current fertility-preserving strategies depend
second (L2) and third (L3) lumbar vertebrae. on the use of a surrogate mother, as RT to the
L1
Selective dose reduction within the intact
uterus from 40 Gy (A) to 30 Gy (B) in the L2
uterus precludes carrying a pregnancy to term.
periphery to 20 Gy (C) in the inner
L3
layer of the myometrium Due to the availability of newer RT techniques,
and endometrium L4
L5
selective sparing of ovaries, uterus and
47.8 Gy
40 Gy endometrium is technically feasible.
30 Gy
20 Gy
10 Gy 5 Gy 2 Gy Alternatively it may be possible, although

considerably more challenging given the pelvic
RT, to explore uterine transplantation, as has been
A: 40 Gy
B: 30 Gy
C: 20 Gy
used for patients who have had hysterectomies.
Ovaries should be transpositioned as high as possible.

A marking clip can be fixed near the ovary to guide the
optimal CT planning and dose calculation.
Ovarian tissue is extremely sensitive to radiation,

depending on patient’s age, the radiation dose and
type of ChT administered.
Gonadotrophin analogues given concomitantly with

Only the combination of
systemic ChT have the potential to protect ovarian optimal ovarian transposition and
reserve. Although proven among breast cancer modern RT techniques provides the
patients, this is not routinely used in patients having possibility to keep the mean ovarian
dose <5 Gy, better <2 Gy
chemoradiation for cervical cancer.
REVISION QUESTIONS
1. What are the current fertility-sparing options in locally advanced CC?
2. Does pelvic RT preclude pregnancy?
3. What is the potential role of gonadotrophin analogues?
41
Cervical cancer and pregnancy
CC diagnosed in pregnant women is an oncological

challenge. There is very little data.
Patients should be counselled and treated in clinical

institutions with interdisciplinary expert teams.
In very early CC, postponing surgical oncological therapy
until foetal viability seems to be a safe option.
CC, Cervical cancer.

Twin pregnancy in
a 35-year-old patient with
Stage IB1 CC
In locally advanced cancer, ChT during the 2nd–3rd

trimesters is recommended to avoid tumour progression
before delivery.
An essential precondition for ChT is the absence of LN

metastases (laparoscopic staging) during the 2nd or
3rd trimester of pregnancy.
A systematic analysis evaluated cisplatin (20 mg/m2,

days 1, 2, 3 q21d) in 20 pregnant women. All patients Cisplatin concentration
had obstetric examination and colposcopy every month.
A median of 3 cycles of ChT was delivered (range 2–4). 100
There was no progressive disease. 90
80
70
Cisplatin concentration in the foetal compartment 60
reached 11%–65% of the cisplatin concentration of the % 50
40
maternal compartment. Treatment was well tolerated. 30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Patient number
REVISION QUESTIONS
1. What is your recommendation for a woman who is 15 weeks’ pregnant with a CC?
2. Which pregnant patients would you NOT treat with ChT?
3. Why is ChT not more toxic to the foetus?
42
Treatment of distant metastases and relapsed disease
In primary metastatic CC (excluding para-aortic LN) and in

Survival By Treatment Group
relapsed disease, ChT is the treatment of choice.
Local RT can be applied in RT-naïve patients merely
for palliative local control.
Cisplatin in combination with other cytotoxics is more

active than monotherapy. Cisplatin–topotecan was the
first combination to increase PFS and OS.
Cisplatin 50 mg/m2 day 1 +

topotecan 0.75 mg/m2 days 1–3
q21d had statistically superior
outcomes to cisplatin 50 mg/m2
q21d alone
For de-novo metastatic patients, cisplatin gives a better

Prior platinum therapy OS than carboplatin when combined with paclitaxel
Yes (most CDDP) 59 68 0.69 0.47 to 1.02
No 64 53 1.57 1.06 to 2.32
(13.0 vs 23.2 months, hazard ratio: 1.57).
Platinum-free interval, months
<6 20 12 1.69 0.78 to 3.65 On the contrary, for patients previously exposed to
≥6, <12 18 22 0.57 0.29 to 1.11 cisplatin (even as part of their curative chemoradiation
≥12 21 34 0.71 0.36 to 2.32
No prior platinum therapy 64 53 1.57 1.06 to 2.32 schedule), carbo- and cisplatin with paclitaxel are equally
Overall 123 121 0.99 0.76 to 1.31 effective.
0.25 0.5 1 2 4
After failure of platinum treatment, paclitaxel weekly is an
effective regimen.
Favours TC Favours TP
CDDP, Cisplatin; TC, paclitaxel plus carboplatin; TP, paclitaxel plus cisplatin.
The addition of bevacizumab to cisplatin–paclitaxel Chemotherapy Chemotherapy +

significantly improved objective response rate, PFS and (n=225) Bev (n=227)
1.0 Events, n (%) 140 (62) 131 (58)
OS (by 3.7 months), but with significantly higher toxicity. Median OS, mos 13.3 17.0
0.9
0.8 HR=0.71 (97% CI, 0.54-0.94)
This survival benefit of bevacizumab disappears
P=0.0035
0.7
Median follow-up 20.8 mos
in cisplatin-free combinations, as with paclitaxel + 0.6
topotecan. 0.5
0.4
Future trials are evaluating the survival benefit and 0.3
toxicity profile of induction ChT prior to chemoradiation, 0.2
e.g. INTERLACE, OUTBACK. 0.1

0.0
0 12 24 36
Months on study
Bev, Bevacizumab; CI, confidence interval; HR, hazard ratio.
REVISION QUESTIONS
1. What are the standard and most efficient cytotoxic regimens for metastasised and relapsed CC?
2. What is the role of targeted agents in the treatment of CC?
3. What is the role of ChT plus chemoradiation in locally advanced disease?
43
Summary: Non-surgical treatment of cervical cancer
• Chemoradiation is the standard treatment option for ≥FIGO Stage IIB and/or LN-positive patients
• Patients with para-aortic LN metastases have a poorer prognosis and require radiation with an extended field
• Modern and innovative IMRT techniques have been shown to result in lower rates of gastrointestinal toxicity
• Platinum-based chemoradiation is superior to radiation alone for locally advanced cervical cancer
• Trimodality treatment (radical surgery + chemoradiation) doubles the risk of long-term toxicity
• Cisplatin is more active than carboplatin in metastatic CC
• Combination cisplatin-based regimens such as cisplatin–topotecan are more active than monotherapy
• The addition of bevacizumab to ChT in recurrent or advanced disease significantly prolongs OS
• Modern pelvic irradiation techniques can retain patients’ fertility
• CC in pregnancy remains a therapeutic dilemma
Further Reading
Bazan JG, Luxton G, Kozak MM, et al. Impact of chemotherapy on normal tissue complication probability models of acute hematologic
toxicity in patients receiving pelvic intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 2013; 87:983–991.
Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy
for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008;
26:5802–5812.
Ghadjar P, Budach V, Köhler C, et al. Modern radiation therapy and potential fertility preservation strategies in patients with cervical
cancer undergoing chemoradiation. Radiat Oncol 2015; 10:50.
Gouy S, Morice P, Narducci F, et al. Prospective multicenter study evaluating the survival of patients with locally advanced cervical
cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography
imaging. J Clin Oncol 2013; 31:3026–3033.
Köhler C, Oppelt P, Favero G, et al. How much platinum passes the placental barrier? Analysis of platinum applications in 21 patients
with cervical cancer during pregnancy. Am J Obstet Gynecol 2015; 213:206.e1–5.
Marnitz S, Schram J, Budach V, et al. Extended field chemoradiation for cervical cancer patients with histologically proven para-aortic
lymph node metastases after laparaoscopic lymphadenectomy. Strahlenther Onkol 2015; 191:421–428.
Mazeron R, Castelnau-Marchand P, Dumas I, et al. Impact of treatment time and dose escalation on local control in locally advanced
cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy. Radiother Oncol 2015;
114:257–263.
Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-
modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003; 56:1354–1360.
44
B
More advanced knowledge

8 Epidemiology and risk factors for ovarian,
uterine and cervical cancers
Epidemiology and risk factors for endometrial cancer
Endometrial carcinoma (EC) is the most common Corpus uteri

ASR (W) per 100,000 all ages
gynaecological cancer in developed countries and the Male Female
North America
second after cervical cancer in developing countries. Central and Eastern Europe Median age
More developed regions of diagnosis
Northern Europe 61 y
In the developed world, the incidence of EC is rising Southern Europe
Australia/New Zealand
(currently 5.9 per 100 000) and the mortality rate is Polynesia Risk of being
diagnosed with
2.4 per 100 000. Micronesia
Western Europe
EC is 1.4%
from 50 to 70
Caribbean
Melanesia
Eastern Asia
World 68% of cases
Western Asia are limited to
Central America uterus
Southern Africa
Less developed regions
South America
South Eastern Asia
Eastern Africa
30 20 10 0 10 20 30
Incidence Mortality
EC, Endometrial carcinoma.
Epidemiological factors in different subtypes of endometrial carcinomas

Type I Type II
Frequency 60%-70% 30%-40% Type I uterine cancers represent 80% of EC cases, have
Onset of menopause After age 50 years Younger than age 50 better prognosis and are preceded by intraepithelial
Oestrogen associated Yes No neoplasia. They have endometrioid histology, and are
Pathology and grade Endometrioid grade 1-2 Endometrioid grade 3 thought to be primarily caused by unopposed oestrogens.
Non-endometrioid
(clear cell, serous)
Precursor lesion May be intraepithelial No Type II uterine cancers are not clearly induced by
neoplasia oestrogen stimulation, have a poorer prognosis and
Background endometrium Hyperplasia Atrophy include poorly differentiated endometrioid and non-
Prognosis Favourable Poor endometrioid histological subtypes.
Risk of extension to lymph node Low High
Sensitivity to progestogens High Low
5-year survival 86% 59%
Risk factors include excess endogenous oestrogens

found in obesity, chronic anovulation (e.g. polycystic ovary
syndrome [PCOS]) and oestrogen-secreting tumours,
exogenous unopposed oestrogen therapy or selective
oestrogen receptor modulators (SERM), e.g. tamoxifen.
Lynch syndrome accounts for 2%–5% of cases, with

lifetime risk of 27%–71%, most presenting at younger
age (46–54 years). But the majority are endometrioid and
present at early stage.
Protective factors identified include progestogens,
childbearing at an older age, physical activity, coffee and
green tea. CI, Confidence interval; RR, relative risk.
REVISION QUESTIONS
1. What is the most common histological type of uterine cancer?
2. Which is the most common gynaecological cancer in developing countries?
3. What is the main risk factor for endometrioid carcinoma of the uterus and are there any protective factors?
47
Gonzalez Martin
Epidemiology and risk factors for ovarian cancer
Among gynaecological cancers, ovarian cancer (OC) Ovary

is the second most common in the developed world, Male Female
but the most common cause of gynaecological cancer Central and Eastern Europe
Northern Europe
Median age
death (fifth highest in women). More developed regions
Southern Europe of diagnosis
63 y
Northern America
Melanesia
Median age of diagnosis is 63 years. 95% of OC are Australia/New Zealand
Western Europe
epithelial and 75% of these are serous. Polynesia

South Eastern Asia 70%-80%
World are diagnosed
The majority of patients are diagnosed with advanced South America
Northern Africa
in FIGO Stage III
or IV
Eastern Africa
stage. 70%–80% have FIGO Stage III-IV, and high-grade Western Asia
Southern Africa
serous histology accounts for 80% of advanced cases. Less developed regions
Central America
Caribbean
80% of advanced
South Central Asia cases have high-grade
Eastern Asia histology
Middle Africa
Western Africa
Micronesia
15 10 5 0 5 10 15
Incidence Mortality
The risk of OC increases with age, and is associated with

higher numbers of ovulatory cycles, e.g. early menarche,
late menopause, nulliparity and infertility.
Endometriosis is associated with endometrioid, clear

cell and serous low-grade OC subtypes. The risk of
malignant transformation is 2.5%.
Approximately 15% of OC are related to BRCA gene

mutation and 1% to Lynch syndrome. Lifetime risk of OC
in BRAC 1 mutated is 40% and for BRCA 2 is 20%.
CI, Confidence interval; OR, odds ratio; RR, relative risk.
Protective factors for ovarian cancer

In the general population who do not have identified
genetic mutations, obesity increases the risk of • Any use reduces risk with RR 0.73 (95% CI: 0.70-0.76)
developing and dying of OC. Oral contraceptives • Protective effect increases with longer duration and persists
after cessation
• Nurses’ Health Study showed a reduction (HR: 0.76; 95% CI:

Protective factors that protect against OC include Tubal ligation 0.64-0.90) that was more significant for serous (RR: 0.57;
95% CI: 0.40-0.82). However, meta-analysis of 13 studies
oral contraceptives, tubal ligation, bilateral salpingo- showed a greater reduction in non-serous
oophorectomy, hysterectomy and breastfeeding. Hysterectomy without • Reduced the risk of ovarian cancer in meta-analysis (OR:
0.66; 95% CI: 0.50-0.86) and in the Nurses’ Health Study
oophorectomy (OR: 0.80: 95% CI: 0.66-0.97)
• Reduces the risk of ovarian cancer but minimal residual risk

Salpingo-oophorectomy of peritoneal carcinomatosis persists
• A cumulative duration >12 months breastfeeding was

Breastfeeding associated with a reduction in risk (RR: 0.72; 95% CI:
0.54-0.97)
CI, Confidence interval; HR, hazard ratio; OR, odds ratio; RR, relative risk.
REVISION QUESTIONS
1. What is the most common stage at diagnosis and most frequent histological type of OC?
2. List some important risk factors for developing OC.
3. Which factors protect individuals from developing OC?
48
Epidemiology and risk factors for ovarian, uterine and cervical cancers
Epidemiology, risk factors and screening for cervical cancer
Cervical cancer (CC) is the second most common type Cervix uteri
of cancer (17.8 per 100 000 women) and cause of cancer Male Female
Eastern Africa
deaths (9.8 per 100 000) in countries without screening Melanesia
Southern Africa
programmes. Middle Africa
Western Africa
Central America
Caribbean
86% of the new cases in the world (530 000) occur in South America
South Central Asia
developing countries. Screening in developed countries South Eastern Asia
Central and Eastern Europe
has decreased the incidence of invasive CC by 75% to Less developed regions
World
4.4 per 100 000. Polynesia
More developed regions
Northern Europe
In developed countries, median age at diagnosis is Micronesia
Southern Europe
48 years and the lifetime risk of developing CC is 0.75% Eastern Asia
Western Europe
Northern Africa
Northern America
Australia/New Zealand
Western Asia
60 40 20 0 20 40 60
Incidence Mortality
Human papillomavirus (HPV) is the cause of 99.7% of

cases of CC. HPV Types 16 and 18 are responsible for
70% of all cases.
Approximately 69% are squamous cell carcinomas

histologically, while 25% are adenocarcinomas.
Although 70%–80% of sexually active adults acquire
HPV
genome HPV <50 years, only a minority develop CC.
In general, the risk factors for developing CC relate to a

a reduced immune response to the virus or an increased
HPV, Human papillomavirus. risk of acquiring HPV. Oral contraceptives are also
associated with CC.
Comparison of cervical cancer screening guidelines

Screening has decreased the incidence Population Current Guidelines Prior ACS guideline Prior ACOG guideline Prior USPSTF guideline
of and mortality from CC. Methods ACS/ACOG/USPSTF 2012 2002/2003 2009 2003
Females younger Begin screening at age 21 Begin 3 yr following the onset of vaginal Begin 3 yr following the Begin within 3 yr of onset
include Papanicolaou test (cytology) than 21 yr intercourse, but no later than 21 yr onset of vaginal intercourse, of sexual activity or age 21,
of age but no later than 21 yr whichever is earliest
and testing for high-risk types of HPV. Females age Conventional Pap or liquid- Conventional Pap: Annually; every 2-3 yr Cytology every 2 yr Conventional Pap: At least
21–29 yr based cytology alone every 3 yr for females ≥ 30 with 3 negative cytology every 3 yr
tests Liquid-based cytology:
In a meta-analysis of 12 case-control Liquid-based cytology: Every 2 yr; every
2-3 yr for females ≥ 30 years with
Insufficient evidence
If HPV testing used: Insufficient
studies, cytology screening was 3 negative cytology tests
If HPV testing used: Every 3 yr if HPV
evidence
associated with decreased risk of Females age HPV and Pap smear co-testing
negative and cytology negative
HPV and cytology co-testing
invasive CC (odds ratio [OR]: 0.35, 30–65 yr every 5 yr or Pap smear alone
every 3 yr. Do not use HPV
every 3 yr
95% confidence interval [CI]: 0.30–0.41). testing alone

Women older Stop screening if adequate Stop screening in women ≥ 70 years Stop between 65 and 70 yr No screening if adequate prior
than 65 yr prior negative screening result with 3 or more recent, consecutive of age after > 3 consecutive negative screening result and
HPV testing is more sensitive than and women not at high risk negative tests and no abnormal tests in negative cytology tests over women not at high risk
previous 10 yr the past 10 yr
cytology, and increases referrals for Women after No screening if removal of Discontinue if hysterectomy for benign Stop screening Discontinue if hysterectomy
colposcopy, leading to earlier diagnoses, hysterectomy cervix and no prior high grade
pre-cancer or cervical cancer
reasons and no previous high-grade CIN done for benign reasons
but may not alter overall survival in the Women who

were immunised
Same as non-immunised
women
No vaccines recommended for use at this
time period
Same as non-immunised
women
No vaccines recommended for
use at this time period
longer term. with HPV
ACS, American Cancer Society; ACOG, American Congress of Obstetricians and Gynecologists; CIN, cervical
intraepithelial neoplasia; HPV, human papillomavirus; USPSTF, United States Preventive Services Task Force.
REVISION QUESTIONS
1. Is the incidence of CC the same across different regions?
2. Are all the risk factors associated with HPV transmission?
3. Is there a unique screening programme?
49
Gonzalez Martin
Summary: Epidemiology and risk factors for ovarian, uterine and
cervical cancers
• EC is the most common gynaecological cancer in developed countries
• The main risk factor for type I tumours is long-term endogenous or exogenous exposure to oestrogens
• Lynch syndrome accounts for 2%–5% of cases, most of whom will present with uterine cancer at a younger age
(46–54 years), and have a lifetime risk of 27%–71%
• OC is the second most common gynaecological cancer but the most common cause of gynaecological cancer death.
It is the fifth leading cause of cancer death in women
• 15% of epithelial serous (or G3 endometrioid) OC are associated with germline BRCA mutations
• Endometriosis is associated with non-serous OC
• Oral contraceptives, tubal ligation, bilateral salpingo-oophorectomy, hysterectomy and breastfeeding are protective
factors for OC
• CC is the second most common cancer in developing countries. It is also the second most common cause of cancer
death in these countries
• HPV causes 99.7% of cases of CC
• Risk factors for acquiring HPV and a decrease in immunity lead to increased risk of CC
• CC screening with cytology (Pap smear) and/or HPV testing significantly decreases the incidence and mortality
from CC
• Vaccines against HPV 16 and 18 have demonstrated a clear reduction in the development of pre-invasive lesions.
However, the rate of implementation is variable worldwide and even inside the same country. Therefore, screening with
HPV detection with or without Pap smear following international consensus guidelines is still needed
Further Reading
Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women
with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012; 30:2654–2663.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the
efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378:771–784.
Gates MA, Rosner BA, Hecht JL, Tworoger SS. Risk factors for epithelial ovarian cancer by histologic subtype. Am J Epidemiol 2010;
171:45–53.
International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell
carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma
and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 2007; 120:885–891.
McGraw SL, Ferrante JM. Update on prevention and screening of cervical cancer. World J Clin Oncol 2014; 5:744–752.
Pearce CL, Templeman C, Rossing MA, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer:
a pooled analysis of case-control studies. Lancet Oncol 2012; 13:385–394.
Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective
observational studies. Lancet 2008; 371:569–578.
Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet 2007; 370:890–907.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9.
Tsilidis KK, Allen NE, Key TJ, et al. Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European
Prospective Investigation into Cancer and Nutrition. Br J Cancer 2011; 105:1436–1442.
50
Epidemiology and risk factors for ovarian, uterine and cervical cancers
9 Diagnosis and treatment of vulvar cancer
Epidemiology, pathogenesis
Vulvar cancer (VC) is rare, representing 3%–5% of female

genital tract cancers in developed countries; incidence: HPV+ Vulvar superficial
HPV-
2.5–4.0/100 000, mortality rate: 0.5–1.9/100 000. The squamous epithelium
average age of women with invasive tumours ranges from HR-HPV Immunological factors
and mechanical factors
64 to 69 years. infection (itch-scratch cycle)
The incidence of VC has ↑ in the past 30 years due to the Vulvar dermatoses
VIN, usual type (vulvar dystrophies)
higher prevalence of high-risk papillomavirus (HR-HPV) in Lichen sclerosus
younger women, and the increasing lifespan of humans. Lichen simplex chronicus
HPV positive HPV negative Gene mutations (p53)

The pathogenesis of vulvar precancerous lesions and (30%-40%) (60%-70%)
spinocellular carcinomas is summarised in the figure.
Squamous cell carcinoma VIN, differentiated type
HPV, Human papillomavirus; HR-HPV, high-risk papillomavirus; VIN, vulvar intraepithelial neoplasia.
The most common tumour is spinocellular carcinoma.

30%–40% of cases are a result of HR-HPV infection.
A B
Clear dominance of Type 16, followed by Type 33;
other types are rare. Its precancerous stage is vulvar
intraepithelial neoplasia of usual type (u-VIN).
The incidence of u-VIN ↑ in premenopausal women;

it is associated with ↑ risk of cervical (cervical
intraepithelial neoplasia [CIN] and cancer), vaginal
C D
(vaginal intraepithelial neoplasia [VaiN] and cancer) and
anal (anal intraepithelial neoplasia [AIN] and cancer)
neoplasia. These are often multifocal and tend to spread
along the surface to the perianal, vaginal or urethral area.
Untreated u-VIN progresses to carcinoma with usually

favourable biological behaviour (basaloid, warty, verrucous).
A, u-VIN, basaloid type; B, squamous cell carcinoma, basaloid type; C, u-VIN, warty type; Keratinising and non-keratinising variations of spinocellular
D, squamous cell carcinoma, warty type.
cancer may also be associated with HR-HPV, but in most
cases HPV- or p16-positivity cannot be proven.
Squamous cell carcinomas (keratinising, non-keratinising)

arise in atrophic epithelium with chronic inflammatory
disorders (lichen sclerosus, lichen simplex chronicus). A B
Precursors are d-VIN (differentiated-type vulvar

intraepithelial neoplasia) and they are HPV-negative.
One of their main aetiological factors is aberrant p53
function.
The tumours in this group have more aggressive

behaviour, grow quickly into the dermis (infiltrative growth) A, d-VIN; B, squamous cell carcinoma, keratinising type.
and metastasise into the regional lymph nodes in the
inguinofemoral area.
REVISION QUESTIONS
1. What percentage of spinocellular carcinomas is associated with HPV?
2. Which precancerous lesions are not associated with HPV?
3. What percentage does VC account for, relative to all female genital tract cancers?
51
Rob & Skapa
Clinical presentation, histopathology, diagnosis
The most common first symptom of precancerous

lesions and malignant tumours is persistent itching and
soreness in the vulvar area. Hyperpigmentation or red
lesions, itchy ulcer or elevated warts, that itch or bleed
slightly after rubbing, are an alarming sign.
Pain and foul-smelling discharge are late symptoms.
Squamous cell carcinoma is the most common vulvar

malignancy (90%–92%). Melanoma (diagnosed in 5%
of cases) is highly malignant with lymphogenous and
haematogenous spread.
Epithelial malignant tumours (92%–94%)

Squamous cell carcinoma (90%–92%)
Keratinising
Non-keratinising Diagnosis can be achieved through excision of the
Basaloid
suspected lesion (elevated or ulcerous, skin with colour
Warty
Verrucous change) and performing a histopathological examination.
Basal cell carcinoma
If the changes are diagnosed in the precancerous
Adenocarcinoma (1%–2%)
stage (u-VIN, d-VIN), the excision of the altered
Neuroendocrine tumours – rare epithelium is sufficient.
Malignant melanoma (4%–6%)
Recurrence in the surrounding epithelium is common
Malignant soft tissue tumours (1%–2%)
in precancerous lesions. Invasive tumours require
Neuroectodermal tumours (Ewing sarcoma) – rare specialised care.
Germ cell tumours – rare
Lymphoid and myeloid tumours – rare
Diagnosis is performed by a gynaecologist or gynae-

oncologist: clinical examination (including palpation
and ultrasonography of the inguinofemoral area),
colposcopy (vulvoscopy) and excision with histological
examination are standard protocols.
In more advanced conditions, additional examination

is required (computed tomography [CT], magnetic
resonance imaging [MRI], positron emission tomography/
computed tomography [PET/CT]) to refine the extent of
tumour involvement.
REVISION QUESTIONS
1. What is the most common symptom?
2. What is the percentage of spinocellular carcinomas and their histological variations?
3. Which malignant tumour of the vulva is the second most common?
52
Diagnosis and treatment of vulvar cancer
Therapy
The primary treatment modality is surgery. Its extent is Radical excision + unilateral sentinel lymph Radical excision + bilateral SLN
determined by the disease stage. node (SLN)
Because of its low tumour incidence, treatment should

take place in specialised gynae-oncological centres.
In disease Stage IA, a “conservative” surgical procedure

with wide excision can be performed. In the case of
invasive cancer (IB and more), there is a significant Radical vulvectomy + En bloc radical vulvectomy
inguinofemoral lymphadenectomy
trend towards the reduction of radicality of local surgical
treatment, where radical vulvectomies are replaced by
radical excisions.
Inguinofemoral lymphadenectomies are replaced by

sentinel lymph node (SLN) detection (in tumours less
than 4 cm, no suspect groin). Detection is performed
after administration of a lymphotropic substance (patent
blue and technetium radioisotope) in the tumour
surroundings.
The SLN is the first lymph node or nodes located
between the tumour and regional lymphatics.
Thorough processing of the lymph node with the

highest risk of metastatic spread increases the safety
of the patient undergoing surgery.
FIGO 2009
surgical staging for
carcinoma of the vulva
Stage I Tumour confined to the vulva
IA Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal
Radiotherapy is applied as an additional method of invasion ≤1.0 mm, no nodal metastasis
IB Lesions >2 cm in size or with stromal invasion >1.0 mm, confined to the
treatment after surgery. Other treatment modalities have vulva or perineum, with negative nodes
minimal use. Stage II Tumour of any size with extension to adjacent perineal structures
(1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes
Treatment consequences: radical surgical treatment can Stage III Tumour of any size with or without extension to adjacent perineal structures
(1/3 lower urethra, 1/3 lower vagina, anus) with positive inguino-femoral
lead to swelling of the lower extremities (lymphoedema), lymph nodes
impaired sexual function (due to clitoris removal as a part IIIA (i) With 1 lymph node metastasis (≥5 mm), or
of radical surgery) and significant narrowing of the vaginal (ii) 1-2 lymph node metastasis(es) (<5 mm)
IIIB (i) With 2 or more lymph node metastases (≥5 mm), or
opening. (ii) 3 or more lymph node metastases (<5 mm)
IIIC With positive lymph nodes with extracapsular spread
Modern surgical techniques consisting of reduced Stage IV Tumour invades other regional (2/3 upper urethra, 2/3 upper vagina),
or distant structures
local radicality and detection of SLNs are attempts to IVA Tumour invades any of the following:
minimise these complications. Adequate free margins (i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa,
or fixed to pelvic bone, or
– 1 cm – are necessary. Neoadjuvant radiotherapy or (ii) fixed or ulcerated inguino-femoral lymph nodes
chemotherapy is an option in locally advanced VC. IVB Any distant metastasis including pelvic lymph nodes
REVISION QUESTIONS
1. What is the role of surgery in VC?
2. What is the trend in local surgical treatment?
3. What is SLN mapping?
53
Rob & Skapa
Summary: Diagnosis and treatment of vulvar cancer
• VC is a rare type of cancer accounting for only 3%–5% of cancers of the female genital tract
• d-VIN precursors are HPV-negative
• u-VIN precursors are HPV-negative
• Spinocellular carcinomas are found in 30%–40% of all cases, as a result of HR-HPV infection (mostly by Type 16). In
60%–70% of cases, there is no association with HR-HPV types
• Local surgical treatment and regional lymphadenectomy are the primary treatment methods
• In tumours less than 4 cm and non-suspect inguinofemoral lymph nodes, there is a trend to a reduction of surgical
treatment radicality
• The trend in local surgical treatment is to reduce the radicality from radical vulvectomy to radical excision
• The trend in surgical treatment in the regional inguinofemoral lymph nodes is to detect sentinel nodes
• Less radical surgery shows objectively better quality of life results
Further Reading
Kurman RJ, Carcangiu ML, Herrington CS, Young RH (Editors). WHO Classification of Tumours of Female Reproductive Organs. IARC:
Lyon, 2014.
Levenback CF, van der Zee AG, Rob L, et al. Sentinel lymph node biopsy in patients with gynecologic cancers. Expert panel statement
from the International Sentinel Node Society Meeting, February 21, 2008. Gynecol Oncol 2009; 114:151–156.
Novackova M, Halaska MJ, Robova H, et al. A prospective study in detection of lower-limb lymphedema and evaluation of quality of life
after vulvar cancer surgery. Int J Gynecol Cancer 2012; 22:1081–1088.
Oonk MH, de Hullu JA, van der Zee AG. Current controversies in the management of patients with early-stage vulvar cancer. Curr Opin
Oncol 2010; 22 481–486.
Oonk MH, van Os MA, de Bock GH, et al. A comparison of quality of life between vulvar cancer patients after sentinel lymph node
procedure only and inguinofemoral lymphadenectomy. Gynecol Oncol 2009; 113:301–305.
Rob L, Robova H, Pluta M, et al. Further data on sentinel lymph node mapping in vulvar cancer by blue dye and radiocolloid Tc99.
Int J Gynecol Cancer 2007; 17:147–153.
Tachezy R, Smahelova J, Salakova M, et al. Human papillomavirus genotype distribution in Czech women and men with diseases
etiologically linked to HPV. PLoS One 2011; 6(7):e21913.
van der Velden J, Fons G, Lawrie TA. Primary groin irradiation versus primary groin surgery for early vulvar cancer. Cochrane Database
Syst Rev 2011; 11:CD002224.
Van der Zee AG, Oonk MH, De Hullu JA, et al. Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol
2008; 26:884–889.
54
Diagnosis and treatment of vulvar cancer
10 Rare gynaecological cancers
Epidemiology, management, organisation
Rare gynaecological cancers (RGCs, defined as EPIDEMIOLOGY

<6/100 000/year) represent 55% of all gynaecological Incidence of rare versus common cancers in Europe, 2003
cancers. This major proportion is highly specific to
Common gynec. Rare gynec.
gynaecology (except sarcomas). cancers
cancers
478 806
Rarity may be due to unusual histology (e.g. sex cord,
trophoblastic), localisation (e.g. vaginal melanoma),
or histological subtype (e.g. mucinous, clear cell Common of any
carcinoma). Rare of other site
any other site 15030
The histological definition is based on pathological 4043
classification and molecular biology subgroup, which may
increase heterogeneity.
Histological review by an expert pathologist is required,

since diagnosis discordance has been observed in
10%–35% of rare tumour cases. Molecular biology
analysis can specify subgroups of patients and lead to
targeted therapies (mentioned below).
Quality of surgery is of high importance. In cases of

suboptimal quality, reoperation must be considered
and discussed. Fertility-sparing surgery should be
discussed with affected patients who wish to have
children if certain cancer-specific criteria apply.
Harmonisation of treatment of RGCs is urgently needed.

Specific trial designs and efficient national network
organisations should be designed with dedicated data
collection for new strategies.
NEEDS
The French national network dedicated to RGCs • Local diagnosis with expert
second opinion
(www.ovaire-rare.org) is a relevant example for
daily management, diagnosis and participation in • Centralised data
international trials (e.g. ALIENOR trial, NTC01770301). • National network
• International collaboration
International collaboration (e.g. GCIG: Gynaecologic
Cancer InterGroup) in sharing of data will enhance
the conduct of dedicated translational research and
randomised clinical trials.
REVISION QUESTIONS
1. When should a clinician suspect a RGC?
2. What must a clinician do when a rare tumour is diagnosed?
3. Which organisations may optimise rare cancer management?
55
Ray-Coquard & Vanacker
Some specific rare ovarian cancers
Sex cord tumours (7% of ovarian malignancies)

occur over a wide age range but mostly in peri- and
postmenopausal women. The differential histological
diagnosis is a major issue.
Detected at early stage they have an overall good

prognosis. A tendency for late recurrence requires long-
term follow-up. Surgery is the cornerstone: conservative
for selected young patients or repeated at relapse.
For advanced or recurrent disease, a platinum-based
regimen, such as BEP (bleomycin, etoposide, platinum)
is the standard, with 63%–80% response rate. Endocrine Diagnosed 70% Stage I. Overall survival 85% at 10 years
therapy is an option for indolent disease.
Subtype Frequency Blood markers Germ cell tumours (3% of ovarian malignancies) occur
Dysgeminoma 35%-45% LDH, hCG
predominantly in girls, adolescents, and young women.
Endodermal sinus tumour (yolk sac) 20% AFP (commonly) Often early stage, unilateral. Advanced-stage disease
rarely α1-antitrypsin occurs in approximately 30% of patients.
Teratoma (+/- mature) 20% Immature: AFP
LDH, Ca125 High volume leads to 20% pre-surgical rupture. Germ
Embryonal carcinoma Rare AFP and hCG cell tumours need rapid diagnosis and management
Polyembryoma Rare AFP and hCG
since they are aggressive and curable. Blood markers
Choriocarcinoma Very rare hCG
are needed for diagnosis, follow-up and are predictive
Polyembryoma Rare AFP and hCG
Mixed GCT 10%-20% Dependent on cells
for treatment efficacy.
AFP, Alpha-foetoprotein; GCT, germ cell tumour; hCG, human chorionic gonadotrophin;
LDH, lactate dehydrogenase. Therapy includes non-radical surgery with adjuvant
chemotherapy (3–4 BEP according to type, stage and
residue), which will not modify fertility.
Low malignant potential tumours (LMPT, = borderline

tumours) are an independent group whose molecular Epithelial stromal tumours overview
origin is similar to low-grade serous carcinoma (LGSC),
• Low-grade
but have no infiltration or stromal invasion. They affect • Slow growing
young patients, with localised stage. No data exist to - low-grade serous carcinoma
support adjuvant therapy. - low-grade endometrioid carcinoma
LGSC may follow LMPT, mostly in advanced stage progress from borderline tumours
and at younger age. It is more indolent, partially
chemosensitive compared to high-grade serous
carcinoma (HGSC). Hormone receptor (oestrogen
receptor [ER]/progesterone receptor [PR]) positivity
• High-grade
indicates hormonal suppression. Surgery is the • Evolve rapidly
cornerstone of treatment, possibly fertility sparing. • Include:
- high-grade serous carcinoma
Ovarian mucinous carcinomas are primarily of ovarian or - carcinosarcoma
- undifferentiated carcinoma
metastatic origin. Mostly in women 20–40 years old, at an - and some clear cell carcinomas
early stage the prognosis after complete surgery is good. • Widespread DNA copy number changes
Advanced stages respond poorly to standard platinum

combination and the prognosis is worse than for HGSC.
REVISION QUESTIONS
1. Who is eligible for conservative surgery?
2. Which blood markers are needed?
3. Which tumours are / are not chemosensitive?
56
Rare gynaecological cancers
Overview: focus on some selected subtypes; molecular biology
Ovarian small cell carcinomas share the characteristics Overview of gynaecological tumour types
(SMARCA4) of paediatric rhabdoïd tumours. They are Ovarian EPITHELIAL
GERM CELL
very aggressive, and treated by surgery, chemotherapy SEX CORDS
and adjuvant radiotherapy.
Ovarian clear cell carcinomas (CCC) are mostly early

stage and present in Asian populations. Bilateral disease
may be metastatic renal CCC. Mostly chemoresistant,
Uterine
treatments include complete surgery and chemotherapy
for early stage, maximum debulking for advanced stage. EPITHELIAL
(serous ADK/carcinosarcoma…)
Trophoblastic disease is usually a tumour with high MESENCHYMAL +metastasis
of other site
(sarcoma: ESS, HGUS, LMS)
human chorionic gonadotrophin (hCG) in postpartum. CERVICAL
Treatment includes local surgery, radiotherapy, and (SCC, ADK)
methotrexate-based mono/polychemotherapy, according
ADK, Adenocarcinoma; ESS, endometrial stromal sarcoma; HGUS, high-grade uterine sarcoma;
to prognostic factors. Subsequent pregnancy is possible. LMS, leiomyosarcoma; SCC, squamous cell carcinoma.
IDENTIFIED MOLECULAR ALTERATIONS Uterine carcinosarcoma includes both carcinomatous

FOXL2 Sex cords (adult granulosa cell tumour)
and sarcomatous elements and may be a metaplastic
DICER-1 Sex cords (juvenile granulosa / Sertoli-Leydig) carcinoma, as a highly aggressive epithelial disease. It is
K-RAS Mucinous borderline, ovarian low-grade serous mostly detected in advanced stage, with very poor
B-RAF Melanoma, ovarian borderline, low-grade serous prognosis. There is no consensus on treatment, but surgery
PI3KCA CCC, carcinosarcoma and carboplatinum seems better than a sarcoma regimen.
PTEN CCC, mucinuous, endometrioid
HER-2 Mucinuous Vulvo-vaginal melanoma seems similar to mucosal
BRCA Serous, endometrioid, CCC, undifferentiated and acral melanomas. Localised tumours are treated
p53 Serous high-grade, carcinosarcomas by surgery and radiotherapy. For non-resectable
t(7;17) Endometrial stromal sarcoma
(p15;q21)
disease, decisions are based on extrapolation from
ARID1A CCC skin melanoma data, although there are limited data
βcatenin Endometrioid regarding therapies and biology (including BRAF
YHMEA HGUS mutation status).
FAM 21/22
CCC, Clear cell carcinoma; HGUS, high-grade uterine sarcoma.
Endometrial stromal sarcomas are usually low-grade,

MESENCHYMAL UTERINE CANCERS: SARCOMAS
ER/PR-positive in 80%-95%; t(7;17)(p15;q21) in 60%.
Surgery is the main treatment, with hormonal therapy
P
for residual disease or metastatic stage (20%).
R
Leiomyosarcoma is aggressive, with poor prognosis. O
Chemotherapy has few reported benefits, also in the G
N
metastatic phase. Adjuvant radiotherapy is not confirmed
O
to change the prognosis. S
High-grade undifferentiated sarcoma is an aggressive I
S
disease, always ER/PR-negative; t(10;17) translocation in
30%. Overall survival ranges from 12–23 months (even for
early stage).
REVISION QUESTIONS
1. What are the main types of rare ovarian, uterine or vaginal cancers?
2. Which tumours seem aggressive or indolent?
3. How do we define the prognosis of uterine sarcoma?
57
Ray-Coquard & Vanacker
Summary: Rare gynaecological tumours
• Any gynaecological cancer should be anticipated as possibly rare, since rare cancers account for up to 55% of
gynaecological cancers
• The first step in diagnosis includes clinical examination, identification markers (Ca125, AFP, LDH, hCG for ovarian
germline tumours, inhibin for granulosa, neuroendocrine markers, etc.) and imaging data
• Pathological analysis must include a second review by an expert pathologist for confirmation, and further molecular
explorations are needed. Discordance in diagnosis is frequent
• Molecular biology is increasingly used to define tumour subtype (FOXL2, DICER-1), to direct oncogenetic (germline
BRCA) and targeted treatments (BRCA, B-RAF)
• Quality of surgery for staging or for treatment must be assessed by multidisciplinary experts. Tumour rupture or
morcellation are key pointers for worse prognosis, compared to optimal surgery
• Fertility-sparing surgery is an acceptable option for young women with certain localised tumours (germ cell tumours,
sex cord or borderline tumours)
• Adjuvant treatment with chemotherapy is based on histology, staging, postoperative residue and prognostic factors.
Adjuvant hormone therapy can be discussed for ER/PR+ tumours (endometrial stromal tumours) of advanced/
metastatic stage
• The development of new diagnostic resources to define new specific entities is ongoing. Each subtype of rare tumour
suffers from a lack of knowledge regarding genesis, diagnosis and treatments
• Centralisation of data, networking and international collaboration are urgently needed to enhance the conduct of
dedicated translational research and randomised clinical trials, in order to improve knowledge on management and
prognosis in these patients
Further Reading
Amant F, Floquet A, Friedlander M, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for endometrial stromal sarcoma.
Int J Gynecol Cancer 2014; 24(9 Suppl 3):S67–S72.
Berton-Rigaud D, Devouassoux-Shisheboran M, Ledermann JA, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for
uterine and ovarian carcinosarcoma. Int J Gynecol Cancer 2014; 24(9 Suppl 3):S55–S60.
Brown J, Friedlander M, Backes FJ, et al. Gynecologic Cancer Intergroup (GCIG) consensus review for ovarian germ cell tumors. Int J
Gynecol Cancer 2014; 24(9 Suppl 3):S48–S54.
Gourley C, Farley J, Provencher DM, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian and primary peritoneal
low-grade serous carcinomas. Int J Gynecol Cancer 2014; 24(9 Suppl 3):S9–S13.
Harter P, Gershenson D, Lhomme C, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian tumors of low malignant
potential (borderline ovarian tumors). Int J Gynecol Cancer 2014; 24(9 Suppl 3):S5–S8.
Ledermann JA, Luvero D, Shafer A, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for mucinous ovarian carcinoma.
Leitao MM Jr, Cheng X, Hamilton AL, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas. Int J
Gynecol Cancer 2014; 24(9 Suppl 3):S117–S122.
Mackay HJ, Brady MF, Oza AM, et al; Gynecologic Cancer InterGroup. Prognostic relevance of uncommon ovarian histology in women
with stage III/IV epithelial ovarian cancer. Int J Gynecol Cancer 2010; 20:945–952.
Maillet D, Goulvent T, Rimokh R, et al. Impact of a second opinion using expression and molecular analysis of FOXL2 for sex cord-
stromal tumors. A study of the GINECO group & the TMRO network. Gynecol Oncol 2014; 132:181–187.
Okamoto A, Glasspool RM, Mabuchi S, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for clear cell carcinoma of the
ovary. Int J Gynecol Cancer 2014; 24(9 Suppl 3):S20–S25.
Pautier P, Nam EJ, Provencher DM, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for high-grade undifferentiated
sarcomas of the uterus. Int J Gynecol Cancer 2014; 24(9 Suppl 3):S73–S77.
Ray-Coquard I, Pujade-Lauraine E, Ledermann JA. New clinical research strategies for rare gynecologic malignancies. Curr Opin Obstet
Gynecol 2015; 27:53–57.
Ray-Coquard I, Weber B, Lotz JP, et al. Management of rare ovarian cancers: the experience of the French website “Observatory for rare
malignant tumours of the ovaries” by the GINECO group: interim analysis of the first 100 patients. Gynecol Oncol 2010; 119:53–59.
Sagae S, Susumu N, Viswanathan AN, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for uterine serous carcinoma.
58
Rare gynaecological cancers
11 Hereditary ovarian and uterine cancer syndromes
Genetic basis
Most cancers have many chromosomal abnormalities,

both in number and in structure, whereas some show
only a single aberration.
Evidence from the recent molecular era indicates that
cancers can arise from small numbers of events that
affect common cell birth and death processes.
Knudson suggested that multiple “hits” to DNA were

necessary to cause cancer.
Autosomal-dominant inheritance
Autosomal-dominant inheritance: genetic inheritance

pattern where an abnormal gene (inherited from one
parent) is dominant over the normal gene (inherited from
the other parent).
The individual shows the characteristics associated

with the abnormal gene, e.g. high risk of cancer.
Males and females are usually affected with equal

frequency, but may develop different cancers.
BRCA1 and BRCA2 maintain genomic integrity.

Mutations that affect the mechanisms involved in the
detection, stabilisation and repair of DNA damage
cause genome instability.
Genetic susceptibility to cancer is attributed to

deleterious germline mutations in the DNA mismatch
repair (MMR) gene. These genetic defects in the DNA
MMR system result in DNA replication errors, including
base substitutions and insertion-deletion loops (IDLs),
known as microsatellite instability (MSI).
These mutations are associated with hereditary non-

polyposis colorectal cancer (HNPCC) syndrome, also
known as “Lynch syndrome” (LS). Two manifestations
of hereditary ovarian cancer are currently recognised:
the hereditary breast and ovarian cancer (HBOC) HBOC, Hereditary breast and ovarian cancer; MMR, mismatch repair.
syndrome and the HNPCC syndrome.
REVISION QUESTIONS
1. What is the “two-hit theory”?
2. What are the most important genes predisposing to ovarian and endometrial cancer?
3. Why are mutations in BRCA1 or BRCA2 associated with cancer?
59
Marth
Genetic predisposition
The MMR system corrects replication errors in newly DNA-mismatch repair (MMR) genes
synthesised DNA. Mismatches and small IDLs are Initiation of MMR by recognising the DNA
damage by the MutSα or ß complex and
detected by one of two heterodimers, MutSa or MutSb. recruiting the MutLα-complex
Mismatch-Repair
MutSa is involved in the repair of base mismatches

and misalignments of one or two nucleotides. MutSb
recognises larger IDLs. MutLa introduces random nicks
at sites spanning the mismatch. The repair process is Excision of the damaged strand and resynthesis
in which exonuclease ExoI, proliferating cell
finalised by polymerase d and its cofactors proliferation nuclear antigen (PCNA), DNA polymerase δ or ε
and DNA helicase I are suggested to play a role
cell nuclear antigen (PCNA) and replication factor C (RFC),
which fill in the single-stranded gap.
The MMR system is also involved in apoptotic response
to a variety of DNA-damaging agents.
Genetic predisposition to cancer

Syndrome Primary Associated Genes
Cancers Neoplasms Heterozygous germline loss-of-function mutations
Hereditary breast Breast, ovary Pancreas, male breast, BRCA1, BRCA2, of the genes encoding the crucial components of the
& ovarian cancer prostate, stomach, RAD51C, MMR system (MLH1, MSH2, MSH6 or PMS2) cause LS,
syndrome (HBOC) thyroid, gallbladder RAD51D, a dominant cancer associated with HNPCC and other
CHEK2, PALB2
malignancies.
Peutz-Jeghers Colon, Small intestine, STK11/LKB1
syndrome oesophagus, pancreas, lung, breast,
stomach uterus, ovary
Inherited mutations play a major role in the development
Cowden Breast, thyroid, Ovary PTEN
syndrome endometrium of about 5%–10% of all cancers.
Li-Fraumeni Breast, sarcomas, Tumours in many sites TP53
syndrome CNS, leukaemia, Genetic mutations associated with more than 50
adrenocortical hereditary cancer syndromes have been identified, and
Lynch syndrome Colon, Ovary, small intestine, MMR gene: genetic tests can help tell whether a person from an
(HNPCC) endometrium oesophagus, MLH1, MSH2,
ureter, renal pelvis, MSH6, PMS1, affected family has one of these mutations.
glioblastoma PMS2,
EPCAM
CNS, Central nervous system; HNPCC, hereditary non-polyposis colorectal cancer;
MMR, mismatch repair.
A woman’s lifetime risk of developing ovarian cancer is BRCA mutation and HBOC
greatly increased if she inherits a harmful mutation in BRCA1 BRCA2
BRCA1 or BRCA2.
Breast cancer (females) 55%-85% 45%-84%
Generally, women have a 1.4% chance of developing Ovarian cancer 39%-44% 11%-17%
ovarian / tubal / peritoneal cancer by the age of 70 years.
Cowden syndrome Low 6%
This contrasts with a risk of 39%–44% and 11%–17%
for those with a harmful BRCA1 and BRCA2 mutation, Prostate cancer 9%
respectively. HBOC, Hereditary breast and ovarian cancer.
BRCA1 / BRCA2 increase the risk of other cancers in

addition to breast and ovarian cancer. Men carrying
BRCA1 / 2 harmful mutations have a lower incidence of
cancers but their female offspring will have a 50% chance
of inheritance.
REVISION QUESTIONS
1. What is the mechanism of action of mismatch repair genes?
2. How frequent are inherited mutations as a cause for gynaecological cancer?
3. What are the criteria for HBOC?
60
Hereditary ovarian and uterine cancer syndromes
Screening and surveillance
HNPCC syndrome (LS) ↑ the risk of some gynaecological Lynch syndrome = Hereditary non-polyposis colorectal cancer syndrome
malignancies (endometrial, ovarian and ureter).
In women with LS, the risk for developing endometrial

cancer exceeds colorectal cancer, with more than 50% of
first-arising “sentinel” tumour cases being gynaecological
tumours.
Diagnosis of LS is possible only by mutation analysis.
Screening in asymptomatic individuals should be
performed only if they belong to high-risk families.
CNS, Central nervous system; HNPCC, hereditary non-polyposis colorectal cancer.
Criteria such as Amsterdam II, Modified Bethesda or

Testing for Lynch syndrome
Society of Gynecologic Oncology criteria have been
published to guide screening and testing.
Patients at increased risk for LS undergo pre-screening

with MSI analysis and/or immunohistochemistry (IHC).
However, discordant results are sometimes observed
between IHC and replication error phenotyping.
MSI is a type of genomic instability in tumour tissue

caused by DNA mismatch failure, resulting in a variety
of mutations throughout the genome of the tumour
cells, including alterations in the length of small repetitive
microsatellite sequences throughout the genome.
Surveillance for Lynch Syndrome Carriers

For patients with LS, the only surveillance which has Cancer Intervention Recommendation Institution Evidence
demonstrated a beneficial effect is colonoscopy starting
Colon Colonoscopy At age 20-25 y or 2-5 y NCCN/ +++
at young age. prior the earliest colon AWMF
cancer. Repeat annual or
biennial
Theoretically, endometrial surveillance for HNPCC Endometrium Endometrium At 35 y annually AWMF -
carriers, by transvaginal ultrasound from age of 35–40 biopsy (Pipelle) (Option, no clear evidence) NCCN
years, may lead to the detection of atypical hyperplasia Endometrium Transvaginal At 35 y annually AWMF -
sonography (Option, no clear evidence) NCCN
and early cancers but this is not of proven benefit. Ovary Transvaginal At 25 y annually AWMF -
sonography (Option, no clear evidence) NCCN
+/- CA125
Prophylactic surgery is an appropriate treatment option
Urothelium/ Urinalysis At 25-30 y annually NCCN -
for BRCA mutation-associated cancer. Prophylactic bladder (Option, no clear evidence)
bilateral salpingo-oophorectomy lowers the ovarian CNS Physical/neurological At 25-30 y NCCN -
examination (Option, no clear evidence)
cancer risk by more than 90%.
Gastric Gastroscopy At 30-35 y, every 3-5 y NCCN/ +/-
AWMF
AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften;
CNS central nervous system; NCCN, National Comprehensive Cancer Network.
REVISION QUESTIONS
1. How is a diagnosis of LS made?
2. What is MSI?
3. What strategies for cancer prevention in women with harmful mutation in BRCA1 or BRCA2 or mutations in mismatch repair
genes do you know?
61
Marth
Summary: Hereditary ovarian and uterine cancer syndromes
• Approximately 5%–10% of cancers arise due to inherited mutations in genes
• Two manifestations of hereditary ovarian cancer are currently recognised: the HBOC syndrome and the HNPCC
syndrome
• A woman’s lifetime risk of developing breast, ovarian or endometrial cancer is greatly increased if she inherits a harmful
mutation in BRCA1 or BRCA2 or mutation in MMR genes
• Germline BRCA mutations are associated with longer survival rates after ovarian cancer diagnosis and a generally
favourable response to platinum-based therapy
• HNPCC syndrome, also known as “Lynch syndrome” (LS), has been defined clinically and genetically and is an
autosomal-dominant cancer predisposition syndrome that increases the risk for several forms of malignancy, including
colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, glioblastoma as seen in Turcot
syndrome, and sebaceous gland adenocarcinomas / keratoacanthomas in Muir-Torre syndrome
• Patients with LS-associated malignancies have an improved outlook clinically
• Patients at increased risk for LS undergo pre-screening with MSI analysis and/or IHC on affected tumour tissue
• For affected individuals with LS, the only screening of proven benefit is colonoscopy starting 10 years prior to youngest
affected family member
• Prophylactic surgery is another appropriate option for individuals carrying harmful BRCA mutations and LS
Further Reading
Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women
with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012; 30:2654–2663.
Buchanan DD, Rosty C, Clendenning M, et al. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause
of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet 2014; 7:183–193.
Cohen SA, Leininger A. The genetic basis of Lynch syndrome and its implications for clinical practice and risk management. Appl Clin
Genet 2014; 7:147–158.
Helleman J, van Staveren IL, Dinjens WN, et al. Mismatch repair and treatment resistance in ovarian cancer. BMC Cancer 2006; 6:201.
Kim TM, Laird PW, Park PJ. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 2013;
155:858–868.
Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1:157–162.
Kobayashi H, Ohno S, Sasaki Y, Matsuura M. Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep 2013;
30:1019–1029.
Lancaster JM, Powell CB, Chen LM, Richardson DL; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on
risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 2015; 136:3–7.
McLornan DP, List A, Mufti GJ. Applying synthetic lethality for the selective targeting of cancer. N Engl J Med 2014; 371:1725–1735.
Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl
J Med 2006; 354:261–269.
Vasen HF, Blanco I, Aktan-Collan K, et al; Mallorca group. Revised guidelines for the clinical management of Lynch syndrome (HNPCC):
recommendations by a group of European experts. Gut 2013; 62:812–823.
Westin SN, Lacour RA, Urbauer DL, et al. Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome.
J Clin Oncol 2008; 26:5965–5971.
62
Hereditary ovarian and uterine cancer syndromes
12 New drugs and novel treatment strategies for
Antiangiogenic treatment of ovarian cancer
Angiogenesis refers to the formation of new blood vessels.

Vascular endothelial growth factor (VEGF) is an important Tumour
mediator of angiogenesis which plays an important role in “Angiogenic
the genesis of ovarian cancer (OC). switch”
After reaching a certain size, a tumour needs supply VEGF

with nutrition and oxygen via its own blood vessels, 105 to 106 tumour cells
(1 to 10 mm3)
a process termed angiogenic switch.
Angiogenesis has been shown to play an important role in “Dormancy” Tumour growth
the genesis and progression of many different cancers, Proliferation = apoptosis Proliferation >> apoptosis
including epithelial OC.
VEGF, Vascular endothelial growth factor.
Bevacizumab, a humanised monoclonal antibody

against VEGF activity, is licensed in combination with
chemotherapy for first- and second-line treatment of
N N
epithelial OC.
N
O
To date, neither predictive nor surrogate markers of response
N
are validated for treatment with bevacizumab. It may be less
O NH effective in a proposed immunogenic type of OC than in an
O F
N O angiogenic type, based on preliminary data by Gurley et al.
O N
N O N H
O
Cediranib and nintedanib are small molecule tyrosine
Cediranib Nintedanib kinase inhibitors. Trebananib is a synthetic peptibody.
They all target angiogenesis.
Cell rounding and Tumour

surface blebbing Angiogenic
Vascular disrupting agents (VDAs) reversibly bind to of proliferating growth factors
endothelial cells
tubulin, disrupting the cytoskeleton of the endothelial cells
of the tumour vasculature in preference to normal tissues.
This causes clogging of tumour vessels within minutes of
application of the VDA, leading to haemorrhagic necrosis
of the tumour.
Combretastatin A4 phosphate (CA4P, fosbretabulin) has

shown activity in several early phase III clinical trials,
including OC patients. VDA
Pericytes Endothelial cells
VDA, Vascular disrupting agent.
REVISION QUESTIONS
1. Why is angiogenesis a crucial event in the progression of a tumour?
2. What is the mechanism of action of antiangiogenic and VDAs?
3. What is the mechanism behind combining VDAs with antiangiogenic agents?
63
Zweifel & Sessa
Antiangiogenic treatment of ovarian cancer
Antiangiogenic drugs prevent the formation of new Tumour rim Tumour centre
tumour blood vessels, while VDAs disrupt existing
}
tumour blood vessels. Distinct areas of a tumour show Highly angiogenic:
different sensitivities to treatments. sensitive to
antiangiogenic drugs
VDAs may induce mobilisation of endothelial progenitor
Well oxygenated: VDA-sensitive
cells from the bone marrow, resulting in vascularisation
sensitive to area
and growth of the tumour rim.
radiation therapy
This unwanted effect may be inhibited by combining
VDAs with antiangiogenic drugs. Robust tumour cell
proliferation/repopulation:
sensitive to chemotherapy
VDA, Vascular disrupting agent.
1.00
Neither nintedanib nor pazopanib improved outcomes

0.75 when given as maintenance therapy after first-line
treatment of patients with Stage IIIc / IV OC.

0.50
However, maintenance cediranib after platinum-based
chemotherapy prolongs both progression-free survival
0.25
(PFS) and overall survival (OS) in platinum-sensitive
Chemotherapy
Maintenance recurrent disease.
0.00
0 6 12 18 24 30
Months
Chemotherapy 118 106 89 46 27 11
Maintenance 164 159 139 89 48 22
100 Olaparib group

Cediranib plus olaparib
80
Progression-free survival
Preclinical evidence of downregulation of DNA repair

genes / proteins in hypoxic conditions prompted 60
evaluation of combination therapy – olaparib and
cediranib – in relapsed OC. 40
Results of the phase II trial suggest that the combination

20
could be synergistic (cediranib particularly augmenting
response in the BRCA wild-type group) and further
0
evaluation will be done in a phase III trial (ICON 9). 0 6 12 18 24 30
Number at risk Months
Olaparib group 46 27 13 6 1 0
Cediranib plus 44 38 24 11 3 0
olaparib group
REVISION QUESTIONS
1. Which antiangiogenic drugs are approved or have been clinically evaluated in OC?
2. Name the key differences in modes of action between tyrosine kinase inhibitors and VEGF inhibitors.
3. Describe some of the mechanisms for combining antiangiogenics with alternative targeted agents.
64
New drugs and novel treatment strategies for gynaecological cancers
PARP inhibitors
Damage to DNA is repaired by different pathways: Type of Single- Double- Bulky O6-
damage: strand strand adducts alkylguanine
single-strand breaks (SSBs) by base-excision repair breaks breaks Insertions
(BER), nucleotide-excision repair or mismatch repair; (SSBs) (DSBs) & deletions
double-strand breaks (DSBs) by error-prone non-

homologous end-joining (NHEJ) and homologous Mismatch
recombination (HR). repair
Repair Base Recombinational Nucleotide Direct
pathway: excision repair excision reversal
repair repair
BRCA1 and BRCA2 are required for efficient HR repair;
HR NHEJ
their functional loss leads to the use of the NHEJ Repair
pathway with cell death or genetic instability. enzymes: PARP ATM DNA-PK XP, MSH2,
poly- MLH1
AGT
merases
HR, Homologous recombination; NHEJ, non-homologous end-joining;

PARP, poly(ADP-ribose) polymerase.
One of the poly(ADP-ribose) polymerase enzymes

(PARP-1), a component of the BER pathways, binds to
DNA breaks with ribosylation and recruits other DNA
repair pathway components.
PARP inhibition results in persisting SSBs,

accumulation of DSBs and, where there is functional
loss of BRCA1 or BRCA2, activation of NHEJ with
consequent cell lethality.
Concomitant targeting of two genes in two interacting

pathways is the basis of the selective synthetic lethality
approach.
Up to 50% of high-grade serous ovarian cancer (HGSOC)

patients have DNA repair defects due to BRCA 1 or 2 germline
(15%) or somatic mutation, or “BRCAness” – i.e. mutations in
Questions in PARPi development
other repair genes, or promoter hypermethylation. BRCAness
(BRCA-like behaviour) is associated with higher sensitivity to DNA Development of combination with
chemotherapy
damaging agents and responses to PARP inhibitors (PARPi). molecular targeted agents (Pl3Ki, antiangiogenics)
PARPi (olaparib, rucaparib, veliparib) are small molecule Optimal timing of therapy
first line/recurrence
tyrosine kinase inhibitors (TKIs) of PARP1, shown to be maintenance
effective in platinum-sensitive relapse HGSOC (response
rate: >50%) and in germline-mutant BRCA1, 2 platinum- Discovery and validation of predictive biomarkers
BRCA1/2 loss
resistant patients (response rate: 30%). RAD51 foci
γ H2 Ax foci
Olaparib is licensed for the maintenance treatment of platinum-
PARPi, PARP inhibitor.
sensitive relapsed OC with germline and/or somatic-mutated
BRCA1/2 detected by the BRACAnalysis CDx (Food and Drug
Administration-approved companion test).
REVISION QUESTIONS
1. What is meant by selective synthetic lethality?
2. What are the main clinical characteristics of BRCAness patients?
3. What are the current licensed indications for the PARPi olaparib?
65
Zweifel & Sessa
Other areas currently being explored and developed
The tumour suppressor protein, p53, is a transcription

factor which controls cellular response to stress signals MDM2
through the induction of cell cycle arrest, apoptosis or
senescence. p14ARF
p53 p21, puma, bax,
Mutant MDM2, etc
More than 80% of Type II ovarian tumours harbour TP53 TP53
mutations and p53 is an attractive therapeutic target.
HPV-E6
p53 inactivation occurs by point mutation in TP53 itself, and
compounds able to reactivate mutant p53 are currently
being examined and have completed first clinical testing.
K-RAS and BRAF mutations are rarely detected in

HGSOC but are present in 30%–50% of low-grade
serous ovarian cancer (LGSOC) and 50% of the very rare
mucinous OC.
Single-agent MEK inhibitors have shown a 15%

objective response in patients with LGSOC, and
MAPK pathway inhibitors are being tested in Phase III
studies in this histological subtype. Further studies
are under way (LOGS).
Programmed death-1 (PD-1) is a co-inhibitory receptor

expressed on activated T cells which regulates
antitumour immunity.
Nivolumab, a fully-humanised IgG4 antibody that blocks

the engagement of PD-1 by PD-1 ligands, showed
durable responses in platinum-resistant OC.
Of 20 patients, two complete responses (PFS 17 and
14 months) were seen. Single and combined treatment
targeting PD-1 might be an important option in future.
REVISION QUESTIONS
1. What are the main mechanisms of deactivation of TP53 function?
2. In which histological subtype of OC have K-RAS mutations been mainly described?
66
New drugs and novel treatment strategies for gynaecological cancers
Summary: New drugs and novel treatment strategies for
• Angiogenesis plays an important role in genesis and progression of epithelial OC
• Bevacizumab, a monoclonal antibody, neutralises VEGF and is licensed in combination with chemotherapy and
subsequent maintenance for the first-line and platinum-sensitive relapse treatment of patients with OC
• Biomarkers predicting response to antiangiogenics are urgently required
• Small molecule TKIs targeting angiogenesis and VDAs are promising new drugs in the treatment of OC
• PARPi have shown activity in patients with high-grade serous platinum-sensitive OC, especially those with germline
BRCA1 or 2 mutations. Olaparib is licensed for maintenance therapy of patients who have been treated for platinum-
sensitive relapse and who carry BRCA1 or 2 germline and/or somatic mutations
• Immunological strategies are potentially exciting future therapeutic developments in OC
Further Reading
Ashworth A. A synthetic lethal therapeutic approach: poly (ADP) ribose polymerase inhibitors for the treatment of cancers deficient in
DNA double-strand break repair. J Clin Oncol 2008; 26:3785–3790.
Cheok CF, Verma CS, Baselga J, Lane DP. Translating p53 into the clinic. Nat Rev Clin Oncol 2011; 8:25–37.
Folkman J. Tumour angiogenesis: therapeutic implications. N Engl J Med 1971; 285:1182–1186.
Gourley C, McCavigan A, Perren T, et al. Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome
following bevacizumab. J Clin Oncol 2014; 32:5s (suppl; abstr 5502).
Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 2014;
25:32–40.
Nathan P, Zweifel M, Padhani AR, et al. Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients
with advanced cancer. Clin Cancer Res 2012; 18:3428–3439.
Rouleau M, Patel A, Hendzel HJ, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer 2010; 10:293–301.
Rustin GJ, Shreeves G, Nathan PD, et al. A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients
with advanced cancer. Br J Cancer 2010; 102:1355–1360.
Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science
2006; 313:1785–1787.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in
human rectal cancer. Nat Med 2004; 10:145–147.
67
Zweifel & Sessa
Appendix 1: WHO Classification
Tumours of the ovary Undifferentiated and unclassified tumours

Undifferentiated carcinoma
Surface epithelial-stromal tumours Adenocarcinoma, not otherwise specified
Serous tumours Sex cord-stromal tumours
Malignant Granulosa-stromal cell tumours
Adenocarcinoma
Surface papillary adenocarcinoma Granulosa cell tumour group
Adenocarcinofibroma (malignant adenofibroma) Adult granulosa cell tumour
Borderline tumour Juvenile granulosa cell tumour
Papillary cystic tumour Thecoma-fibroma group
Surface papillary tumour Thecoma, not otherwise specified
Adenofibroma, cystadenofibroma Typical
Benign Luteinised
Cystadenoma Fibroma
Papillary cystadenoma Cellular fibroma
Surface papilloma Fibrosarcoma
Adenofibroma and cystadenofibroma Stromal tumour with minor sex cord elements
Sclerosing stromal tumour
Mucinous tumours Signet-ring stromal tumour
Malignant Unclassified (fibrothecoma)
Adenocarcinoma Sertoli-stromal cell tumours
Adenocarcinofibroma (malignant adenofibroma)
Borderline tumour Sertoli-Leydig cell tumour group (androblastomas)
Intestinal type Well differentiated
Endocervical-like Of intermediate differentiation
Benign Variant with heterologous elements (specify type)
Cystadenoma Poorly differentiated (sarcomatoid)
Adenofibroma and cystadenofibroma Variant with heterologous elements (specify type)
Mucinous cystic tumour with mural nodules Retiform
Mucinous cystic tumour with pseudomyxoma peritonei Variant with heterologous elements (specify type)
Sertoli cell tumour
Endometrioid tumours including variants with squamous Stromal-Leydig cell tumour
differentiation Sex cord-stromal tumours of mixed or unclassified cell types
Malignant Sex cord tumour with annular tubules
Adenocarcinoma, not otherwise specified Gynandroblastoma (specify components)
Adenocarcinofibroma (malignant adenofibroma) Sex cord-stromal tumour, unclassified
Malignant müllerian mixed tumour (carcinosarcoma)
Adenosarcoma Steroid cell tumours
Endometrioid stromal sarcoma (low grade) Stromal luteoma
Undifferentiated ovarian sarcoma Leydig cell tumour group
Borderline tumour Hilus cell tumour
Cystic tumour Leydig cell tumour, non-hilar type
Adenofibroma and cystadenofibroma Leydig cell tumour, not otherwise specified
Benign Steroid cell tumour, not otherwise specified
Cystadenoma Well differentiated
Adenofibroma and cystadenofibroma Malignant
Clear cell tumours Germ cell tumours
Malignant Primitive germ cell tumours
Adenocarcinoma
Adenocarcinofibroma (malignant adenofibroma) Dysgerminoma
Borderline tumour Yolk sac tumour
Cystic tumour Polyvesicular vitelline tumour
Adenofibroma and cystadenofibroma Glandular variant
Benign Hepatoid variant
Cystadenoma Embryonal carcinoma
Adenofibroma and cystadenofibroma Polyembryoma
Non-gestational choriocarcinoma
Transitional cell tumours Mixed germ cell tumour (specify components)
Malignant Biphasic or triphasic teratomas
Transitional cell carcinoma (non-Brenner type)
Malignant Brenner tumour Immature teratomas
Borderline Mature teratomas
Borderline Brenner tumour Solid
Proliferating variant Cystic
Benign Dermoid cyst
Brenner tumour Fetiform teratoma (homunculus)
Metaplastic variant Monodermal teratoma and somatic-type tumours associated with
Squamous cell tumours dermoid cysts
Squamous cell carcinoma Thyroid tumour group
Epidermoid cyst Struma ovarii
Mixed epithelial tumours (specify components) Benign
Malignant (specify type)
Malignant Carcinoid group
Borderline Insular
Benign Trabecular
69
Mucinous Tumour of uncertain origin
Strumal carcinoid
Desmoplastic small round cell tumour
Mixed
Neuroectodermal tumour group Epithelial tumours
Ependymoma Primary peritoneal serous adenocarcinoma
Primitive neuroectodermal tumour Primary peritoneal borderline tumour (specify type)
Medulloepithelioma Others
Glioblastoma multiforme
Others
Carcinoma group Tumours of the fallopian tube
Adenocarcinoma Epithelial tumours
Other Malignant
Melanocytic group Serous adenocarcinoma
Malignant melanoma Mucinous adenocarcinoma
Melanocytic naevus Endometrioid adenocarcinoma
Sarcoma group (specify type) Clear cell adenocarcinoma
Sebaceous tumour group Transitional cell carcinoma
Sebaceous adenoma Squamous cell carcinoma
Sebaceous carcinoma Undifferentiated carcinoma
Pituitary-type tumour group Others
Retinal anlage tumour group Borderline tumour (of low malignant potential)
Others Serous borderline tumour
Germ cell sex cord-stromal tumours Mucinous borderline tumour
Gonadoblastoma Endometrioid borderline tumour
Variant with malignant germ cell tumour Others
Mixed germ cell-sex cord-stromal tumour Carcinoma in situ (specify type)
Variant with malignant germ cell tumour Benign tumours
Papilloma (specify type)
Tumours of the rete ovarii Cystadenoma (specify type)
Adenocarcinoma Adenofibroma (specify type)
Adenoma Cystadenofibroma (specify type)
Cystadenoma Metaplastic papillary tumour
Cystadenofibroma Endometrioid polyp
Miscellaneous tumours Others
Tumour-like epithelial lesions
Small cell carcinoma, hypercalcaemic type Tubal epithelial hyperplasia
Small cell carcinoma, pulmonary type Salpingitis isthmica nodosa
Large cell neuroendocrine carcinoma Endosalpingiosis
Hepatoid carcinoma
Primary ovarian mesothelioma Mixed epithelial-mesenchymal tumours
Wilms tumour Malignant müllerian mixed tumour (carcinosarcoma; metaplastic carcinoma)
Gestational choriocarcinoma Adenosarcoma
Hydatidiform mole Soft tissue tumours
Adenoid cystic carcinoma
Basal cell tumour Leiomyosarcoma
Ovarian wolffian tumour Leiomyoma
Paraganglioma Others
Myxoma Mesothelial tumours
Soft tissue tumours not specific to the ovary Adenomatoid tumour
Others
Germ cell tumours
Tumour-like conditions
Teratoma
Luteoma of pregnancy Mature
Stromal hyperthecosis Immature
Stromal hyperplasia Others
Fibromatosis
Massive ovarian oedema Trophoblastic disease
Others Choriocarcinoma
Lymphoid and haematopoietic tumours Placental site trophoblastic tumour
Hydatidiform mole
Malignant lymphoma (specify type) Placental site nodule
Leukaemia (specify type) Others
Plasmacytoma
Lymphoid and haematopoietic tumours
Malignant lymphoma
Tumours of the peritoneum Leukaemia
Secondary tumours
Peritoneal tumours
Mesothelial tumours
Diffuse malignant mesothelioma Tumours of the broad ligament and
Well differentiated papillary mesothelioma
Multicystic mesothelioma
other uterine ligaments
Adenomatoid tumour
Epithelial tumours of müllerian type
Smooth muscle tumour Serous adenocarcinoma
Leiomyomatosis peritonealis disseminate Endometrioid adenocarcinoma
70
Mucinous adenocarcinoma Mixed epithelial and mesenchymal tumours
Clear cell adenocarcinoma
Carcinosarcoma (malignant müllerian mixed tumour; metaplastic carcinoma)
Borderline tumour (of low malignant potential), (specify type)
Adenosarcoma
Adenoma and cystadenoma (specify type)
Carcinofibroma
Miscellaneous tumours Adenofibroma
Wolffian adnexal tumour Adenomyoma
Ependymona Atypical polypoid variant
Papillary cystadenoma (with von-Hippel-Lindau disease) Gestational trophoblastic disease
Uterus-like mass
Trophoblastic neoplasms
Adenosarcoma
Choriocarcinoma
Others
Placental site trophoblastic tumour
Mesenchymal tumours Epithelioid trophoblastic tumour
Malignant Molar pregnancies
Benign Hydatidiform mole
Complete
Secondary tumours Partial
Invasive
Tumours of the uterine corpus Metastatic
Non-neoplastic, non-molar trophoblastic lesions
Placental site nodule and plaque
Epithelial tumours and related lesions Exaggerated placental site
Endometrial carcinoma Miscellaneous tumours
Endometrioid adenocarcinoma
Variant with squamous differentiation Sex cord-like tumours
Villoglandular variant Neuroectodermal tumours
Secretory variant Melanotic paraganglioma
Ciliated cell variant Tumours of germ cell type
Mucinous adenocarcinoma Others
Serous adenocarcinoma Lymphoid and haematopoietic tumours
Clear cell adenocarcinoma Malignant lymphoma (specify type)
Mixed cell adenocarcinoma Leukaemia (specify type)
Transitional cell carcinoma Secondary tumours
Small cell carcinoma
Undifferentiated carcinoma
Others
Endometrial hyperplasia Tumours of the uterine cervix
Nonatypical hyperplasia
Simple Epithelial tumours
Complex (adenomatous) Squamous tumours and precursors
Atypical hyperplasia Squamous cell carcinoma, not otherwise specified
Simple Keratinising
Complex Non-keratinising
Endometrial polyp Basaloid
Tamoxifen-related lesions Verrucous
Mesenchymal tumours Warty
Papillary
Endometrial stromal and related tumours
Lymphoepithelioma-like
Endometrial stromal sarcoma, low grade
Squamotransitional
Endometrial stromal nodule
Early invasive (microinvasive) squamous cell carcinoma
Undifferentiated endometrial sarcoma
Squamous intraepithelial neoplasia
Smooth muscle tumours
Cervical intraepithelial neoplasia (CIN) / squamous cell carcinoma in situ
Leiomyosarcoma
Benign squamous cell lesions
Epithelioid variant
Condyloma acuminatum
Myxoid variant
Squamous papilloma
Smooth muscle tumour of uncertain malignant potential
Fibroepithelial polyp
Leiomyoma, not otherwise specified
Glandular tumours and precursors
Histological variants
Adenocarcinoma
Mitotically active variant
Mucinous adenocarcinoma
Cellular variant
Endocervical
Haemorrhagic cellular variant
Intestinal
Epithelioid variant
Signet-ring cell
Myxoid
Minimal deviation
Atypical variant
Villoglandular
Lipoleiomyoma variant
Endometrioid adenocarcinoma
Growth pattern variants
Clear cell adenocarcinoma
Diffuse leiomyomatosis
Serous adenocarcinoma
Dissecting leiomyoma
Mesonephric adenocarcinoma
Intravenous leiomyomatosis
Early invasive adenocarcinoma
Metastasising leiomyoma
Adenocarcinoma in situ
Miscellaneous mesenchymal tumours
Glandular dysplasia
Mixed endometrial stromal and smooth muscle tumour
Benign glandular lesion
Perivascular epithelioid cell tumour
Müllerian papilloma
Adenomatoid tumour
Endocervical polyp
Other malignant mesenchymal tumours
Other benign mesenchymal tumours
71
Other epithelial tumours Small cell carcinoma
Adenosquamous carcinoma Undifferentiated carcinoma
Glassy cell carcinoma variant Mesenchymal tumours and tumour-like conditions
Adenoid cystic carcinoma
Adenoid basal carcinoma Sarcoma botryoides
Neuroendocrine tumours Leiomyosarcoma
Carcinoid Endometrioid stromal sarcoma, low grade
Atypical carcinoid Undifferentiated vaginal sarcoma
Small cell carcinoma Leiomyoma
Large cell neuroendocrine carcinoma Genital rhabdomyoma
Undifferentiated carcinoma Deep angiomyxoma
Postoperative spindle cell nodule
Mesenchymal tumours and tumour-like conditions
Mixed epithelial and mesenchymal tumours
Leiomyosarcoma
Endometrioid stromal sarcoma, low grade Carcinosarcoma (malignant müllerian mixed tumour; metaplastic carcinoma)
Undifferentiated endocervical sarcoma Adenosarcoma
Sarcoma botryoides Malignant mixed tumour resembling synovial sarcoma
Alveolar soft part sarcoma Benign mixed tumour
Angiosarcoma Melanocytic tumours
Malignant peripheral nerve sheath tumour Malignant melanoma
Leiomyoma Blue naevus
Genital rhabdomyoma Melanocytic naevus
Postoperative spindle cell nodule
Miscellaneous tumours
Mixed epithelial and mesenchymal tumours
Tumours of germ cell type
Carcinosarcoma (malignant müllerian mixed tumour; metaplastic carcinoma) Yolk sac tumour
Adenosarcoma Dermoid cyst
Wilms tumour Others
Adenofibroma Peripheral primitive neuroectodermal tumour / Ewing tumour
Adenomyoma Adenomatoid tumour
Melanocytic tumours Lymphoid and haematopoietic tumours
Malignant melanoma Malignant lymphoma (specify type)
Blue naevus Leukaemia (specify type)
Miscellaneous tumours Secondary tumours
Tumours of germ cell type
Yolk sac tumour
Dermoid cyst
Mature cystic teratomas
Tumours of the vulva
Lymphoid and haematopoietic tumours Epithelial tumours
Malignant lymphoma (specify type) Squamous and related tumours and precursors
Leukaemia (specify type) Squamous cell carcinoma, not otherwise specified
Keratinising
Secondary tumours Non-keratinising
Basaloid
Tumours of the vagina Warty
Verrucous
Keratoacanthoma-like
Epithelial tumours Variant with tumour giant cells
Squamous tumours and precursors Others
Squamous cell carcinoma, not otherwise specified Basal cell carcinoma
Keratinising Squamous intraepithelial neoplasia
Non-keratinising Vulvar intraepithelial neoplasia (VIN) 3 / squamous cell carcinoma in situ
Basaloid Benign squamous lesions
Verrucous Condyloma acuminatum
Warty Vestibular papilloma (micropapillomatosis)
Squamous intraepithelial neoplasia Fibroepithelial polyp
Vaginal intraepithelial neoplasia 3 / squamous cell carcinoma in situ Seborrheic and inverted follicular keratosis
Benign squamous lesions Keratoacanthoma
Condyloma acuminatum Glandular tumours
Squamous papilloma (vaginal micropapillomatosis)
Fibroepithelial polyp Paget disease
Glandular tumours Bartholin gland tumours
Clear cell adenocarcinoma Adenocarcinoma
Endometrioid adenocarcinoma Squamous cell carcinoma
Mucinous adenocarcinoma Adenoid cystic carcinoma
Mesonephric adenocarcinoma Adenosquamous carcinoma
Müllerian papilloma Transitional cell carcinoma
Adenoma, not otherwise specified Small cell carcinoma
Tubular Adenoma
Tubulovillous Adenomyoma
Villous Other
Other epithelial tumours Tumours arising from specialised anogenital mammary-like glands
Adenosquamous carcinoma Adenocarcinoma of mammary gland type
Adenoid cystic carcinoma Papillary hidradenoma
Adenoid basal carcinoma Others
Carcinoid Adenocarcinoma of Skene gland origin
72
Adenocarcinomas of other types
Adenoma of minor vestibular glands
Mixed tumour of the vulva
Tumours of skin appendage origin
Malignant sweat gland tumours
Sebaceous carcinoma
Syringoma
Nodular hidradenoma
Trichoepithelioma
Trichilemmoma
Others
Soft tissue tumours
Sarcoma botryoides
Leiomyosarcoma
Proximal epithelioid sarcoma
Alveolar soft part sarcoma
Liposarcoma
Dermatofibrosarcoma protuberans
Deep angiomyxoma
Superficial angiomyxoma
Angiomyofibroblastoma
Cellular angiofibroma
Leiomyoma
Granular cell tumour
Other
Melanocytic tumours
Malignant melanoma
Congenital melanocytic naevus
Acquired melanocytic naevus
Blue naevus
Atypical melanocytic naevus of the genital type
Dysplastic melanocytic naevus
Miscellaneous tumours
Yolk sac tumour
Merkel cell tumour
Peripheral primitive neuroectodermal tumour / Ewing tumour
Haematopoietic and lymphoid tumours
Malignant lymphoma (specify type)
Leukaemia (specify type)
Secondary tumours
73
Appendix 2: FIGO Ovarian, Fallopian Tube,
and Peritoneal Cancer Staging System and
Corresponding TNM
Tumour confined to ovaries or
fallopian tube(s) Carcinoma of the vulva
TNM staging FIGO staging (2009) Description TNM staging FIGO staging (2009) Description
T1a-N0-M0 Stage IA Tumour limited to one ovary (capsule Tx Nx Mx Tumour confined to the vulva but cannot
intact) or fallopian tube; no tumour be assessed
on ovarian or fallopian tube surface; T0 N0 M0 No evidence of primary tumour
no malignant cells in the ascites or Tis N0 M0 Carcinoma in situ (preinvasive)
peritoneal washings
T1a N0 M0 Stage IA Lesions ≤2 cm in size, confined to the
T1b-N0-M0 Stage IB Tumour limited to both ovaries (capsules vulva or perineum and with stromal
intact) or fallopian tubes; no tumour invasion ≤1.0 mm*, no nodal metastasis
on ovarian or fallopian tube surface;
no malignant cells in the ascites or T1b N0 M0 Stage IB Lesions >2 cm in size or with stromal
peritoneal washings invasion >1.0 mm*, confined to the vulva
or perineum, with negative nodes
T1c-N0-M0 Stage IC1 Tumour limited to one or both ovaries or
fallopian tubes, with surgical spill T2 N0 M0 Stage II Tumour of any size with extension to
adjacent perineal structures (1/3 lower
T1c-N0-M0 Stage IC2 Tumour limited to one or both ovaries or urethra, 1/3 lower vagina, anus) with
fallopian tubes, with capsule ruptured negative nodes
before surgery or tumour on ovarian or
fallopian tube surface T3 N1a/b M0 Stage IIIA Tumour of any size with or without
extension to adjacent perineal structures
T1c-N0-M0 Stage IC3 Tumour limited to one or both ovaries or (1/3 lower urethra, 1/3 lower vagina, anus)
fallopian tubes, with malignant cells in
the ascites or peritoneal washings Stage IIIAi With 1 lymph node metastasis (<5 mm)
Stage IIIAii 1–2 lymph node metastasis(es) (≥5 mm)
T2a-N0-M0 Stage IIA Extension and/or implants on uterus and/
or fallopian tubes and/or ovaries T3 N2a/b M0 Stage IIIB Tumour of any size with or without
extension to adjacent perineal structures
T2b-N0-M0 Stage IIB Extension to other pelvic intraperitoneal (1/3 lower urethra, 1/3 lower vagina, anus)
tissues
Stage IIIBi With 2 or more lymph node metastases
T1/T2-N1-M0 Stage IIIA1 Positive retroperitoneal lymph nodes only
(<5 mm)
(cytologically or histologically proven)
Stage IIIBii 3 or more lymph node metastases
Stage IIIA1(i) Metastasis up to 10 mm
(≥5 mm)
Stage IIIA1(ii) Metastasis more than 10 mm
T3 N2c M0 Stage IIIC Tumour of any size with or without
T3a2-N0/N1-M0 Stage IIIA2 Microscopic extrapelvic (above the pelvic
extension to adjacent perineal
brim) peritoneal involvement with or
structures (1/3 lower urethra, 1/3 lower
without positive retroperitoneal lymph
vagina, anus) with positive nodes and
nodes
extracapsular spread
T3b-N0/N1-M0 Stage IIIB Macroscopic peritoneal metastasis
T3 any N M0 Stage IVA Tumour invades other regional structures
beyond the pelvis up to 2 cm in greatest
(2/3 upper urethra, 2/3 upper vagina), or
dimension, with or without metastasis to
distant structures
the retroperitoneal lymph nodes
T3c-N0/N1-M0 Stage IIIC Macroscopic peritoneal metastasis T3 N2c M0 Stage IVAi Tumour invades any of the following:
beyond the pelvis more than 2 cm in upper urethral and/or vaginal mucosa,
greatest dimension, with or without bladder mucosa, rectal mucosa, or fixed
metastasis to the retroperitoneal lymph to pelvic bone
nodes (includes extension of tumour Stage IVAii Fixed or ulcerated inguino-femoral lymph
to capsule of liver and spleen without nodes
parenchymal involvement of either organ)
Any T, any N, M1 Stage IVB Any distant metastasis including pelvic
Any T, any N, M1 Stage IVA Pleural effusion with positive cytology lymph nodes
*The depth of invasion is defined as the measurement of the tumour from the epithelial-stromal
Any T, any N, M1 Stage IVB Parenchymal metastases and metastases junction of the adjacent most superficial dermal papilla to the deepest point of invasion.
to extra-abdominal organs (including
inguinal lymph nodes and lymph nodes
outside of the abdominal cavity)
J Gynecol Oncol 2015; 26:87-89.
74
Appendix 2: FIGO Ovarian, Fallopian Tube, and Peritoneal Cancer Staging System and Corresponding TNM
Carcinoma of the cervix uteri Carcinoma of the uterus
TNM staging FIGO staging (2009) Description TNM staging FIGO staging (2009) Description
Tx N0 M0 Primary tumour cannot be assessed Tx N0 M0 Primary tumour cannot be assessed
T0 N0 M0 No evidence of primary tumour T0 N0 M0 No evidence of primary tumour
Tis N0 M0 Carcinoma in situ (preinvasive carcinoma) Tis N0 M0 Carcinoma in situ (preinvasive carcinoma)
T1a any N M0 Stage IA Invasive carcinoma which can be T1a N0 M0 Stage IA* Tumour confined to the corpus uteri with
diagnosed only by microscopy no or less than half myometrial invasion
T1a1 any N M0 Stage IA1 Stromal invasion ≤3.0 mm in depth and T1b N0 M0 Stage IB* Invasion equal to or more than half of the
extension of ≤7.0 mm myometrium
T1a2 any N M0 Stage IA2 Stromal invasion of >3.0 mm and not
T2 N0 M0 Stage II* Tumour invades cervical stroma, but does
<5.0 mm with extension <7.0 mm
not extend beyond the uterus**
T1b any N M0 Stage IB Clinically visible lesions limited to the
T3a N0 M0 Stage IIIA* Tumour invades the serosa of the corpus
cervix uteri or pre-clinical cancers greater
uteri and/or adnexae*
than Stage IA*
T1b1 any N M0 Stage IB1 Clinically visible lesion ≤4.0 cm in T3b N0 M0 Stage IIIB* Vaginal and/or parametrial involvement*
greatest dimension
T1b2 any N M0 Stage IB2 Clinically visible lesion >4.0 cm in Any T N1/2 M0 Stage IIIC* Metastases to pelvic and/or para-aortic
greatest dimension lymph nodes*
T2a any N M0 Stage IIA Cervical carcinoma invades into upper Any T N1 M0 Stage IIIC1* Positive pelvic nodes only
2/3 vagina without parametrial invasion Any T N2 M0 Stage IIIC2* Positive para-aortic lymph nodes +/-
T2a1 any N M0 Stage IIA1 ≤4.0 cm in greatest dimension positive pelvic lymph node
T2a2 any N M0 Stage IIA2 >4.0 cm in greatest dimension
T4 any N M0 Stage IVA* Tumour invasion of bladder and/or bowel
T2b any N M0** Stage IIB Cervical carcinoma invades into upper mucosa
2/3 vagina with parametrial invasion
Any T, any N, M1 Stage IVB* Distant metastases, including intra-
T3a any N M0 Stage IIIA Tumour involves lower third of the vagina, abdominal metastases and/or inguinal
with no extension to the pelvic side wall lymph nodes
or hydronephrosis / non-functioning
kidney *Either G1, G2, or G3 and any positive cytology has to be reported separately without changing
the stage.
T3b any N M0** Stage IIIB Extension to the pelvic wall and/or **Endocervical glandular involvement only should be considered as Stage I and no longer as
hydronephrosis or non-functioning kidney Stage II. http://www.csh.org.tw/dr.tcj/educartion/Cancer%20center/PDF/2010/FIGO%20
staging%20revision%202009.pdf
T4a any N M0** Stage IVA Spread of the cancer to involve the Int J Gyn and Obstet 2009; 105:103-104.
mucosa of adjacent organs in pelvis – ie
mucosa of bladder or rectum (bullous
oedema, as such, does not permit a case
to be allotted to Stage IV)
T4b any N M1 Stage IVB Spread to distant organs
*All macroscopically visible lesions—even with superficial invasion—are allotted to Stage IB
carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00
mm and a horizontal extension of <7.00 mm. Depth of invasion should not be >5.00 mm taken
from the base of the epithelium of the original tissue—superficial or glandular. The depth of
invasion should always be reported in mm, even in those cases with “early (minimal) stromal
invasion” (~1 mm). The involvement of vascular/lymphatic spaces should not change the stage
allotment.
**On rectal examination, there is no cancer-free space between the tumour and the pelvic wall.
All cases with hydronephrosis or non-functioning kidney are included, unless they are known to
be due to another cause.
75
Appendix 2: FIGO Ovarian, Fallopian Tube, and Peritoneal Cancer Staging System and Corresponding TNM
Appendix 3: Selected treatment schedules
Ovary
Regimen Drug Dose Days Route Cycle
General principles: Carboplatin doses are calculated according to renal function. Where AUC 4/5 or 5/6 is stated, the lower value relates to EDTA calculation and the higher value to the
calculated dose (Cockcroft and Gault).
Carboplatin allergy occurs in 27%+ patients receiving repeated treatment (especially after a gap). In these instances, premedication with antihistamines (chlorphenamine
4 mg orally 3 times a day) and dexamethasone (8 mg orally twice a day) from the day before treatment and a slow rate of infusion should be tried initially. If unsuccessful, the
carboplatin desensitisation protocol can be utilised or cisplatin (70 mg/m2 every 21 days or 30-40 mg/m2 weekly) substituted for carboplatin (~9% chance of cross-hypersensitivity) [1]
Advanced ovarian cancer, first line
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x6 [2]
Paclitaxel 175 mg/m 2
d1 i.v. q 21d x6
Carboplatin / weekly paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x6 [3]
Paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d x6
Carboplatin Carboplatin AUC 5/6 d1 i.v. q 21d x5-6 [4]
Weekly carboplatin / Carboplatin AUC 2 d1, d8, d15 i.v. q 21d or 28d [5]
weekly paclitaxel
Paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d or 28d
Carboplatin / docetaxel Carboplatin AUC 5/6 d1 i.v. q 21d x6 [6]
Docetaxel 75 mg/m2 d1 i.v. q 21d x6
Bevacizumab Bevacizumab 15 mg/kg or 7.5 mg/kg d1 i.v. q 21d x12-15 months [7,8]
[only given alongside carboplatin and
paclitaxel – either 175 mg/m 2
or weekly (80 mg/m2) and as

maintenance beyond, but not alone.
Its indication is in suboptimally
surgically debulked patients who gain
significant progression-free survival
and overall survival benefit]
Intraperitoneal chemotherapy [9,10]
Cisplatin / paclitaxel Cisplatin 75-100 mg/m2 d1 i.p. [10]
Paclitaxel 135 mg/m2 d1 i.v.

Paclitaxel 60 mg/m2 d8 i.p.
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.p. [11]

d8 i.p.
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.p. [12]
Paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d

Intraperitoneal regimens described [13]
are also safe with bevacizumab 15

mg/kg or 7.5 mg/kg i.v. q 21d with
chemo and as maintenance for 12-15
months or disease progression
[bevacizumab is generally given
alongside many concomitant
chemotherapy regimens and as
maintenance beyond]
Platinum-sensitive relapsed ovarian cancer
Carboplatin Carboplatin AUC 5/6 d1 i.v. q 21d x5-6 [14]
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x6 [15]
Paclitaxel 175 mg/m2 d1 i.v. q 21d x6 [16]
Carboplatin / weekly paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x6
d1, d8, d15 i.v. q 21d x6 [17]
76
Carboplatin / gemcitabine / Carboplatin AUC 4/5 d1 i.v. q 21d x6 (-10) [18]
bevacizumab
Gemcitabine 1000 mg/m2 d1, d8 i.v. q 21d x6 (-10) [19]
Bevacizumab 15 mg/kg d1 i.v. q 21d to progression
Carboplatin / liposomal doxorubicin Carboplatin AUC 5 d1 i.v. q 28d x4-6 cycles [20]
Liposomal doxorubicin 30 mg/m2 d1 i.v. q 28d x4-6 cycles
Carboplatin / topotecan Carboplatin AUC 5/6 d1 i.v. q 21d [21]
Topotecan 1.5-2 mg/m2 d1, d8 i.v. q 21d [22]
Platinum-resistant ovarian cancer
Liposomal doxorubicin Liposomal doxorubicin 40 mg/m2 d1 i.v. q 28d x4-8 cycles [23]
Weekly paclitaxel Paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d or 28d x4 cycles [24]
Oral cyclophosphamide Cyclophosphamide 50-100 mg daily p.o. continuous [25-27]
Topotecan Topotecan 1.5 mg/m 2
d1-5 i.v. q 21d x4-6 cycles [28]
Treosulfan Treosulfan 7 g/m2 d1 i.v. q 21d [28]
Bevacizumab Bevacizumab 15 mg/kg d1 i.v. q 21d to progression [29,30]
[bevacizumab can be given with
liposomal doxorubicin, weekly
paclitaxel, oral cyclophosphamide
and topotecan in the platinum-
resistant setting and as maintenance
beyond to prolong remission]
Gemcitabine Gemcitabine 1000 mg/m2 d1, d8, d15 i.v. q 28d [31,32]
Gemcitabine / treosulfan Gemcitabine 1000 mg/m2 d1 i.v. q 21d [33]
Treosulfan 5 g/m2 d1 i.v. q 21d
Trabectedin Trabectedin 1.1 mg/m 2
d1 i.v. q 21d [34]
Trabectedin / liposomal doxorubicin Trabectedin 1.1 mg/m2 d1 i.v. q 28d [35]
Liposomal doxorubicin 30 mg/m2 d1 i.v. q 28d [36]
Cisplatin / etoposide Cisplatin 60 mg/m2 d1, d8, d15 i.v. q 28d x2 cycles [37]
Etoposide 50 mg d1-14 p.o. q 28d x2 cycles [38]
Oral etoposide Etoposide 50 mg d1-21 p.o. q 28d x4 cycles [39,40]
Tamoxifen Tamoxifen 20 mg d1-28 p.o. continuous [41,42]
Other (BRCA mutant patients with platinum-sensitive relapse)
Olaparib Olaparib 400 mg b.d., d1-28 p.o. continuous but could well require dose
reductions for myelosuppression / nausea
recommended that first dose reduction,
if needed, is made to 200 mg b.d. then
100 mg b.d. if necessary [43]
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Uterus
Metastatic uterus cancer: examples of treatment regimens recommended
Serous papillary uterine cancer
Adjuvant / first line
Carboplatin/ paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x6 [1]
d1 i.v. q 21d x6
or paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d x6
Endometrioid / clear cell uterine cancer
Cisplatin / doxorubicin Doxorubicin 60 mg/m2 d1 i.v. q 21d x4-6 [2]
Cisplatin 60 mg/m2 d1 i.v. q 21d x4-6
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d [3]
Paclitaxel 175 mg/m2 d1 i.v. q 21d
or paclitaxel 80 mg/m 2
d1, d8, d15 i.v. q 21d
78
Relapse - any uterine cancer
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x4-6 [4]
d1 i.v. q 21d x6 [5]
or paclitaxel 80 mg/m 2
d1, d8, d15 i.v. q 21d x4-6
Doxorubicin Doxorubicin 70 mg/m2 d1 i.v. q 21d x4-6
Liposomal doxorubicin Liposomal doxorubicin 40 mg/m2 d1 i.v. q 28d [6]
Carboplatin / liposomal doxorubicin Carboplatin AUC 4/5 d1 i.v. q 28d x4-6 [7]
Liposomal doxorubicin 30 mg/m2 d1 i.v. q 28d x4-6
Cisplatin / doxorubicin Doxorubicin 60 mg/m2 d1 i.v. q 21d x4-6 [8]
Cisplatin 60 mg/m2 d1 i.v. q 21d x4-6
Paclitaxel weekly Paclitaxel 60-80 mg/m 2
d1, d8, d15 i.v. q 21-28d x4-6
Megestrol acetate or Provera Megace 160 mg d1-28 p.o. continuous [9]
Provera 200 mg d1-28 p.o. continuous [10]
Tamoxifen 20 mg d1-28 p.o. continuous or alternating with Megace / Provera [11,12]
Aromatase inhibitors Arimidex 1 mg d1-28 p.o. continuous [13]
Letrozole 2.5 mg d1-28 p.o. continuous [14]
LHRH Zoladex 1.8 mg d1-28 intradermal d1 (continuous)
Uterine leiomyosarcoma
Doxorubicin Doxorubicin 60-75 mg/m2 d1 i.v. q 21d x6 [15]
Gemcitabine / docetaxel Gemcitabine 675-900 mg/m2 d1, d8 i.v. q 21d x6 [16]
Docetaxel 75-100 mg/m2 d1 i.v. q 21d x6
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7. Ang JE, Shah RN, Everard M, et al. A feasibility study of sequential doublet chemotherapy comprising carboplatin-doxorubicin and carboplatin-paclitaxel for advanced endometrial adenocarcinoma and
carcinosarcoma. Ann Oncol 2009; 20:1787–1793.
8. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.
J Clin Oncol 2004; 22:2159–2166.
9. Lentz SS, Brady MF, Major FJ, Reid GC, Soper JT. High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1996; 14:357–361.
10. Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology
Group. J Clin Oncol 1999; 17:1736–1744.
11. Thigpen JT, Brady MF, Homesley HD, et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2001; 19:364–367.
12. Fiorica JV, Brunetto VL, Hanjani P, et al. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol
Oncol 2004; 92:10–14.
13. Rose PG, Brunetto VL, VanLe L, et al. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2000; 78:212–216.
14. Ma B, Oza A, Eisenhauer E, et al. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers – a study of the National Cancer Institute of
Canada Clinical Trials Group. Int J Gynecol Cancer 2004; 14:650–658.
15. Pautier P, Nam EJ, Provencher DM, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for high-grade undifferentiated sarcomas of the uterus. Int J Gynecol Cancer 2014; 24(9 Suppl
3):S73–677.
16. H
ensley ML, Blessing JA, Degeest K, et al. Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study.
Gynecol Oncol 2008; 109:323–328.
Cervix
Radical treatment for cervical cancer
Cisplatin and radiotherapy Cisplatin 40 mg/m2 d1, d8, d15, d22, d29, d35 i.v. x6 weeks [1]
Radiotherapy d-35 [2,3]
Metastatic cervix cancer

First line (no previous platinum) [4]
Cisplatin / paclitaxel Cisplatin 50 mg/m 2

d1 i.v. q 3 weeks
or paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d
79
Cisplatin / topotecan / bevacizumab Cisplatin 50 mg/m2 d1 i.v. q 3 weeks [5]
Topotecan 0.75 mg/m2 d1, d2, d3 i.v.
Bevacizumab 15 mg/kg d1 i.v.
Second line or first line previous platinum (incl cisplatin/radiotherapy) or palliative situation
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.v. q 3 weeks [6,7]
or paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d
Cisplatin / vinorelbine Cisplatin 50 mg/m2 d1 i.v. q 21d [8,9]
Vinorelbine 30 mg/m2 d1, d8 i.v./p.o. q 21d
Cisplatin/topotecan Topotecan 0.75 mg/m2 d1-5 i.v. q 21d [10]
Cisplatin 50 mg/m2 d1-5 i.v. q 21d
Cisplatin/gemcitabine Cisplatin 40 mg/m2 d1 i.v. q 21d [11]
Gemcitabine 125 mg/m2 d1, d8, d15 i.v. q 21d
Paclitaxel weekly Paclitaxel 60-80 mg/m2 d1, d8, d15 i.v. q 21d x4-6
Topotecan Topotecan 1.5 mg/m2 d1-5 i.v. q 21d
References
1. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340:1144–1153.
2. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340:1137–1143.
3. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;
340:1154–1160.
4. Kitagawa R, Katsumata N, Shibata T, et al. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505.
J Clin Oncol 2015; 33:2129–2135.
5. Tewari K, Sill M, Long H, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014; 370:734–743.
6. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: A Gynecologic Oncology
Group study. J Clin Oncol 2004; 22:3113–3119.
7. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.
Clin Oncol 2009; 27:4649–4655.
8. Morris M, Blessing JA, Monk BJ, et al. Phase II study of cisplatin and vinorelbine in squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 2004; 22:3340–3344.
9. Brewer CA, Blessing JA, Nagourney RA, et al. Cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Gynecol
Oncol 2006; 100:385–388.
10. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol
2005; 23:4626–4633.
11. Zarbá JJ, Jaremtchuk AV, Gonzalez Jazey P, et al. A phase I-II study of weekly cisplatin and gemcitabine with concurrent radiotherapy in locally advanced cervical carcinoma. Ann Oncol 2003; 14:1285–1290.
Vulva and vagina

Radical therapy
Cisplatin and radiotherapy Cisplatin 40 mg/m2 (max 70 mg) d1, d8, d15, d22, d29, d35 i.v. q 7d [1,2]
Radiotherapy 1.5 Gy daily 25-27 fractions
Palliative / second line [3]
Carboplatin / paclitaxel Carboplatin AUC 5/6 d1 i.v. q 21d x4-6 [4]
d1, d8, d15 i.v. q 21 or 28d x4-6
Capecitabine Capecitabine 1250 mg/m2 b.d. d1-10 or 14 p.o. q 21d x4-6
Paclitaxel weekly Paclitaxel 60-80 mg/m2 d1, d8, d15 i.v. q 21-28d x4-6 [5,6]
Topotecan / cisplatin Topotecan 0.75 mg/m2 d1-3 i.v. q 21d [7]
Cisplatin 50 mg/m2 d1 i.v. q 21d
5-Fluorouracil / cisplatin 5-Fluorouracil 1000 mg/m2 d1-5 i.v. q 21d [8]
Cisplatin 100 mg/m 2
d1 i.v. q 21d
References
1. Mak RH, Halasz LM, Tanaka CK, et al. Outcomes after radiation therapy with concurrent weekly platinum-based chemotherapy or every-3–4-week 5-fluorouracil-containing regimens for squamous cell
carcinoma of the vulva. Gynecol Oncol 2011; 120:101–107.
2. Moore DH, Ali S, Koh WJ, et al. A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally advanced squamous cell carcinoma of the vulva: a Gynecologic
Oncology Group Study. Gynecol Oncol 2012; 124:529–533.
3. Reade C, Eriksson L, Mackay H. Systemic therapy in squamous cell carcinoma of the vulva: Current status and future directions. Gynecol Oncol 2014; 32:780–789.
4. Han SN, Vergote I, Amant F. Weekly paclitaxel/carboplatin in the treatment of locally advanced, recurrent, or metastatic vulvar cancer. Int J Gynecol Cancer 2012; 22:865–868.
5. Witteveen PO, van der Velden J, Vergote I, et al. Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of
the EORTC-GCG (European Organisation for Research and Treatment of Cancer—Gynaecological Cancer Group). Ann Oncol 2009; 20:1511–1516.
6. Abbas A, Nehme E, Fakih M. Single-agent paclitaxel in advanced anal cancer after failure of cisplatin and 5-fluorouracil chemotherapy. Anticancer Res 2011; 31:4637–4640.
7. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol
2005; 23:4626–4633.
8. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An Intergroup Trial of the
Eastern Cooperative Oncology Group. J Clin Oncol 2005; 23:3562–3567.
80
Germ cell and other (rare)
Metastatic teratoma or rising markers on surveillance, first line
BEP (5 day) Bleomycin 30000 units or 30 mg total d1, d8, d15 i.v. q 3 weeks x3 [1]
Etoposide 100 mg/m 2
d1-5 i.v. [2]
Cisplatin 20 mg/m 2
d1-5 i.v.
BEP (3 day – more neurological Bleomycin 30000 units or 30 mg total d1, d8, d15 i.v. q 3 weeks x3
toxicity possible, e.g. hearing loss/
tinnitus)
Etoposide 165 mg/m2 d1, d2, d3 i.v.
Cisplatin 50 mg/m2 d1, d2 i.v.
VIP Ifosfamide* 1000 mg/m 2
d1-5 i.v. q 3 weeks [3]
* + Mesna 500 mg/m 2 [4]
Cisplatin 20 mg/m2 d1-5 i.v.

Etoposide 100 mg/m2 d1, 3, 5 i.v.
POMB ACE Cisplatin 120 mg/m2 d5 i.v. Give 2 cycles of POMB 14 days apart (if blood
Vincristine 1 mg/m2 d1 i.v. count allows) then alternate ACE and POMB until
biochemical remission for 12 weeks [5]
Methotrexate 300 mg/m2 d1 i.v.
Folinic acid rescue 15 mg b.d. x4 d2 p.o.
Bleomycin 15 mg/24 h d2, d3 i.v.
Actinomycin D 0.5 mg d3, d4, d5 i.v. Alternate with POMB (above)
Cyclophosphamide 500 mg/m 2
d5 i.v.
Etoposide 100 mg/m2 d1, d2, d3, d4, d5 i.v.
For patients who have advanced germ cell tumours and are systemically unwell - minimises risks of tumour lysis syndrome etc
Low dose EP Etoposide 100 mg/m2 d1, d2, d3 i.v. every 10-14 days x 2-3 cycles then follow with
POMB ACE or GemTIP [5]
Cisplatin 20 mg/m2 d1, d2, d3 i.v.
Conventional dose salvage therapy for relapsed teratoma - prior to stem cell transplant x 1 or 2
VIP As above
OR
TIP Paclitaxel 120 mg/m2 d1-2 i.v. q 3 weeks + G-CSF for 4x TIP [6]
Ifosfamide 1200 mg/m 2
d1-5 i.v.
Cisplatin 20 mg/m2 d1-5 i.v.
OR
Gem TIP Gemcitabine 1000 mg/m² d1, d5 i.v.
TIP as above
Stage I teratoma, high risk - adjuvant
BEP As above 2 cycles [7]
Stage I dysgerminoma high risk - adjuvant
Carboplatin Carboplatin AUC 7 d1 i.v. 1 cycle [8-11]
Metastatic > Stage 1 dysgerminoma
Carboplatin Carboplatin AUC 10 d1 i.v. 3-4 cycles
BEP As above 3-4 cycles
Palliative chemotherapy
Etoposide Etoposide 50 mg d1-14 p.o. q 21 or 28d x4
Granulosa cell tumour
Carboplatin / paclitaxel Carboplatin AUC 5/6
Paclitaxel 175 mg/m2 d1 i.v. q 21d
or weekly paclitaxel 80 mg/m2 d1, d8, d15 i.v. q 21d [12]
BEP As above
Tamoxifen Tamoxifen 20 mg daily p.o. continuous
Arimidex Anastrozole 1 mg daily p.o. continuous
81
Sarcoma
Adjuvant / First line
Doxorubicin Doxorubicin 75 mg/m2 d1 i.v. q 21d [13]
Doxorubicin / ifosfamide Doxorubicin 75 mg/m 2
d1 i.v. q 21d [14]
Ifosfamide* 2.5 g/m 2
d1, d2, d3, d4 i.v. q 21d
* + Mesna 1.5 g/m2 d1, d2, d3, d4 i.v. prior to ifosfamide
1 g/m2 d1, d2, d3, d4 p.o. 2 h after completion of ifosfamide
Second line
Doxorubicin Doxorubicin 60 mg/m2 d1 i.v. q 21d
Doxorubicin / ifsofamide Doxorubicin 60 mg/m 2
d1 i.v. q 21d
ONLY ADD ifosfamide if trying to Ifosfamide* 2.5 g/m2 d1, d2, d3, d4 i.v. q 21d
obtain fast response for symptomatic
reasons as no difference in overall
survival, c.f. single-agent doxorubicin
* + Mesna 1.5 g/m2 d1, d2, d3, d4 i.v. prior to ifosfamide
Gemcitabine / docetaxel Gemcitabine 1000 mg/m2 d1, d8 i.v. q 21d [15]
Docetaxel 75 mg/m 2
d1 i.v. q 21d [16]
Trabectedin Trabectedin 1.1-1.5 mg/m 2
d1 i.v. q 21-28d [17]
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5. Hitchins R, Newlands E, Smith D, et al. Long-term outcome in patients with germ cell tumours treated with POMB/ACE chemotherapy: comparison of commonly used classification systems of good
and poor prognosis. Br J Cancer 1989; 59:236–242.
6. Feldman DR, Hu J, Dorff TB, et al. Paclitaxel, ifosfamide, and cisplatin (TIP) efficacy for first-line treatment of patients (pts) with intermediate- or poor-risk germ cell tumors (GCT). J Clin Oncol 2013;
31:Suppl. abstract no. 4501.
7. Brown J, Friedlander M, Backes FJ, et al. Gynecologic Cancer Intergroup (GCIG) consensus review for ovarian germ cell tumors. Int J Gynecol Cancer 2014; 24(Suppl 3): S48–54.
8. Oliver RT, Mason MD, Von der Masse, H. A randomised comparison of single agent carboplatin with radiotherapy in the adjuvant treatment of stage I seminoma of the testis, following orchidectomy:
MRC TE19/EORTC 30982. J Clin Oncol (Meeting Abstracts) 2004; 22(no. 14) suppl 4517.
9. Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 2005; 366:293–300.
10. Patterson H, Norman AR, Mitra SS, et al. Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: comparison with radiotherapy treatment alone. Radiother Oncol
2001; 59:5–11.
11. Alexander EJ, White IM, Horwich A. Update on management of seminoma. Indian J Urology 2010; 26:82–91.
12. Maillet D, Goulvent T, Rimokh R, et al. Impact of a second opinion using expression and molecular analysis of FOXL2 for sex cord-stromal tumors. A study of the GINECO group & the TMRO network.
Gynecol Oncol 2014; 132:181–187.
13. Amant F, Floquet A, Friedlander M, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for endometrial stromal sarcoma. Int J Gynecol Cancer 2014; 24(Suppl 3):S67–72.
14. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled
phase 3 trial. Lancet Oncol 2014; 15:415-423.
15. Pautier P, Floquet A, Penel N, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed
leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study). Oncologist 2012; 17:1213–1220.
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Gynecol Oncol 2008; 109:329–334.
17. Demetri GD, Chawla SP, von Mehren M, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and
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Declarations of interest
GD Aletti: No conflicts of interest. C Marth: No conflicts of interest.
S Carinelli: No conflicts of interest. M Mirza: No conflicts of interest.
D Cibula: No conflicts of interest. I Ray-Coquard: No conflicts of interest.
CC Fotopoulou: No conflicts of interest. L Rob: No conflicts of interest.
A Gonzalez Martin: No conflicts of interest. C Sessa: No conflicts of interest.
MJ Halaska: No conflicts of interest. P Skapa: No conflicts of interest.
M Hall: Advisory Boards for GlaxoSmithKline, H Vanacker: No conflicts of interest.

Roche, AstraZeneca, Merck.
L Woelber: No conflicts of interest.
D Krell: No conflicts of interest.
M Zweifel: Advisory role for Roche.
S Mahner: No conflicts of interest.
S Marnitz: No conflicts of interest.
84
Declarations of interest
Index
Note: Abbreviations used in the index are listed on page viii
A cervical cancer
actinomycin D, 81 adenocarcinoma, 5, 49
adenocarcinoma, 5, 27–28, 49, 52, 69–73 early stage disease, 31–32, 34, 42
AGO trial, 16 surgical treatment, 34
Amsterdam criteria, 61 epidemiology, 49
anastrozole, 81 histopathology, 5
angiogenesis, 63–64 HPV infection and, 5, 49
see also anti-angiogenic therapy investigations, 32
angiogenic switch, 63 locally advanced, 31–32, 38, 40
anorectal dysfunction, 33–34 chemoradiotherapy, 40, 43
anti-angiogenic therapy in pregnancy, 42
endometrial cancer, 29 surgical treatment, 35
mechanism of action, 63–64 lymph node involvement, 31–32, 34–35, 38, 42
ovarian cancer, 14, 63–64 lymphadenectomy, 33, 35, 38
types of drugs, 63 para-aortic nodes, 31–32, 36, 40
apoptosis, 60, 63, 66 pelvic lymph nodes, 31, 33–34
Arimidex, 79, 81 metastases, 32, 36
ASTEC study, 22 distant, treatment, 38, 43
AURELIA study, 17 palliative chemoradiotherapy, 38
autosomal-dominant inheritance, 59 micrometastases, 32, 34
non-surgical treatment, 38–43
brachytherapy, 39
B chemoradiation, 35, 38–40
basket studies, endometrial cancer, 29 chemotherapy, 42–43
Bcl-2 pathway, 19 chemotherapy in pregnancy, 42
benign–adenoma–carcinoma pathway, 2 chemotherapy schedules, 38, 79–80
BEP regimen, 56, 81 distant metastases and relapses, 43
bevacizumab, 63 fertility and organ preservation, 35, 41
cervical cancer, 43, 80 neoadjuvant chemotherapy, 35
endometrial cancer, 29 in para-aortic disease, 40
ovarian cancer, 14–17, 63, 76–77 radiotherapy, 38–41
bladder dysfunction, 33 by stage, 38
bleomycin, 56, 81 trimodality (with surgery), 38
body mass index (BMI), 19, 23 palliative therapy, 36, 38
brachytherapy pregnancy and, 35, 41–42
cervical cancer, 39 prognostic parameters, 32
endometrial cancer, 25–26 recurrence
BRAF mutations, 2, 57, 66 radiotherapy prolongation, 39
BRCA (BRCA1, BRCA2) gene mutations, 2, 48, 50, 59–61 surgery for, 36
action, DNA repair, 64–65 recurrence rates, 35
cancers associated, 60, 65 relapse, treatment, 43
lifetime risk, 48, 60 risk factors, 49
ovarian cancer, 2, 48, 59–60, 65 screening, 5, 49
germline mutation (gBRCA), 15–16, 59, 65 small cell undifferentiated, 5
platinum sensitivity as “marker”, 15 squamous cell carcinoma, 5, 49
“BRCAness”, 65 staging, 31–32
breast cancer, 41, 59–60 clinical, 32
broad ligament tumours, WHO classification, 70–71 FIGO, 1, 5, 31–32, 38, 53, 74–75
lymph node, 31, 34
C non-surgical treatment and, 38
pathological, 31
CA125, 13, 15, 56, 61
stage IA, 31, 34
cancer causation, two-hit theory, 59
stage IB substaging, 31–32, 35
Cancer Genome Atlas, 29
surgical treatment, 33–36, 38
capecitabine, vulvar and vaginal cancer, 80
chemoradiation vs surgery, 35
carboplatin, paclitaxel with
chemoradiation with, 38
cervical cancer, 43, 80
early stage disease, 34
endometrial cancer, 26–27, 78–79
fertility-sparing, 33, 35
ovarian cancer, 13–14, 16, 76–77
locally advanced disease, 35
rare gynaecological tumours, 57, 81
lymphadenectomy, 33, 35, 38
vulvar and vaginal cancer, 80
neoadjuvant chemotherapy, 35
CDK4/6 inhibitors, 28
outcome and survival rates, 35, 36
cediranib, 17, 63–64
pelvic exenteration, 36
85
Index
postoperative morbidity, 33, 36 E
radiotherapy vs surgery, 38 embryonal carcinoma, 3, 56
WHO classification, 71–72 endodermal sinus tumour, 56
cervical intraepithelial neoplasia (CIN), 5, 49, 51, 71 endometrial cancer, 4
chemoradiotherapy advanced, 4, 20
cervical cancer, 35, 38–40 chemotherapy, 27
distant metastases and relapse, 43 endocrine therapy, 28
endometrial cancer, 26 symptoms, 21
pelvic, in cervical cancer, 40 clear cell carcinoma, 4, 20
chemotherapy (ChT) epidemiology, 47
cervical cancer see cervical cancer histopathology, 4, 19–21
endometrial cancer see endometrial cancer immune system, 29
neoadjuvant incidence and mortality, 19, 25, 47
cervical cancer, 35 lymph node involvement, 20–22
ovarian cancer, 11, 13, 57, 63, 64 Lynch syndrome, 19, 29, 47–48, 61
vulvar cancer, 53 metastases, 20, 21
ovarian cancer see ovarian cancer chemotherapy for, 27
pregnancy and, 42 micrometastases, 22
sex cord tumours, 56 molecular subtypes, 29
choriocarcinoma, 3, 56 non-surgical treatment, 25–29
chromosomal abnormalities, 57, 59 adjuvant chemoradiation, 26
chronic inflammatory disorders, 51 adjuvant radiotherapy, 21–22, 25
cisplatin chemotherapy, 25–27
cervical cancer, 38–40, 42–43, 79–80 chemotherapy for metastatic disease, 27
endometrial cancer, 26–27, 78–79 chemotherapy schedules, 78–79
ovarian cancer, 13, 16, 76–77 endocrine therapy, 28
in pregnancy, 42 future directions for, 29
rare gynaecological tumours, 81 risk groups for adjuvant therapy, 25
vulvar and vaginal cancer, 80 targeted therapy, 29
clear cell carcinoma obesity and, 23, 47
ovarian, 2, 48, 57 oestrogen relationship, 19, 28, 47
uterine corpus, 4, 20 pathogenesis, 19
Cochrane meta-analysis, endometrial cancer, 25 pathology, 19
colonic anastomosis, 10 presentation and examination, 21
colonoscopy, 61 prognostic factors, 20, 22, 25
combretastatin A4 phosphate (CA4P), 63 recurrence risk/rates, 25–26
computed tomography (CT) relapse
cervical cancer, 32 chemotherapy, 79
vulvar cancer, 52 local, radiotherapy, 25
conisation, cervical cancer, 34–35 risk factors and protective factors, 19, 47
Cowden syndrome, 60 staging, 19, 20–23
cyclin A, 28 FIGO, 4, 20
cyclophosphamide surgical, 21–22
ovarian cancer, 17, 77 surgical treatment, 23
rare gynaecological cancers, 81 lymphadenectomy, 22, 26
cytoreduction, ovarian cancer, 9–10, 15 open vs laparoscopic vs robotic, 23
pre-/post-operative risk assessment, 20
D recurrent stage III/IV cancer, 27
dermoid cysts, 3 survival rates/time, 22
DESKTOP III trial, 15 chemotherapy effect, 26
dilatation and curettage (D&C), 21 radiotherapy effect, 25
DNA damage, pathways, 60, 65 type 1 (endometrioid carcinoma), 4, 19, 21, 47
DNA repair (DNA repair genes), 64–65 adjuvant radiotherapy, 25
defects, BRCA1/2 mutations, 65 endocrine therapy, 28
mismatch repair (MMR) gene mutations, 59–60 epidemiology, 47
PARP inhibitor effect, 65 type 2 (serous carcinoma), 4, 19–21, 47
pathways, 65 adjuvant chemoradiation, 26
docetaxel, 76, 82 adjuvant chemotherapy, 25
doxorubicin epidemiology, 47
endometrial cancer, 27, 78–79 reclassification, 20
PLD see pegylated liposomal doxorubicin (PLD) recurrence and survival rates, 26
sarcomas, 82 ultrastaging, 22
dysgerminoma, 3, 56, 81 see also uterine corpus tumours
86
Index
endometrial stromal sarcoma, 4, 57, 71 epidemiology and treatment, 28
endometrioid carcinoma malignant primitive, 3
ovarian, 2, 4, 56 types and blood markers for, 56
uterine corpus see endometrial cancer, type 1 germline mutations, 16, 59–60, 65
endometriosis, 2, 48 GOG 33 study, 21
ENGOT-EN1 trial, 29 GOG 34 study, 26
ENGOT-EN3/PALEO study, 28 GOG 184 study, 26
epidemiology, 47–51, 56, 60 GOG 209 study, 27
cervical cancer, 49 gonadotrophin analogues, 41
endometrial cancer, 47 gonadotrophin-releasing hormone (GnRH) analogues, 28
germ cell tumours, 28 granulosa cell tumours, 3, 81
ovarian cancer, 48, 60 gynandroblastoma, 56
rare gynaecological cancers (RGCs), 55
vulvar cancer, 51
etoposide, 56, 77, 81–82
H
haemorrhagic necrosis, tumour, 63
extended field radiation therapy (EFRT), cervical cancer, 40
HER2/neu mutation, 19
external beam radiotherapy (EBRT)
hereditary breast and ovarian cancer (HBOC) syndrome, 59–60
cervical cancer, 39
hereditary cancer syndromes, 59–61
endometrial cancer, 21, 25
genetic basis, 59–60
intensity-modulated RT (IMRT) vs, 25
screening and surveillance, 61
see also radiotherapy
syndromes, specific cancers, 60
see also BRCA (BRCA1, BRCA2) gene mutations; Lynch syndrome
F hereditary non-polyposis colorectal cancer (HNPCC) 59–61
Fallopian tubes see Lynch syndrome
ovarian tumours involving, 1–2 histopathology, 1–5
tumours, WHO classification, 70 cervical cancer, 5
see also FIGO staging ovarian tumours, 1–3, 48, 56
family history, 9 uterine corpus tumours, 4, 19–21
fertility preservation, in cervical cancer, radiotherapy and, 41 vulvar cancer, 52
fertility-sparing surgery hormonal therapy
cervical cancer, 33, 35 relapsed ovarian cancer, 17
ovarian cancer, 8 type 1 endometrial cancer, 28
rare gynaecological cancers, 55 hormone replacement therapy (HRT), 28
FIGO staging, 74–75 human chorionic gonadotrophin (hCG), 3, 57
cervical cancer, 5, 31–32, 38, 75 human papillomavirus (HPV) infection, 5, 49
endometrial carcinoma, 4, 20 cervical cancer, 5, 49
ovarian tumours, 1, 74 high-risk (HR-HPV), 51
uterine corpus tumours, 75 malignant transformation and, 5
vulvar carcinoma, 74 testing for, 49
fistulae, 36 vulvar cancer and, 51
5-fluorouracil, 80 hypercalcaemia, 3
folinic acid, 81 hyperoestrogenism, 19
fosbretabulin, 63 hysterectomy, 33
radical, cervical cancer, 33, 35–36
nerve-sparing, 34
G simple, cervical cancer, 33–34
gastric cancer, 9
gastrointestinal tract tumour metastases, 3
gemcitabine I
cervical cancer, 80 ICON7 trial, 14
germ cell, 82 ifosfamide, 26, 81–82
ovarian cancer, 16–17, 77 immune system, endometrial cancer, 29
rare gynaecological tumours, 81 immunohistochemical markers
uterine leiomyosarcoma, 79 Lynch syndrome, 61
genetic susceptibility to cancer, 59 ovarian tumours (epithelial), 2
syndromes, specific cancers, 60 in-vitro fertilisation (IVF), 41
genomic characterisation inclusion cysts, 2
rare gynaecological tumours, 57 inguinal lymph nodes, cervical cancer, 31, 74–75
uterine corpus tumours, 4, 29 insertion-deletion loops (IDLs), 59–60
genomic instability, 2, 4, 59, 61, 65 intensity-modulated radiotherapy (IMRT), 25, 39–40
germ cell tumours (GCTs), 1, 3, 52, 56, 81 interval debulking surgery, advanced ovarian cancer, 11, 13
chemotherapy schedules, 81–82 intraperitoneal chemotherapy, 14, 76
87
Index
K modified Bethesda criteria, 61
K-RAS mutations, 19, 66 molecular biology
Knudson’s two-hit theory, 59 endometrial cancer, 29
ovarian cancers, 57
rare gynaecological cancers, 55
L mTOR inhibitors, 29
LAP2 study, 23 mucinous carcinomas, ovarian, 2, 3, 56
laparoscopic surgery mutations see specific genes
endometrial cancer, 23 MutSa/MutSb, 60
not recommended, early-stage ovarian cancer, 8 myometrial invasion, endometrial cancer, 21
laparoscopy, diagnostic, advanced stage ovarian cancer, 9
laterally extended endopelvic resection (LEER), 36
leiomyosarcoma (LMS), uterine, 4, 57, 79 N
letrozole, 28, 79 neoadjuvant chemotherapy see chemotherapy
Li-Fraumeni syndrome, 60 nintedanib, 29, 63–64
LINCE study, 22 nivolumab, 66
loss-of-function mutations, 60, 65 NSGO9501 study, 26
low malignant potential tumours (LMPT), 56
lymph node dissection (LND), pelvic, endometrial cancer, 22 O
lymph node (LN) involvement obesity
cervical cancer see cervical cancer endometrial cancer and, 23, 47
endometrial cancer, 20–22 ovarian cancer, 48
ovarian cancer, 1, 7 OCEANS trial, 16
vulvar cancer, 52 oestrogen, endometrial cancer risk, 19, 28, 47
lymphadenectomy oestrogen receptor/progesterone receptor (EP/PR) status, 28, 56–57
cervical cancer, 33, 38 olaparib, 64–65, 77
early-stage ovarian cancer, 7 ovarian cancer, 16–17, 64–65, 77
endometrial cancer, 22, 26 oral contraceptives, 48–49
inguinofemoral, vulvar cancer, 53 Oslo trial, 25
lymphocoele, pelvic, 33 ovarian cancer
lymphoedema, 33, 38, 53 advanced
lymphotropic substances, 53 chemotherapy, 13, 76–77
lymphovascular space invasion (LVSI), cervical cancer, 34 incidence, 11, 48
Lynch syndrome, 29, 47–48, 59–60 surgery, 9–11
cancers and genes involved, 29, 47–48, 59–60 biology/pathogenesis, 63
diagnosis, mutation analysis, 29, 61 classification, 1, 69–70
endometrial cancer, 19, 29, 47–48, 61 conservative management, results, 8
ovarian cancer, 48, 61 differential diagnoses, 3
screening, surveillance, 61 early stage
LYTEC trial, 22 adjuvant chemotherapy, 13
surgical treatment, 7
M epidemiology, 48, 60
magnetic resonance imaging (MRI) epithelial, 1–2, 48
brachytherapy guided by, 39 see also ovarian carcinoma
cervical cancer, 32 GI tract tumour metastases vs, 3
medroxyprogesterone, 28 hereditary, 59–61
Megace, 28, 79 histopathology, 1–3, 48, 56
MEK inhibitors, 66 incidence, 1, 11
melanoma low-grade serous carcinoma, 2, 56
vulvar, 52 metastases, 1, 3, 7
vulvo-vaginal, 57 extra-abdominal, 1
mesenchymal uterine cancers, 4, 57 neoadjuvant chemotherapy, 11, 13
mesna, 81–82 non-epithelial, 3
metastases see individual cancers germ cell see germ cell tumours (GCTs)
methotrexate, 57, 81 sex cord–stromal, 1, 3
micrometastases undifferentiated, 3
cervical cancer, 32, 34 prognosis, 1, 7
endometrial cancer, 22 relapsed disease, 15–17
microsatellite instability (MSI), 2, 4, 19, 29, 59, 61 survival times/rates, 7, 10, 16
mismatch repair (MMR) gene mutations, 59–60 protective factors, 48
MITO END-2 trial, 29 rare, 56–57
recurrence, 3, 8, 64
88
Index
relapse, 15 P
platinum-resistant, 17, 77 p53, 66
platinum-sensitive, 15–16, 64–65, 76–77 p53 gene mutations, 2, 4, 19, 51
symptoms, 17 paclitaxel
risk factors, 48 cervical cancer, 43, 79–80
site of origin, 1–2 endometrial cancer, 26–27, 78–79
staging, 1, 7 ovarian cancer, 13–14, 16, 76–77
chemotherapy by stage, 13 relapse of platinum-resistant disease, 17
FIGO, 1, 74 rare gynaecological tumours, 81
surgical treatment, 7–11 vulvar and vaginal cancer, 80
advanced stage disease, 9–11 palbociclib, 28
aims, 10 para-aortic lymph nodes
complete resection, 7, 10–11 cervical cancer, 31–32, 36
debulking (optimal), 10, 13 lymphadenectomy, 33
debulking (suboptimal), 9–10 non-surgical treatment, 40
en-bloc resection, 10 endometrial cancer, 20, 22
fertility-sparing, 8 parametrectomy, radical, 33
interval debulking surgery, 11, 13 parametrium, resection, 33, 35
open surgery importance, 8, 11 PARP inhibitors (PARPi), 16, 65
rare tumours, 57 drugs included, 65
relapsed cancer, debulking, 15 mechanism of action, 65
residual disease, 10, 13 pazopanib, 64
retroperitoneal approach, 10 PD-1 (programmed death-1), 66
systemic treatment, 13–17 pegylated liposomal doxorubicin (PLD)
adjuvant chemotherapy, 13 endometrial cancer, 79
advanced cancer, 13–14, 76–77 ovarian cancer, 16–17, 77
aims, in platinum-resistance, 17 pelvic exenteration, cervical cancer, 36
anti-angiogenic drugs, 14, 63–64 pelvic lymph nodes, cervical cancer, 31, 33–34
chemotherapy schedules, 76–77 lymphadenectomy, 33
follow-up, 15 pelvic metastases
hormonal therapy, 17 endometrial cancer, 20
indications, 13 ovarian cancer, 1, 10
intraperitoneal chemotherapy, 14 pelvic surgery, ovarian cancer, 10–11
maintenance cediranib, 64 perimenopause, tumours, 1, 4, 56
neoadjuvant vs adjuvant chemotherapy, 13 peripheral neuropathy, taxane-related, 26
new drugs, 17, 63–64 peritoneal biopsy, 7, 21
platinum-based chemotherapy, 13, 15–16 peritoneal carcinomatosis, 11
platinum-resistant relapse, 17, 77 peritoneal cytology/washing, 1, 7
platinum-responsive, 15–16, 64–65, 76–77 peritoneal metastases, ovarian tumours, 1–2, 8
unilateral, 3 peritoneal stripping, 11
WHO classification, 69–70 peritoneum
ovarian carcinoma, 1–2 advanced ovarian cancer, surgery, 10–11
classification, 2 tumours, WHO classification, 70
histopathology, 2, 56 Peutz-Jeghers syndrome, 60
small cell, 57 PI3K/AKT pathway, 19, 29
type 1, 2, 48, 56 platinum-free interval, 15, 43
clear cell, 2, 48, 57 platinum responsiveness
endometrioid, 2, 48 cervical cancer, 43
low grade serous, 2, 56 ovarian cancer, 15–16, 64–65, 76–77
mucinous, 2–3, 56 poly(ADP-ribose) polymerase (PARP), 65
type 2, 2, 56 see also PARP inhibitors (PARPi)
high grade serous, 2, 56, 65–66 polycystic ovarian syndrome, 19, 47–48
ovarian tissue/function polyembryoma, 56, 69
preservation in cervical cancer, 41 POMP ACE regimen, 81
radiation sensitivity, 41 PORTEC-3 study, 26
ovarian transposition, 41 pregnancy, cervical cancer and, 35, 42
ovarian tumours, 1 progestogen therapy, endometrial cancer, 28, 79
benign and borderline epithelial, 2 programmed death-1 (PD-1), 66
malignant see ovarian cancer proliferation cell nuclear antigen (PCNA), 60
Provera, 28, 79
89
Index
Q surgery
quality of life (QOL), ovarian cancer, 17 cervical cancer see cervical cancer
endometrial cancer see endometrial cancer
ovarian cancer see ovarian cancer
R prophylactic, Lynch syndrome, 61
radiotherapy rare gynaecological cancers, 55
cervical cancer, 38–41 sex cord tumours, 56
chemotherapy with see chemoradiotherapy specialisation of team, 9
endometrial cancer, 21–23, 25–26 vulvar cancer, 52
fertility and organ preservation, 41
intensity-modulated (IMRT), 25, 39–40
pelvic, endometrial cancer relapse, 25 T
second malignancy risk, 25 tamoxifen, 28
toxicity decrease, methods, 39–40 endometrial cancer, 19, 28, 47, 79
vulvar cancer, 53 ovarian cancer, 17, 77
rare gynaecological cancers (RGCs), 55–57 rare gynaecological tumours, 81
epidemiology, 55 targeted therapy, endometrial cancer, 27, 29
histological definition/review, 55 teratomas, 3, 56
ovarian, 56–57 chemotherapy schedules, 81
treatment thecoma, 56, 69
chemotherapy schedules, 81–82 TIME-C trial, 25
national network organisations, 55 TNM staging, 31
surgical, 55 cervical carcinoma, 75
uterine, 57 ovarian/fallopian tube tumours, 74
RAS-RAF-ERK-MERK pathway, 29 uterine carcinoma, 75
replication factor C (RFC), 60 vulvar carcinoma, 74
robotic surgery topotecan
early-stage ovarian cancer, 8 cervical cancer, 43, 80
endometrial cancer, 23 ovarian cancer, 17, 77
rucaparib, 65 vulvar and vaginal cancer, 80
TP53 mutations, 60, 66
trabectedin, 77, 82
S trachelectomy, 33, 35, 38
salpingo-oophorectomy, prophylactic, 61 trebananib, 63
SEER analysis, endometrial cancer, 20, 22 treosulfan, 17, 77
sentinel lymph node (SLN), 53 trophoblastic disease, 3, 57, 70–71
cervical cancer, 34 tumour suppressor gene, p53 gene mutations, 2, 4, 19, 51
endometrial cancer, 22 tunnelled catheters, 14
mapping techniques, 22 tyrosine kinase inhibitors, 29, 63, 65
vulvar cancer, 53
SEPAL study, 22
serous carcinoma U
ovarian, 2 ultrasonography, 21, 52, 61
high-grade (type 2), 2, 56, 65–66 ultrastaging, SLN
low-grade (type 1), 2, 56 cervical cancer, 34
uterine corpus see endometrial cancer, type 2 endometrial cancer, 22
serous intraepithelial carcinoma (STIC) (ovarian), 2 uterine carcinosarcoma, 26, 57
Sertoli cell tumours, 3 uterine cervical tumours see cervical cancer
Sertoli-Leydig cell tumours, 56–57, 69 uterine corpus tumours
sex cord(s), 3, 55–56 classification, 4, 71
sex cord tumours, 56 epithelial see endometrial cancer
types, 28 histopathology, 4
sex cord–stromal tumours (SCSTs), 1, 3 mesenchymal, 4, 57, 71
sexual development disorders, 3 mixed epithelial/mesenchymal, 1, 4, 71
SHAPE trial, 34 prognostic subgroups, 4, 20
sigmoid colon, resection, 10 rare tumours, 57
small cell carcinomas, ovarian, 57 sarcomas, 4, 57, 82
spinocellular carcinoma, vulvar, 51 staging, 19–21
splenectomy, 11 FIGO, 4, 75
squamous cell carcinoma WHO classification, 71
cervical, 5, 49 uterine leiomyosarcoma (LMS), 4, 57, 79
vulvar, 51–52 uterine ligaments, tumours, WHO classification, 70–71
steroid cell tumours, 3, 69 uterine transplantation, 41
90
Index
V
vaginal bleeding/discharge, 21
vaginal tumours
chemotherapy schedules, 80
WHO classification, 72
vaginectomy, 33
vascular disrupting agents (VDAs), 63–64
vascular endothelial growth factor (VEGF), 63
monoclonal antibody see bevacizumab
VEGF tyrosine kinase inhibitor, 29
veliparib, 65
vincristine, 81
vinorelbine, 80
VIP regimen, 81
voiding dysfunction, 33
vulval discharge, 52
vulvar cancer (VC), 51–53
clinical presentation, 52
diagnosis and investigations, 52
epidemiology, 51
histopathology/types, 52
metastases, 51–52
pathogenesis, 51
recurrence, 52
spinocellular carcinoma, 51
squamous cell carcinoma, 51–52
staging, 52, 74
treatment, 52
chemotherapy schedules, 80
surgical, 52
WHO classification, 72–73
vulvar intraepithelial neoplasia (VIN), 51–52
differentiated-type (d-VIN), 51
usual-type (u-VIN), 51
vulvectomy, 52–53
vulvo-vaginal melanoma, 57
W
WHO classification, 69–73
Y
yolk sac tumours, 3, 56
Z
Zoladex, 79
91
Index
www.esmo.org www.esmo.org
Andreas du Bois - Marcia Hall - Christina C Fotopoulou

edited by
GYNAECOLOGICAL GYNAECOLOGICAL
Andreas du Bois
Marcia Hall
TUMOURS TUMOURS
E S S E N T I A L S forC L I N I C I A N S E S S E N T I A L S forC L I N I C I A N S
GYNAECOLOGICAL TUMOURS
edited by PA
Andreas du Bois CI
Marcia Hall PS
Christina C Fotopoulou EI
OB
Gynaecological tumours is the 4th edition of the popular “Essentials for
Clinicians” series. Gynaecological tumours: Essentials for Clinicians
is divided into two sections. It starts with the essential information or
“what every oncologist should know”. In this section staging and treatment
strategies for the more common Gynaecological cancers is explained.
The second section builds upon the first by offering more advanced
information on rare tumours, new drugs and novel treatment options.
Progress in oncology is moving quickly and it is becoming an increasingly
complicated speciality, for people interested in specialising or simply
learning about oncology knowing where to start can be difficult,
this is why ESMO has developed the Essential series. These books
E S S E N T I A L S forC L I N I C I A N S
provide the essential information in a visual and interactive format. Endometrioid Mucinous Clear Cell Serous
Complicated concepts in the management of tumours are explained MDM2 • Low-grade
be
• Slow growing
Tu
in a concise, clear and accessible way, giving the reader a p14ARF
an
opi
- low-grade serous carcinoma
- low-grade endometrioid carcinoma
Fall
Type I Tumours
strong theoretical foundation that can then be built upon.
p21, puma, bax, progress from borderline tumours
Mutant p53 MDM2, etc
TP53 • High-grade
• Evolve rapidly
• Include:
Type II Tumours - high-grade serous carcinoma
Ovary - carcinosarcoma
Fim - undifferentiated carcinomas
HPV-E6 bri
a - and some clear cell carcinomas
• Widespread DNA copy
number changes
Endometrioid Carcinosarcoma Clear Cell Serous

ESMO Press
ISBN 978-88-941795-1-4
ESMO Press · ISBN 978-88-941795-1-4
ESMO Press ESMO Press
9 788894 179514
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Andreas du Bois - Marcia Hall - Christina C Fotopoulou

Complicated concepts in the management of tumours are explained MDM2 • Low-grade

Endometrioid Carcinosarcoma Clear Cell Serous

ESMO Press ESMO Press

GynaecoTumours2017.indd 1 14/06/2017 17:52

© 2017 European Society for Medical Oncology

Printed through s | s | media limited, Rickmansworth, Hertfordshire, UK

A. What every oncologist should know

B. More advanced knowledge

Andreas du Bois, MD, PhD

AIN Anal intraepithelial neoplasia PCNA Proliferation cell nuclear antigen

What every oncologist should know

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

Stage III: Tumour involves 1 or both ovaries or Fallopian tubes, or primary

Primary ETs are classified based on histological type

Endometrioid and clear cell carcinomas may arise in

Serous borderline tumours can develop from inclusion

Non-epithelial tumours are typically unilateral. Those

Granulosa cell tumours are low-grade malignant tumours Germ cells

Steroid cell tumours can be malignant. Staging is Foetal ovary

Most GCTs are benign mature teratomas (dermoid

Among undifferentiated cancers, some mimic Metastatic carcinoma

Metastatic tumours from the gastrointestinal tract may

In the uterine corpus there are three major categories

Uterine leiomyosarcoma (LMS) is the most common

Endometrial stromal sarcoma is less frequent than

Grade 1 Grade 3 FIGO staging of endometrial carcinoma: Stage I:

There are two stereotypes of endometrial carcinoma.

Type 2 (10%), or serous carcinoma, arises in atrophic

A third minor type, clear cell carcinoma, shows

An integrated genomic characterisation of endometrial

Cervical cancer is the most serious complication of

Two viral reading frames, E6/E7, deregulate reparative

The declining incidence of cervical cancer over the last

HPV, Human papillomavirus.

FIGO staging: Stage I: limited to the cervix; Stage II: initial

Squamous cell carcinoma accounts for 70% of

Invasive carcinoma is usually of the non-keratinising type.

Adenocarcinomas account for 20%–25% of cervical

Small cell undifferentiated carcinoma is the least frequent,

Complete surgical staging and tumour removal is a

In assumed early-stage ovarian cancer, only thorough

Complete staging in assumed early-stage ovarian cancer

peritoneal mapping, peritoneal washing and systematic

It is difficult to assess the individual effect of each 1.0

may just be surrogate parameters for thorough general .3

In case of ovarian cancer confined to one of the ovaries,

Since the overall recurrence rate is higher in fertility- Zanetta el al

sparing surgery, all patients need to be counselled American series

Open incision surgery is the standard approach for

Laparoscopy as well as robotic surgery has been

Methodological limitations prohibit definitive conclusions

Given the biology and tumour spread of ovarian cancer,

To avoid under-diagnosis of peritoneal and retroperitoneal

For optimal surgical assessment and resection of

Specialisation of the surgical team, as well as all the other

Numerous, mostly retrospective, studies have evaluated

In some patients it may be possible to predict that they

However, since patients also benefit from suboptimal

Diagnostic laparoscopy can be useful in patients with

This picture shows findings of a premenopausal

The central aim of all surgical effort in patients with

A. What every oncologist should know