Access to this full-text is provided by Wiley.
Content available from International Journal of Gynecology & Obstetrics
This content is subject to copyright. Terms and conditions apply.
Int J Gynecol Obstet. 2021;155(Suppl. 1):61–85.
|
61wileyonlinelibrary.com/journal/ijgo
1 | INTRODUCTION
1.1 | Primary sites: ovarian, fallopian tube, and
peritoneal cancer
In 2014, FIGO’s Committee for Gyne cologic Oncolog y revised the stag-
ing to incorporate ovarian, fallopian tube, and peritoneal cancer in the
same system. Changing the staging system required extensive interna-
tional consultation. The primary site (i.e. ovary, fallopian tube, or peri-
toneum) is de signated, where pos sible. When it is not possible to clear ly
delineate the primary site, these should be listed as “undesignated”.1,2
It has been presumed that fallopian tube malignancies were
rare.2 However, histologic, molecular, and genetic evidence shows
that as many as 80% of tumors that were classified as high- grade se-
rous carcinomas of the ovar y or peritoneum may have originated in
the fimbrial end of the fallopian tube.3– 8 Therefore, the incidence of
fallopian tube cancers may have been substantially underestimated.
These new data suppor t the view that high- grade serous ovarian,
fallopian tube, and peritoneal cancers should be considered collec-
tively, and that the convention of designating malignancies as having
an ovarian origin should no longer be used, unless that is clearly the
origination site. It has been suggested that extrauterine tumors of
serous histology arising in the ovary, fallopian tube, or peritoneum
might be described collectively as “Müllerian carcinomas”1,2 or “pel-
vic serous carcinomas”.9 The latter tumor designation is contro-
versial because some peritoneal tumors might arise in extrapelvic
DOI: 10.1002/ijgo .13878
FIGO CANCER REPORT 2021
Cancer of the ovary, fallopian tube, and peritoneum: 2021
update
Jonathan S. Berek1 | Malte Renz1 | Sean Kehoe2,3 | Lalit Kumar4 |
Michael Friedlander5,6
This is an op en access ar ticle under the terms of the Creative Commons Attribution License, whic h permits u se, distribution and reproduct ion in any medium,
provide d the original work is properly cited.
© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of Internation al Federation of Gynecology
and Obstetrics
1Stanford Women’s Cancer Center,
Stanford Cancer Institute, Stanford
University Schoo l of Medicine, Stanford,
California, USA
2Oxford Gynecologi cal Cancer Center,
Churchill Hospital, Oxford, UK
3St Peter’s College, Oxford, UK
4Depar tment of Medical Oncology, All
India Ins titute of Medical Scien ces, New
Delhi, India
5Royal Hosp ital for Women, Sydney,
Australia
6Prince of Wales Clinical School,
University of New South Wales, Sydney,
Australia
Correspondence
Jonathan S. Berek, Stanford Women’s
Cancer Center, Stanford Cancer Institute,
Stanford Universit y School of Medicine,
Stanford, CA, USA.
Email: jberek@stanford.edu
Abstract
In 2014, FIGO’s Committee for Gynecologic Oncology revised the staging of ovarian
cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same sys-
tem. Most of these malignancies are high- grade serous carcinomas (HGSC). Stage IC
is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before
surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the
ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC
based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dis-
semination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in great-
est dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2
is now “microscopic extrapelvic peritoneal involvement with or without positive ret-
roperitoneal lymph node” metastasis. This review summarizes the genetics, surgical
management, chemotherapy, and targeted therapies for epithelial cancers, and the
treatment of ovarian germ cell and stromal malignancies.
KEYWORDS
cancer staging, chemotherapy, fallopian tube, FIGO Cancer Report, ovarian, ovary, peritoneum
62
|
BE REK Et al.
peritoneum. Therefore, the simple term “serous carcinoma" is pre-
ferred, and most of these are high- grade serous carcinomas (HGSC).
Although there has been no formal staging for peritoneal can-
cers, the FIGO staging system is used with the understanding that it
is not possible to have a Stage I peritoneal cancer.
1.1.1 | Primary site
Ovarian epithelial tumors may arise within endometriosis or cortical
inclusions of Müllerian epithelium, likely a form of endosalpingiosis.
These include low- grade endometrioid carcinomas, clear cell carci-
nomas, borderline and low- grade serous carcinomas, and mucinous
carcinomas. These tumors are thought to evolve slowly from lower-
grade precursor conditions (endometriotic cysts, cyst adenomas, etc)
and are classified as type I tumors.5 Fallopian tube carcinomas arise
in the dist al fallopian tube and the majority of these are high- grade
serous carcinomas. These are thought to evolve rapidly from more
obscure precursors and are designated as type II tumors.5,6 This lat-
ter group encompasses high- grade endometrioid carcinomas and
carcinosarcomas. All of these high- grade carcinomas are nearly al-
ways associated with mutations in the TP53 gene.5
1.1.2 | Lymphatic and lymph node drainage
The lymphatic drainage of the ovaries and fallopian tubes is via the
utero- ovarian, infundibulopelvic, and round ligament pathways and
an external iliac accessory route into the following regional lymph
nodes: ex ternal iliac, common iliac, hypogastric, lateral sacral, para-
aorti c lymph nodes an d, occasionall y, t o the inguinal nod es.1,1 0– 1 2 The
peritoneal surfaces can drain through the diaphragmatic lymphatics
and hence to the major venous vessels above the diaphragm.
1.1.3 | Other metastatic sites
The peritoneum, including the omentum and pelvic and abdominal
viscera, is the most common site for dissemination of ovarian and
fallopian tube cancers. This includes the diaphragmatic and liver sur-
faces. Pleural involvement is also seen. Other extraperitoneal or ex-
trapleural sites are relatively uncommon, but can occur.1,1 0– 1 2 After
systematic pathologic analysis has excluded a tubal or ovarian site of
origin, malignancies that appear to arise primarily on the peritoneum
have an identical spread pattern, and frequently may involve the
ovaries and fallopian tubes secondarily. These “peritoneal” tumors
are thought to arise in endosalpingiosis.
1.2 | Classification rules
Although CT scans can delineate the intra- abdominal spread of
disease to a certain extent, ovarian, fallopian tube, and peritoneal
cancers should be staged surgically. Operative findings determine
the precise histologic diagnosis, stage, and therefore the prognosis,
of the patient.1,9,10,12– 14
In selected patients with advanced stage disease, it may be ap-
propriate to initiate chemotherapy prior to surgical intervention, and
in these cases there should be histologic or cytologic confirmation of
the diagnosis prior to starting neoadjuvant chemotherapy (see 5.2.2.
below).
Chest radiograms may serve as a screen for pleural ef fusions. As
distant metastases are infrequent, there is no requirement for other
radiological evaluation unless symptomatic. Serum CA125 levels
may be useful in determining response to chemotherapy, but they
do not contribute to staging.
1.2.1 | Fallopian tube involvement
Fallopian tube involvement can be divided into three categories. In
the first, an obvious intraluminal and grossly apparent fallopian tube
mass is seen with tubal intraepithelial carcinoma (carcinoma in situ)
that is presumed to have arisen in the fallopian tube. These cases
should be staged surgically with a histologic confirmation of disease.
Tumor extension into the submucosa or muscularis and to and be-
yond the serosa can therefore be defined. These features, together
with the laterality and the presence or absence of ascites, should all
be taken into consideration.1,3,6,7
In the second scenario, a widespread serous carcinoma is asso-
ciated with a tubal intraepithelial carcinoma. A visible mass in the
endosalpinx may not be seen but the histologic findings should be
noted in the pathology report since they may indicate a fallopian
tube primary. Tumors obliterating both fallopian tube and ovary
may belong to this group but whether a presumptive assignment of
a tubal origin can be made in such cases is controversial given that
tubal intraepithelial carcinoma cannot be confirmed.
In the third scenario— risk- reducing salpingo- oophorectomy—
tubal intraepithelial carcinoma may be the only finding. It should be
reported as originating in the fallopian tube and managed accord-
ingly. The majority of early serous cancers detected are found in the
fallopian tube, irrespective of genetic risk.15,16
1.2.2 | FIGO staging
The updated, revised FIGO staging system combines the classifica-
tion for ovarian, fallopian tube, and peritoneum cancer. It is based
on findings made mainly through surgical exploration (as outlined
above). Table 1 presents the 2014 FIGO staging classification for
cancer of the ovary, fallopian tube, and peritoneum. The equivalents
within the Union for International Cancer Control (UICC) TNM clas-
sification are presented in Table 2.
In addition to these changes, several other modifications of the for-
mer staging system have been made to better prospec tively capture
the data. Stage IC is now divided into three categories: IC1 (surgical
|
63
BEREK Et al .
spill); IC2 (capsule ruptured before surgery or tumor on ovarian or
fallopian tube surface); and IC3 (malignant cells in the ascites or peri-
toneal washings). Stage IIC has been eliminated. The updated staging
includes a revision of the Stage IIIC based on spread to the retroperito-
neal lymph nodes alone without intraperitoneal dissemination because
an analysis of these patients indicates that their sur vival is significantly
better than those who have intraperitoneal dissemination.18 This cat-
egory is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest
dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension).
Stage IIIA 2 is now “microscopic extrapelvic peritoneal involvement
with or without positive retroperitoneal lymph node” metastasis. The
wording of Stage IIIB has been modified to reflect the lymph node sta-
tus. Stage IVB now includes metastases to the inguinal lymph nodes.
Regional lymph nodes (N)
• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph node metastasis.
• N1: Regional lymph node metastasis.
Distant metastasis (M)
• MX: Distant metastasis cannot be assessed.
• M0: No distant metastasis.
• M1: Distant metastasis (excluding peritoneal metastasis).
1.3 | Histopathologic classification
The majority of cases of ovarian cancer are of epithelial origin. FIGO
endorses the WHO histologic typing of epithelial ovarian tumors. It
is recommended that all ovarian epithelial tumors be subdivided ac-
cording to the classification given below.19
The histologic classification of ovarian, fallopian tube, and peri-
toneal neoplasia is as follows:
• Serous tumors.
• Mucinous tumors.
• Endometrioid tumors.
• Clear cell tumors.
• Brenner tumors.
• Undifferentiated carcinomas (this group of malignant tumors is of
epithelial structure, but they are too poorly differentiated to be
placed in any other group).
• Mixed epithelial tumors (these tumors are composed of two or
more of the five major cell types of common epithelial tumors.
The types are usually specified).
• Cases with high- grade serous carcinoma in which the ovaries
and fallopian tubes appear to be incidentally involved and not
the primary origin can be labeled as peritoneal carcinoma or
TABLE 1 FIGO staging classification for cancer of the ovary, fallopian tube, and peritoneum
Stage I: Tumor confined to ovaries or fallopian tube(s) T 1 - N 0 - M 0
IA: Tumor limited to 1 ovary (capsule intac t) or fallopian tube; no tumor on ovarian or fallopian tube surface; no malignant
cells in the ascites or per itoneal washings
T 1 a - N 0 - M 0
IB: Tumor limited to both ovaries (capsules int act) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no
malignant cells in the ascites or peritoneal washings
T 1 b - N 0 - M 0
IC: Tumor limited to 1 or both ovaries or fallopian tubes, with any of the following:
IC1: Surgical spill T 1 c 1 - N 0 - M 0
IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface T 1 c 2 - N 0 - M 0
IC3: Malignant cells in the ascites or peritoneal washings T1c3- N0- M0
Stage II: Tumor involves 1 or both ovaries or fallopian tubes with pelvic ex tension (below pelvic brim) or peritoneal cancer T 2 - N 0 - M 0
IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries T 2 a - N 0 - M 0
IIB: Extension to other pelvic intraperitoneal tissues T 2 b - N 0 - M 0
Stage III: Tumor involves 1 or both ovaries or fallopian tubes, or peritoneal cancer, with cytologically or histologically
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes
T1-3/N0-1/M0
IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically proven): T 1 / T 2 - N 1 - M 0
IIIA1(i) Metastasis up to 10 mm in greatest dimension
IIIA1(ii) Metastasis more than 10 mm in greatest dimension
IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph node s T 3 a 2 - N 0 / N 1 - M 0
IIIB: Macroscopic peritoneal met astasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to
the retroperitoneal lymph nodes
T3b- N0/N1- M0
IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis
to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal
involvement of either organ)
T 3 c - N 0 / N 1 - M 0
Stage IV: Distant metas tasis excluding peritoneal metastases Any T, any N, M1
Stage IVA: Pleural effusion with positive cytology
Stage IVB: Parenchymal metastases and metastases to extra- abdominal organs (including inguinal lymph nodes and lymph
nodes outside of the abdominal cavity)
64
|
BE REK Et al.
serous carcinoma of undesignated site, at the discretion of the
pathologist.
Epithelial tumors of the ovary and fallopian tube are further
subclassified by histologic grading, which can be correlated with
prognosis. This grading system does not apply to nonepithelial tu-
mors.20 Two grading systems are applied. For nonserous carcinomas
(most endometrioid and mucinous), grading is identical to that used
in the uterus, based on architecture with a one- step upgrade if there
is prominent nuclear atypia, as follows:
• GX: Grade cannot be assessed.
• G1: Well differentiated.
• G2: Moderately differentiated.
• G3: Poorly differentiated.
Serous carcinomas are the most common in both the ovar y and
tube. More than 90% of fallopian tube carcinomas are serous or high-
grade endometrioid adenocarcinoma. Other cell types have been
reported, but are rare.1,2,21 Serous carcinomas are graded in a two-
grade system befitting their biology. High- grade serous carcinomas,
including both classic appearing and those with SET features (solid,
endometrioid- like, and transitional) carry a high frequency of muta-
tions in TP53.2 2– 24 Low- grade serous carcinomas are often associated
with borderline or atypical proliferative serous tumors, often contain
mutations in BRAF and KRAS and contain wild- type TP53. Most “mod-
erately differentiated” serous carcinomas carry mutations in TP53 and
should be combined with the high- grade tumors.2 0,2 3– 25
Nonepithelial cancers, although uncommon, are extremely im-
portant. These include granulosa cell tumors, germ cell tumors,
sarcomas, and lymphomas. They are discussed below as separate
entities. Metastatic neoplasms to the ovary, such as tumors aris-
ing in the breast, lower reproductive tract sites (cervix or uterine
carcinomas) and gastrointestinal tract (signet ring cell [Krukenberg]
carcinomas, low grade appendiceal or pancreaticobiliary mucinous
tumors and other neoplasms) are graded and staged in accordance
with their respective sites of origin.1,2
2 | EPIDEMIOLOGY
Malignant tumors of the ovaries occur at all ages with variation in
histologic subtype by age. For example, in women younger than
20 years of age, germ cell tumors predominate, while borderline
tumors t ypically occur in women in their 30s and 40s— 10 or more
years younger than in women with invasive epithelial ovarian can-
cers, which mostly occur after the age of 50 years.
The lifetime risk of a woman in the USA developing ovarian
cancer is approximately 1 in 70. Approximately 23% of gyneco-
logic cancers are ovarian in origin, but 47% of all deaths from
cancer of the female genital tract occur in women with ovarian
cancer. Overall, epithelial ovarian cancer accounts for 4% of all
new cancer diagnoses in women and 5% of all cancer- related
deaths.1,2,26
The overall incidence of epithelial tumors varies from 9– 17 per
100 000 and is highest in high- income countries, with the exception
of Japan.27 However, this incidence rate increases proportionately
with age. The largest number of patients with epithelial ovarian can-
cer is found in the 60– 64 years age group. The median age is about
a decade earlier in low- income countries.
Established risk factors for epithelial ovarian tumors include re-
productive risk factors. Women who have never had children are
twice as likely to develop this disease. First pregnancy at an early
age, early menopause, and the use of oral contraceptives have been
TABLE 2 Cancer of the ovary, fallopian tube and peritoneum:
FIGO staging (2014) compared with TNM classificationa
FIGO (Designate
primar y: Tov, Tft, Tp,
or Tx)
UICC
T N M
Stage
IA T1a N0 M0
IB T1b N0 M0
IC T1c N0 M0
IIA T2a N0 M0
IIB T2b N0 M0
IIIA T3a N0 M0
T3a N1 M0
IIIB T3b N0 M0
T3b N1 M0
IIIC T3c N0−1 M0
T3c N1 M0
IV Any T Any N M1
Regional nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis (excluding peritoneal
metastasis)
Notes: 1. The primary site— that is, ovary, fallopian tube, or peritoneum—
should be designated where possible. In some cases, it may not be
possible to clearly delineate the primary site, and these should be listed
as “undesignated”.
2. The histologic type should be recorded.
3. The st aging includes a revision of t he Stage III patients and allotment
to Stage IIIA1 is based on spread to the retroperitoneal lymph nodes
without intraperitoneal dissemination, because an analysis of these
patient s indicates that their survival is significantly better than those
who have intraperitoneal dissemination.
4. Involvement of retroperitoneal ly mph nodes must be proven
cytologically or histologically.
5. Extension of tumor from omentum to spleen or liver (Stage IIIC)
should be differentiated from isolated parenchymal splenic or liver
metastases (Stage IVB).
aSource: Prat J.17
|
65
BEREK Et al .
associated with lower risks of ovarian cancer.28 The relationship of
these variables to fallopian tube cancer is unclear.
As noted above, it has been previously presumed that fallopian
tube malignancies were rare; however, this has been challenged by
evidence to show that many tumors that were classified as serous
carcinomas of the ovary or peritoneal cancers appear to have their
origin in the fallopian tube.3– 7 When the origin is uncertain, the con-
vention of designating all serous cancers as originating in the ovary
should no longer be used and the term “undesignated origin” may be
applied at the discretion of the pathologist.19
2.1 | Genetics
Hereditary factors are implicated in approximately 20% of ovarian,
fallopian tube, and peritoneal cancers29– 33:
1. Most hereditary ovarian cancers are due to pathogenic mu-
tations in either the BRCA1 or BRCA2 genes. At least 15%
of women with high- grade nonmucinous ovarian cancers have
germline mutations in BRCA1/2 and, importantly, almost 40%
of these women do not have a family history of breast/ovar-
ian cancer. All women with high- grade nonmucinous invasive
ovarian cancers should be offered genetic testing even if they
do not have a family history of breast/ovarian cancer.
2. Inherited deleterious mutations in BRCA1 and BRCA2 are the
major genetic risk factors. Women who carry germline mutations
in BRCA1 and BRCA2 have a substantially increased risk of ovar-
ian, tubal, and peritoneal cancer— about 20%– 50% with BRCA1
and 10%– 20% with BRCA2.30 – 33 Typically, these cancers occur at
an earlier age than sporadic cancers, particularly in BRCA1 muta-
tion carriers, with a median age of diagnosis in the mid- 40s.
3. A number of other low- to moderate- penetrance genes can also
predispose to ovarian, fallopian tube, or peritoneal cancer. A
study using next generation sequencing of constitutional DNA
samples from 1915 women with ovarian cancer was carried out
to identif y germline mutations using a panel of 20 genes including
BRCA1 and BRCA2, DNA mismatch repair genes, double- stranded
DNA break repair genes such as CHEK2 and AT M, as well as the
BRCA1- associated complex or the BRCA2/Fanconi Anemia path-
way genes (including BRIP1, BARD1, PALB2, R AD50, R A D51 C, and
R AD 51D , among others). About 80% of mutations were in BRCA1
or BRCA2. About 3% of patients carried mutations in the Fanconi
Anemia pathway genes, while only 0.4% had mutations in mis-
match repair genes.34 In an earlier similar study that included 360
patients, 24% carried germline loss- of- function mutations includ-
ing 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2,
MR E11A , MSH6, NBN, PAL B2, RAD50, RA D51 C, or TP53.35,36
4. Inherited mutations in the mismatch repair genes associated with
Lynch syndrome type II. Women carrying these mutations have
an increased risk of a number of cancers including colon, endo-
metrial, and ovarian cancer. Typically, the ovarian cancers that
occur are endometrioid or clear cell histologically and are usually
Stage I.36
Women with a strong family history of epithelial ovarian,
fallopian tube, or peritoneal cancers, particularly if there is a
documented germline BRC A mutation, are advised to have a risk-
reducing bilateral salpingo- oophorectomy after appropriate coun-
seling and at the completion of childbearing. All women who are
suspected of carrying a BRCA germline mutation, based on fam-
ily histor y or young age of diagnosis and a high- grade serous or
high- grade endometrioid cancer, should be offered genetic testing.
BRCA mutations may also occur in women without a family history
of breast/ovarian cancer, and genetic testing should be considered
in patient s from ethnic groups where there is a high incidence
of founder mutations (e.g. Ashkenazi Jewish ancestr y), and in
women with high- grade serous cancers under the age of 70 years.
Australian guidelines advise that all women with invasive epithelial
ovarian cancer apart from mucinous cancers diagnosed under the
age of 70 should be offered BRC A mutation testing independent of
family history and histologic subtype.37 In contrast, the Societ y of
Gynecologic Oncology (SGO) and National Comprehensive Cancer
Network (NCCN) guidelines recommend that all women diagnosed
with ovarian, fallopian tube, or peritoneal carcinoma, regardless
of age or family history, should receive genetic counseling and be
offered genetic testing.38 Women whose family history suggests
Lynch syndrome type II should undergo appropriate genetic coun-
seling and testing.
3 | SCREENING
To date, there are no documented effective screening methods
that reduce the mortality of ovarian, fallopian tube, or peritoneal
cancers. Studies using CA125, ultrasonography of the pelvis, and
pelvic examination do not have an acceptable level of sensitivity
and specificity, based on trials carried out in women in the gen-
eral population39, 40 and those in the high- risk population.41,42 The
US Preventive Services Task Force recommends against screening
asymptomatic women for ovarian cancer with pelvic examination,
pelvic ultrasound, or serum tumor marker measurements.43 The low
prevalence of disease and lack of high- quality screening methods
make it more likely to obtain false- positive results leading to unnec-
essary interventions. A recent study of multimodal screening using
CA125 based on a risk of ovarian cancer algorithm (ROCA) every
4 months and transvaginal ultrasound annually or earlier where indi-
cated by the ROCA in women at high risk of ovarian cancer repor ted
that screening was associated with a low rate of high- volume disease
at primar y surgery and very high rates of no residual disease after
surgery.44 Given that the majority of women with advanced stage
ovarian cancer, even with complete resection, will relapse after
chemotherapy, this does not seem to be a good alternative to risk-
reducing surgery. The authors of the screening study concluded that
66
|
BE REK Et al.
risk- reducing salpingectomy- oophorectomy remains the treatment
choice for women at high risk of ovarian/fallopian tube cancer.44
Women at increased genetic risk should be encouraged to
consider risk- reducing bilateral salpingo- oophorectomy, as this is
the most effective way to reduce mortality in this population of
women.40, 41 A bulletin from the American College of Obstetricians
and Gynecologists (ACOG) has recommended that opportunistic (at
the time of a clinically indicated hysterectomy) bilateral salpingec-
tomy be considered in women not at genetic risk who wish to retain
their ovaries as a way to reduce their risk of later developing high-
grade serous carcinomas.45
4 | DIAGNOSIS
Patients with epithelial ovarian cancers confined to the ovary or fal-
lopian tube at initial diagnosis have a very good prognosis.46– 49 The
symptoms are often very insidious and the duration of symptoms
not very different between patients with early stage or advanced
stage disease.13,14 This may reflect the different biological behav-
ior of the various histologic subtypes; for example, grade 1 serous,
clear cell, mucinous, and endometrioid cancers are commonly early
stage at presentation, whereas high- grade serous cancers are most
often Stage III because of early dissemination by a more aggres-
sive cancer. Tumor markers such as human gonadotropin (hCG) and
alpha- fetoprotein (AFP) are mandatory to exclude germ cell tumors
in younger patients with a pelvic mass or suspicious enlargement
of an ovary.
Approximately two- thirds of all epithelial “ovarian” cancers are
Stage III or St age IV at diagnosis. Presenting symptoms include vague
abdominal pain or discomfort, menstrual irregularities, dyspepsia,
and other mild digestive disturbances, which may have been pres-
ent for only a few weeks.13,14 ,50 As the disease progresses, abdom-
inal distention and discomfort from ascites generally worsen, and
may be associated with respiratory symptoms from increased intra-
abdominal pressure or from the transudation of fluid into the pleural
cavities. Abnormal vaginal bleeding is an uncommon symptom.
Serous fallopian tube and peritoneal cancers present the same as
ovarian cancer. Past analyses have been biased because many fallo-
pian tube cancers have been presumed to arise in the ovaries.
A detailed medical history must be taken to ascertain possible
risk factors, history of other cancers, and history of cancer in the
family. Then a complete physical examination, including general,
breast, pelvic, and rectal examination, must be performed.1
Prior to surgery a chest radiograph should be taken to screen for
a pleural effusion and a CT scan of the abdomen and pelvis should
be performed to delineate the extent of intra- abdominal disease.
However, in the absence of extra- abdominopelvic disease, radio-
logical scanning does not replace surgical staging with laparotomy.
Tumor markers including CA125, and carcinoembryonic antigen
(CEA) should be considered.1 With a high CA125 level, the most
common diagnosis would be epithelial ovarian, fallopian tube, or
peritoneal cancer.
A gastric or colonic primary with metastases to the ovaries may
mimic ovarian cancer, and if CEA or CA19- 9 are elevated, this should
be considered. A ratio of more than 25:1 (CA125 and CE A) favors an
ovarian primary although it does not completely rule out a primar y
in the gastrointestinal tract.51
A current mammogram should be considered as patients are fre-
quently in the age group where breast cancer is prevalent. A colonos-
copy is indicated when symptoms suggest possible colorectal cancer.1
The following factors point to the presence of a malignancy, and
are useful in the clinical assessment of masses:
• Age of the patient (young for germ cell, older for epithelial
malignancies).
• Bilaterality.
• Tumor fixation clinically.
• Ascites.
• Ultrasonographically complex, especially if solid areas.
• CT finding of metastatic nodules.
• Elevated tumor markers.
5 | PRIMARY SURGERY
In general, the prognosis of epithelial ovarian, fallopian, and perito-
neal malignancies is independently affected by the following1,52,53:
• Stage of the cancer at diagnosis.
• Histologic type and grade.
• Maximum diameter of residual disease after cytoreductive
surgery.
5.1 | Staging laparotomy
A thorough staging laparotomy is an important part of early manage-
ment. If the preoperative suspicion is malignancy, a laparotomy should
be performed. If there is no visible or palpable evidence of metast asis,
the following should be performed for adequate staging1,10,11:
• Careful evaluation of all peritoneal surfaces.
• Retrieval of any peritoneal fluid or ascites. If there is none, washings
of the peritoneal cavity should be performed.
• Infracolic omentectomy.
• Selective lymphadenectomy of the pelvic and para- aortic lymph
nodes, at least ipsilateral if the malignancy is unilateral.
• Biopsy or resection of any suspicious lesions, masses, or adhesions.
• Random peritoneal biopsies of normal surfaces, including from the
undersurface of the right hemidiaphragm, bladder reflection, cul-
de- sac, right and left paracolic recesses, and both pelvic sidewalls.
• Total abdominal hysterectomy and bilateral salpingo- oophore ctomy
in most cases.
• Appendectomy for mucinous tumors if the appendix appears
abnormal.
|
67
BEREK Et al .
Upon opening the abdominopelvic cavity, the peritoneal fluid
should be sent for cytology. In the absence of ascites, irrigation
should be performed and washings sent for cytology.
The laparotomy should proceed with a detailed examination of
the content s, including all of the peritoneal surfaces. In addition to
the suspicious sites, biopsies from the peritoneal reflection of the
bladder, the posterior cul- de- sac, both paracolic gutters, subdia-
phragmatic surfaces, and both pelvic sidewalls should be taken. The
primar y tumor, if limited to the ovary, should be examined to look
for capsular rupture. All obvious sites of tumor must be removed
wherever possible in addition to total hysterectomy and bilateral
salpingo- oophorectomy. The omentum, pelvic, and para- aortic
lymph nodes should be removed for histologic examination.
In younger women, fertility preservation may be desired. In
these patients, conservative surgery, with preservation of the
uterus and contralateral ovary, should be considered af ter in-
formed consent.47
Clinical judgment is important in the approach to a pelvic
mass in the young, reproductive- aged woman. If the suspicion is
strong for malignancy, open laparotomy is generally indic ated.
Laparoscopy may be more appropriate if the suspicion is more for
benign disease, where tumor markers (including hCG and AFP) are
normal. A biopsy of any suspicious lesion can be performed and
frozen section obtained in order to proceed expeditiously with de-
finitive surgery.
Ovaries and fallopian tubes should be evaluated as thoroughly as
possible to establish the site of origin. If visible, the entire tube, par-
ticularly the distal portion, should be submitted for pathology and
examined using the SEE- FIM protocol.33 Ovaries should be scruti-
nized for coexisting endometriotic cysts, adenofibromas, or other
benign conditions that could serve as a nidus of tumor development.
5.2 | Cytoreductive (debulking) surgery for
advanced stage disease
5.2.1 | Primary debulking
At least two- thirds of patients with ovarian cancer present with
Stage III or IV disease. This may affect the performance status and fit-
ness for surgery. However, the most important prognostic indicator in
patients with advanced stage ovarian cancer is the volume of residual
disease after surgical debulking. Therefore, patients whose medical
condition permits should generally undergo a primary laparotomy
with total abdominal hysterectomy, bilateral salpingo- oophorectomy,
omentectomy, and maximal attempt at optimal cytoreduc-
tion.1,52,53 This may necessitate bowel resection, and occasionally,
partial or complete resection of other organs. Based on recent data
from the randomized Lymphadenectomy in Ovarian Neoplasm (LION)
trial, the removal of clinically negative lymph nodes during cytoreduc-
tive surgery does not increase the progression- free or overall survival
and should not be undertaken.54 Level of Evidence A.
5.2.2 | Interval debulking
In selected patients with cytologically proven Stage IIIC and IV dis-
ease who may not be good surgic al candidates, 3– 4 cycles of neo-
adjuvant chemotherapy (NACT) may be given initially, followed by
interval debulking surgery and additional chemotherapy as demon-
strated in the EROTC and CHORUS Trials.55,56 These two randomized
prospec tive trials showed that in selected patients, interval debulk-
ing surgery after neoadjuvant chemotherapy showed equivalent
survival with less morbidity compared with primary cytoreductive
surgery. NACT followed by interval debulking surgery may be par-
ticularly useful in patients with a poor performance status, significant
medical comorbidities, visceral metastases, and those who have large
pleural effusions and/or gross ascites.57,5 8 In selected patients whose
primary cytoreduction is considered suboptimal, particularly if a gy-
necologic oncologist did not perform the initial operation, interval
debulking may be considered after 2– 3 cycles of systemic chemo-
therapy.1,55,56,59 Pathologic assessment for residual tumor following
neoadjuvant therapy will enable an estimate of residual disease and
pathological response.60 There are recent data to indicate that pa-
tients who have a good pathological response have a better outcome.
A histopathologic scoring system for measuring response to neoad-
juvant chemotherapy has been developed and validated by Bohm
et al.61 who reported criteria for defining a chemotherapy response
score (CRS) based on a three- tier system. A CRS 3 (complete or near
complete pathological response) was associated with a better prog-
nosis. Recently, these results have been validated in an independent
West Australian cohort.62
6 | CHEMOTHERAPY
6.1 | Chemotherapy for early- stage cancer
The prognosis of patients with adequately staged tumors with
Stage IA and Stage IB grade 1– 2 epithelial cancers of the ovar y is
very good; adjuvant chemotherapy does not provide additional ben-
efits and is not indicated. For higher- grade tumors and for patients
with Stage IC disease, adjuvant platinum- based chemotherapy is
given to most patients, although there has been debate about the
absolute survival benefit in women with Stage IA and IB cancers
who have had thorough surgical staging.46 All patients with Stage II
disease should receive adjuvant chemotherapy. The optimal number
of cycles in patients with Stage I disease has not been definitively
established, but typically between 3 and 6 cycles are administered.
The Gynecologic Oncology Group (GOG) 157 study suggested that
3 cycles of carboplatin and paclitaxel was equivalent to 6 cycles,49
but in subgroup analysis, 6 cycles appeared superior in patients with
high- grade serous cancers.63
There is no evidence to support adjuvant therapy for carcinoma
in situ of the fallopian tube and it is not recommended.1,2,64 Level of
Evidence A.
68
|
BE REK Et al.
6.2 | Chemotherapy for advanced stage
ovarian cancer
Patients who have had primary cytoreduction should receive chem-
otherapy following surgery1,65 (Table 3). The accepted standard is 6
cycles of pl atinum- b ased combinatio n chemothera py, with a platinum
(carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel).66 – 70
Docetaxel is an option in patients who have had a significant allergic
reaction to paclitaxel or who develop early sensor y neuropathy as
it has less neurotoxicity, but it is more myelosuppressive than pacli-
taxel. The SCOT- ROC (Scottish Gynecological Cancer Trials Group)
study randomly assigned 1077 women with Stages IC– IV epithelial
ovarian cancer to carboplatin paclitaxel or docetaxel.71 The efficacy
of docetaxel was similar to paclitaxel. The median progression- free
survival was 15.1 months versus 15.4 months. The MITO- 2 trial ran-
domized over 800 patient s to receive either carboplatin and lipo-
somal doxorubicin (PLD) or carboplatin and paclitaxel. The median
progression- free survival was 19.0 months and 16.8 months with
carboplatin/PLD and carboplatin/paclitaxel, respectively.72 The me-
dian overall survival times were 61.6 months and 53.2 months with
carboplatin/PLD and carboplatin/paclitaxel, respectively (hazard
ratio [HR] 0.89; 95% CI, 0.72– 1.12; P = 0.32). Carboplatin/PLD pro-
duced a similar response rate but different toxicity (less neurotoxic-
ity and alopecia but more hematologic adverse effects) and could
also be considered as an option in patients where paclitaxel cannot
be used.
Although intraperitoneal chemotherapy has been shown to be
associated with improved progression- free survival and overall sur-
vival in selected patients with optimally debulked Stage III ovarian
cancer, it is not widely used out side the USA because of concerns
regarding increased toxicity and catheter- related problems, and
the benefits are still debated.75– 78 The GOG 172 trial compared in-
travenous paclitaxel plus cisplatin with intravenous paclitaxel plus
intraperitoneal cisplatin and paclitaxel in patients with Stage III
ovarian or peritoneal carcinoma, with no residual disease greater
than 1 cm in diameter.77 Only 42% of patients in the intraperitoneal
group completed 6 cycles of the assigned therapy, but the intraper-
itoneal group had an improvement in progression- free survival of
5.5 months (23.8 months vs 18.3 months; P = 0.05) and an improve-
ment in overall survival of 15.9 months (65.6 months vs 49.7 months;
P = 0.03). Level of Evidence A.
More recently, the GOG 252 trial reported a median progression-
free sur vival of approximately 27– 29 months in over 1500 patients
with optimal Stage II– III disease treated with regimens consisting
of different combinations of intravenous and intraperitoneal cispla-
tin, carboplatin, and paclitaxel, in combination with bevacizumab,
which raises questions about the role of intraperitoneal chemother-
apy.79 The treatment arms included intravenous carboplatin AUC 6/
intravenous weekly paclitaxel at 80 mg/m2; intraperitoneal carbo-
platin AUC 6/intravenous weekly paclitaxel at 80 mg/m; and intra-
venous paclitaxel at 135 mg/m2 on day one/intraperitoneal cisplatin
at 75 mg/m2 on day two/intraperitoneal paclitaxel at 60 mg/m2 on
day eight. In addition, each arm received intravenous bevacizumab at
15 mg/kg with cycles 2 through 6 of chemotherapy and then alone
for cycles 7 through 22. The median progression- free survival by
intent- to- treat analysis was 24.9 months (intravenous carboplatin),
27.3 months (intraperitoneal carboplatin), and 26.0 months (intraper-
itoneal cisplatin). An analysis limited to patients with optimal Stage III
tumors and no gross residual disease found a median progression-
free sur vival of 31– 34 months in all three arms. The median overall
survival for all patients enrolled was 75.5 months, 78.9 months, and
72.9 months, respectively, and median overall survival for Stage II/
III with no gross residual disease was 98.8 months, 104.8 months,
and not reached.79 By comparison, the GOG 172 trial comparing
intraperitoneal and intravenous chemotherapy regimens in ovarian
cancer had a median progression- free survival of 23.8 months with
intraperitoneal cisplatin (vs 18.3 months with intravenous) with an
improveme nt in overall survival in favor of intraperitonea l injection.77
In addition, the median progression- free survival was 60 months in
the patients with no residual disease in GOG 172. Differences in the
cisplatin arm from the GOG 172 study include a dose reduction from
100 mg to 75 mg and a shorter infusion time from 24 to 3 h.77 If
TABLE 3 Chemotherapy for advanced epithelial ovarian cancer: recommended regimensa
Drugs
Standard regimens Dose
Administration
(h) Interval No. of treatments
Carboplatin AUC =5– 6 3 Every 3 weeks 6– 8 cycles
Paclitaxel 175 mg /m2
Carboplatin AUC =5– 6 3 Every 3 weeks 6 cycles
Paclitaxel 80 mg/m2Every week 18 week s
Carboplatin AUC =5 3 Every week 6 cycles
Docetaxel 75 mg/m2Every 3 week s
Cisplatin 75 mg /m23 Every 3 weeks 6 cycles
Paclitaxel 135 mg/m2
Carboplatin (single agent)b AUC =5 3 Every 3 weeks 6 cycles, as tolerated
Abbreviation: AUC, area under the curve dose by the methods of C alvert et al.73,74
aReproduced with permission from Berek et al.1
bIn patients who are elderly, frail, or poor performance status.
|
69
BEREK Et al .
intraperitoneal treatment is used it would be appropriate to follow
the GOG 172 protocol rather than the modified protocol with a lower
dose of cisplatin accepting the increased toxicity.
Combination chemotherapy with either intravenous carboplatin
and paclitaxel or intraperitoneal cisplatin and paclitaxel (using the
GOG 172 protocol) are the standard treatment options for patients
with advanced disease, with evidence to support the addition of
bevacizumab as well. The advantages and disadvantages of the in-
travenous versus intraperitoneal routes of administration of these
drugs should be discussed with the patient in light of the results of
GOG 252 discussed above, which did not demonstrate improved
outcomes with intraperitoneal chemotherapy when bevacizumab
was added to intravenous chemotherapy. Intraperitoneal chemo-
therapy is applicable only to patients with advanced disease who
have had optimal debulking and have less than 1 cm residual disease.
It should be used only in centers that have experience with intraper-
itoneal chemotherapy.
The recommended doses and schedule for intravenous che-
motherapy are: carboplatin (star ting dose AUC 5– 6), and paclitaxel
(175 mg /m2), every 3 weeks for 6 cycles.1
The Japanese GOG (JGOG) reported an alternative dose- dense
regimen of carboplatin AUC 6 every 3 weeks for 6 cycles and weekly
paclitaxel 80 mg/m2 and showed improved progression- free survival
and overall survival.80,81 An Italian trial (MITO- 7) investigated a dif-
ferent schedule of weekly carboplatin (AUC 2 mg/mL per min) plus
weekly pa clitaxel (60 mg/m2) compared with carboplatin (AUC 6 mg/
mL per min, administered every 3 weeks) and paclitaxel (175 mg/
m2).82 The co- primar y endpoints were progression- free sur vival
and quality of life, which is quite unique for an ovarian cancer trial.
The weekly regimen did not significantly improve progression- free
survival compared with the conventional regimen (18.8 months vs
16.5 months; P = 0.18), but was associated with better quality of
life and fewer toxic effects and could be considered a reasonable
option, particularly in elderly patients in whom combination chemo-
therapy is planned. The results of the ICON8 trial inves tigating dose-
dense paclitaxel in a non- Japanese population have been recently
reported.83 Over 1500 predominantly white patients were random-
ized to receive one of three regimens: Arm 1: carboplatin AUC 5/6
and paclitaxel 175 mg/m2 every 3 weeks; Arm 2: carboplatin AUC
5/6 every 3 weeks and paclitaxel 80 mg/m2 weekly; and Arm 3: car-
boplatin AUC 2 and paclitaxel 80 mg/m2 weekly. All patients had re-
ceived neoadjuvant chemotherapy with planned interval debulking
or received chemotherapy after initial primary cytoreductive sur-
gery. There was no benefit found for the dose- dense regimens. The
progression- free survival was 24.4 months with every 3- week dos-
ing, compared with 24.9 months and 25.3 months in arms 2 and 3,
respectively. The overall survival was reported recently and the me-
dian overall survival was 47.4 months, 54.1 months, and 53.4 months
in arms 1, 2, and 3, respectively.84 These results are very different
to the JGOG trial and it seems that the likely explanation is due to
pharmacogenomic differences between these two ethnic groups.85
The recommended doses and schedule for intraperitoneal che-
motherapy are paclitaxel 135 mg/m2 intravenously on day one,
followed by cisplatin 100 mg/m2 intraperitoneally on day two, fol-
lowed by paclitaxel 60 mg/m2 intraperitoneally on day eight, every
3 weeks for 6 cycles, as tolerated.77, 78 Many centers modify the dose
of cisplatin to 75 mg/m2 rather than 100 mg/m2 that was used in
GOG 172 to reduce toxicity, but this could be questioned based on
GOG 252 results discussed above. Others substitute carboplatin
(AUC 5– 6) for cisplatin in the regimen and the same caveats regard-
ing lack of evidence apply. The role of intraperitoneal carboplatin is
being evaluated in the JGOG iPocc trial, and the results should be
available in the near future.
Bevacizumab 7.5– 15 mg /kg every 3 weeks may be added to
these regimens. Two studies (GOG 218 and ICON7) have reported a
modest, but statistically significant increase in progression- free sur-
vival in patients receiving maintenance bevacizumab following car-
boplatin, paclitaxel, and concurrent bevacizumab.86,87 The GOG 218
trial randomized patients with Stage III and macroscopic residual
disease as well as Stage IV ovarian cancer to: (1) 6 cycles of carbo-
platin and paclitaxel plus placebo for c ycles 2 through 22 (control
group); (2) 6 cycles of carboplatin and paclitaxel in combination with
bevacizumab (15 mg/kg) for cycles 2 through 6, followed by placebo
(initiation group); and (3) 6 cycles of carboplatin and paclitaxel with
bevacizumab for cycles 2 through 22 (throughout group). The me-
dian progression- free survival was 10.3 months versus 11.2 months
versus 14.1 months in control versus initiation versus throughout
group.87 The ICON7 trial included patients with early- stage high- risk
disease (St age I or IIA clear cell or gr ade 3) and advanced Stage IIB– IV
and randomized to 6 cycles of chemotherapy or 6 cycles of chemo-
therapy plus bevacizumab (7.5 mg/kg), followed by 12 cycles of
maintenance bevacizumab.86 Restricted mean progression- free sur-
vival was statistically different with 22.4 months versus 24.1 months
(control vs bevacizumab) although the clinical significance can be
questioned. There is no evidence to demonstrate an overall survival
benefit, but a subgroup analysis of the ICON7 trial repor ted an im-
proved median survival (30.3 months vs 39.4 months) in patients
with suboptimal Stage III and Stage IV.86,88 The role, optimal dose
(7.5 mg/kg vs 15 mg/kg), timing (primary vs recurrent disease), and
duration of treatment of bevacizumab are still debatable. Similarly,
there was no difference in overall survival between the three arms in
GOG 218, but in an explorator y subgroup analysis the median over-
all survival for Stage IV disease was 32.6 months versus 42.8 months
(control vs throughout).89
van Driel et al.90 reported results of a randomized trial in which
245 patients with Stage III epithelial ovarian cancer who had re-
ceived 3 cycles of neoadjuvant chemotherapy underwent interval
debulking surgery. These patients were then randomized to receive
either 3 more cycles of paclitaxel plus carboplatin with or without
hyperthermic intraperitoneal chemotherapy (HIPEC). The addi-
tion of HIPEC to interval cytoreductive surgery resulted in longer
recurrence- free sur vival (14.2 months vs 10.7 months) and overall
survival (45.7 months vs 33.9 months) and did not result in higher
rates of adverse effects. These findings are provocative and raise
important questions. Unfortunately, the study did not have an arm
with intraperitoneal cisplatin alone without HIPEC, therefore it is
70
|
BE REK Et al.
not possible to know whether the improved survival was due to the
addition of intraperitoneal cisplatin alone or HIPEC. Confirmatory
trials are in progress to determine the role of HIPEC.
In patient s who may not tolerate combination chemotherapy
because of medical comorbidities, frailty, or advanced age, single-
agent, intravenously administered carboplatin (AUC 5– 6) can be
given. However, this approach has been challenged by the EWOC- 1
trial,91 a randomized phase 2 trial that enrolled 120 vulnerable and
elderly patients to either carboplatin (AUC 5) and paclitaxel 175 mg/
m2 every 3 weeks for 6 cycles (Arm A), carboplatin (AUC 5– 6) alone
every 3 weeks for 6 cycles (Arm B), or weekly carboplatin (AUC 2)
and paclitaxel 60 mg/m2 weekly for 18 weeks (Arm C). The median
progression- free survival was 12.5 months (95% CI, 10.3– 15.3),
4.8 months (95% CI, 3.8– 15.3), and 8.3 months (95% CI, 6.6– 15.3),
respectively (P < 0.001), and median overall survival for arm A–
B– C was not reached (NR) (21, NR), 7.4 (5.3– NR), and 17.3 (10.8–
NR), respectively (P = 0.001). The Independent Data Monitoring
Committee (IDMC) recommended that the study be closed as sur-
vival in arm B (carboplatin alone) was significantly worse than the
combination arms. The findings of this trial raise questions about the
place of single- agent carboplatin, but it should be noted that it was a
small trial and the findings need to be confirmed.
6.3 | Neoadjuvant chemotherapy
An increasing proportion of patient s with advanced stage ovarian
cancer are being treated with upfront neoadjuvant chemotherapy
(NACT) for 3– 4 cycles prior to interval debulking and further chemo-
therapy. This is based on the results of four trials that have reported
equivalent outcomes for progression- free survival and overall sur-
vival, but less morbidity and lower mortality compared with primary
debulking surgery (PDS).57 Vergote et al.55 reported the results
in 2010 of the first randomized EORTC- NCIC (National Cancer
Institute of Canada) study of PDS versus three cycles of NAC T fol-
lowed by inter val debulking. All the patients had extensive Stage IIIC
or IV disease. Patients were randomly assigned either to PDS fol-
lowed by at least six courses of platinum- based chemotherapy or to
three cycles of neoadjuvant platinum- based chemotherapy followed
by interval debulking surgery in all patients with a response or sta-
ble disease, followed by at least three fur ther courses of platinum-
based chemotherapy. The median progression- free survival in both
groups was 12 months. The median overall survival was also similar
at 29 months versus 30 months (PDS vs NACT). There was lower
postoperative morbidity and mor tality in the NACT group. The me-
dian overall survival was considerably less than the 60+ months
expected with PDS and optimal cytoreduction followed by chem-
otherapy, suggesting that the study included a cohort of patients
with very advanced disease and poor prognosis. The study provoked
much discussion and debate regarding the role of NACT.
The Chemotherapy or Upfront Surgery (CHORUS) trial random-
ized patients to NACT followed by interval debulking and then three
additional cycles or PDS followed by six cycles of platinum- based
chemotherapy.56 The optimal debulking rate was only 16% in the
PDS group compared with 40% following NACT, which are lower
than would be expected. The median duration of surgery was only
120 min in both groups, which was criticized as it did not seem to
be long enough for aggressive debulking surgery and optimal cy-
toreduction. There was a 5.6% postoperative mortality rate in the
PDS group, which is high. The median progression- free sur vival was
12 months in both groups, and the median overall survival was simi-
lar at 22.6 months versus 24.1 months (PDS vs NACT).
More recently the Japanese Oncology Group (JGOG 0602)
reported the result s of a randomized trial of NACT versus PDS in
selected patients with Stage III– IV ovarian cancer.92 The primary
endpoint was overall survival, and it was designed as a noninferiority
trial. Between 20 06 and 2011, 301 patients were randomize d: 149 to
PDS and 152 to NACT. The median overall sur vival was 49.0 months
and 44.3 months in the PDS and NACT arms respectively. The haz-
ard ratio (HR) for NACT was 1.052 (90.8% CI, 0.835– 1.326), and one-
sided noninferiority P value was 0.24. In contrast to the previous
two trials, the noninferiority of NACT was not confirmed with the
caveat that this was a relatively small trial. The authors concluded
that the noninferiorit y of NACT was not confirmed and that NACT
may not always be a substitute for PDS.
The SCORPION trial investigated whether NACT followed by
interval debulking surgery was superior to PDS in terms of periop-
erative complications and progression- free survival in patients with
advanced epithelial ovarian, fallopian tube, or primary peritoneal
cancer with high tumor burden. Patients underwent initial laparos-
copy to confirm Stage III/IV and to assess suitability for inclusion in
the trial.93 They were randomized on the operating table to either
immediate surgery or NACT. Of the 171 patients included, 84 were
randomized to surgery and 87 to chemotherapy. They achieved a
47% complete resection rate with PDS compared with 77% in the
NACT group and both arms achieved over 90% optimal resec-
tion. The aim was to demonstrate superiority of NACT over PDS,
but the median progression- free survival and overall survival were
14 months and 43 months for PDS and 14 months and 43 months
for NACT. Consistent with other studies, the morbidity was greater
in the PDS group with major complications occurring in 46% of the
patients compared with 9.5% in the NACT group. Of concern, 8.3%
of the PDS group died from surgical complications, while there were
no postsurgical deaths in the NACT group. Hospital stays were sig-
nificantly less for NAC T.
It should be noted that both JGOG 0602 and SCORPION were
carried out in exper t centers selected for the skill and surgical ex-
pertise, but were both underpowered to demonstrate superiority or
noninferiority of NACT versus PDS.
A recent systematic review and meta- analysis that included four
phase 3 trials with a total of 1692 patients conclud ed that NACT with
carboplatin and paclitaxel followed by interval debulking surgery
does not negatively impact the survival of women with advanced
ovarian cancer compared with PDS, but that perioperative complica-
tions and mortalit y are significantly reduced by 70%– 80%.94 Despite
these four trials, there remain divergent views regarding the role of
|
71
BEREK Et al .
NACT. For selected patients with poor prognostic features, NACT
seems advisable given equivalent outcomes for progression- free
survival and overall survival and lower perioperative morbidity and
mortality. NACT is indicated in patients who are medically unfit for
upfront surgery or who have a high risk of surgical morbidity and
mortality, including those with parenchymal liver and lung metasta-
ses. However, PDS should be offered to patients with a good perfor-
mance status and a more favorable prognosis. There are a number of
models from the Mayo Clinic as well as the Memorial Sloan Kettering
Cancer Center, among others, that have been advocated to improve
patient selection for PDS as well as algorithms to guide management.
6.4 | Maintenance chemotherapy
Almost 80% of women with advanced stage disease who respond to
first- line chemotherapy relapse. There have been several trials con-
ducted to determine if there is a benefit of maintenance chemother-
apy in these patients immediately following their primary treatment
in an effort to decrease the relapse rate.95 These were all negative
and there is no evidence to support maintenance chemotherapy
after completion of first- line therapy.
6.5 | Maintenance therapy with PARP inhibitors
There is increasing evidence to support the role of maintenance
therapy with PARP inhibitors following response to treatment in
the first- line therapy setting as well as in patients with platinum-
sensitive recurrent ovarian cancer. In the SOLO1 trial, patient s
with Stage III and IV high- grade serous/high- grade endometrioid
ovarian cancer, a germline or somatic BRCA1 or 2 mutation, and
at least partial response to adjuvant platinum- based chemother-
apy were randomized to olaparib maintenance or placebo.96 A
70% risk reduction for progression of disease or death was seen
for olaparib (HR 0.3) with a median progression- free survival not
reached versus 13.8 months with placebo. Twice as many patients
were progression free after 3 years (60.4% versus 26.9%), which is
unprecedented. More recently, 5- year follow- up data have been
reported; at 5 years, 48% of patients randomized to 2 years of
olaparib were progression free compared with 21% in the placebo
arm. The median progression- free survival was 56 months versus
13.8 months (HR 0.33).
The PRIMA trial enrolled a subset of patients considered to be at
high risk of relapse and included patients with Stage III and IV high-
grade serous and endometrioid ovarian cancer with response to
chemotherapy, regardless of BRCA status, and included those with
suboptimal residual disease for Stage III after surger y as well as pa-
tients who received NACT and all patients with Stage IV.97 Patients
were randomized to niraparib or placebo for 3 years. In the overall
population, the median progression- free sur vival was 8. 2 months
versus 13.8 months (control vs niraparib). In the homologous re-
combination deficient (HRD) subgroup as determined by the Myriad
myChoice test (Myriad Genetics Inc, Salt Lake Cit y, USA), the me-
dian progression- free survival was 10.9 months versus 22.1 months.
In the homologous recombination proficient subgroup, the differ-
ence was smaller although statistically significant (5.4 months vs
8.1 months).
In the PAOLA trial, patient s with Stage III– IV high- grade serous
cancers regardless of BRCA status and at least par tial response were
randomized to bevacizumab or bevacizumab plus olaparib main-
tenance therapy.98 The median progression- free survival for the
intention- to- treat population was 16.6 months versus 22.1 months
(without vs with olaparib); in the BRCA- mutated group, median
progression- free survival was 21.7 months versus 37. 2 months and
in the HRD group excluding BRCA, median progression- free sur vival
was 16.6 mont hs versus 28.1 months. However, in the HRD- negative
or unknown group the median progression- free survival showed no
difference (16 months vs 16.9 months). The PAOLA design did not
include olaparib monotherapy, making it difficult to ascertain the
contribution of bevacizumab.
The VELIA trial randomized patients with advanced stage ovar-
ian cancer to: (1) platinum and paclitaxel chemotherapy (control); (2)
veliparib with chemotherapy, and (3) veliparib with chemotherapy
followed by veliparib maintenance.99 There was significant benefit
from adding veliparib to chemotherapy and maintenance. In the
BRCA mutation group, the median progression- free survival was
22 months versus 34.7 months; in the HRD group, 20.5 months
versus 31.9 months; and in the intention- to- treat population,
17.3 months versus 23.5 months. The result s of the HR proficient
patients were not repor ted.
All PARP inhibitors are associated with mainly low- grade adverse
effects, such as nausea, fatigue, and myelosuppression (anemia can
be caused by all, neutropenia and thrombocytopenia mainly by
niraparib), which can mostly be managed with dose reductions and
interruptions.
There is also good evidence to support the role of PARP inhib-
itors as maintenance therapy following response to chemotherapy
in patient s with recurrent platinum- sensitive ovarian cancer, as well
as monotherapy in selec ted patients with recurrent ovarian can-
cer.100– 104 Patients with BRCA mutations (both germline and somatic)
have the greatest benefit, but a subset of patients with tumors with
homologous recombination deficiency (HRD) also derive benefit from
treatment with PARP inhibitors; the ongoing challenge is how best to
identif y these patients. The results of these trials are summarized in
Table 4. Readers are directed to the article on targeted therapy by
Basu et al.105 for further discussion of PARP inhibitors.
6.6 | Immune checkpoint inhibitors
There may be a potential role for immune checkpoint inhibitors in
the first- line therapy setting in combination with chemotherapy
as well as in maintenance, either alone or in combination with a
PARP inhibitor or angiogenesis inhibitor. A number of trials are ad-
dressing these impor tant questions and the results are awaited.
72
|
BE REK Et al.
Unfortunately JAVELIN100, the first trial to be reported, was a neg-
ative trial.106 This was a randomized, open- label, phase 3 trial that
evaluated avelumab in combination with and/or following chemo-
therapy versus chemotherapy alone in 998 patients with previously
untreated epithelial ovarian cancer. Progression- free survival was
not improved versus control, prespecified futility boundaries were
crossed, and the trial was stopped. Time will tell whether there is a
role for immune checkpoint inhibitors in the first- line treatment of
patients with ovarian cancer or whether it is possible to identify a
subset who are most likely to derive benefit.
7 | SECONDARY SURGERY
7.1 | Second- look laparotomy
A second- look laparotomy (or laparoscopy) was previously per-
formed in patients who have no clinical evidence of disease after
completion of first- line chemotherapy to determine response to
treatment. Although of prognostic value, it has not been shown
to influence survival, and is no longer recommended as part of the
standard of care.107 Level of Evidence C.
7.2 | Secondary cytoreduction
Secondary cytoreduction is defined as an at tempt at cytoreductive
surgery at some stage following completion of first- line chemother-
apy. Retrospec tive studies suggest that patients benefit if all macro-
scopic disease can be removed, which usually means patients with a
solitary recurrence. Patients with a disease- free inter val longer than
12– 24 months and those with only 1– 2 sites of disease appear to de-
rive most benefit.108,109 The role of secondar y cytoreductive surgery
is being evaluated in randomized clinical trials. The role of secondar y
debulking surgery has been addressed in the DESKTOP III trial and
the results recently presented on behalf of the AGO.110 This study
included patients with a progression- free survival of greater than
6 months after first- line chemotherapy and who were considered
to be good candidates for surgery based on a positive AGO Study
Group score, defined as an ECOG performance status score of zero,
ascites of 50 0 mL or less, and complete resection at initial surgery.
Du Bois et al.110 reported that the median progression- free survival
in 204 women who met these criteria and who were randomized
to undergo surgery followed by chemotherapy was 18.4 months,
compared with 14 months in 203 women who were randomized
to receive only second- line chemotherapy. Median overall survival
showed an overall survival benefit of more than 12 months for pa-
tients undergoing complete secondary cytoreduction (60.7 months
vs 46.2 months). Overall survival for patients who underwent sur-
gery and were only incompletely cytoreduced was only 28 months,
stressing the importance of complete cytoreduction. Results of the
GOG 213 trial, h owever, showed no statis tically signi ficant diff erence
in progression- free survival of 18.9 months versus 16.2 months, and
overall sur vival of 50.6 months versus 6 4.7 months (with vs without
secondary cytoreduction).111 In the view of these two trials, second-
ary cy toreduction can be considered a safe option for carefully se-
lected patient s. Level of Evidence B.
8 | FOLLOW- UP FOR MALIGNANT
EPITHELIAL TUMORS
There is no evidence to show that intensive clinical monitoring dur-
ing follow- up after completion of primary surgery and chemother-
apy with early initiation of chemotherapy in asymptomatic women
with recurrent disease improves overall survival or quality of life. In
asymptomatic patients with CA125 progression and small volume
disease or no radiological evidence of recurrence, it is appropriate to
delay starting chemotherapy. However, there may be a subset of pa-
tients who are suitable for secondary debulking surgery at the time
of recurrence.
The objec tives of follow- up include:
• Early recognition and prompt management of treatment- related
complications, including provision of psychological support.
• Early detection of symptoms or signs of recurrent disease.
• Collection of data regarding the efficac y of any treatment and
the complications associated with those treatments in patients
treated in clinical trials.
• Promotion of healthy behavior, including screening for breast
cancer in patients with early- stage disease, and screening for cer-
vical cancer in patients having conservative surgery.
There are no evidence- based guidelines regarding the appro-
priate follow- up schedule. During the first year following treat-
ment, patients are seen every 3 months with a gradual increase
in intervals to every 4– 6 months after 2 years and then annually
after the fifth year. At each follow- up, the patient should have her
history retaken, including any change in family history of cancers
TABLE 4 Progression- free sur vival endpoint in the three phase
trials of maintenance PARP inhibitors
Study
PARP
inhibitor
progression-
free survival
(months)
Placebo
progression-
free survival
(months)
Hazard
ratio
SOLO 2102 19.1 5.5 0.3
NOVA 103
gBRCA 21 5.5 0. 27
Non- BRCA 9.3 3 .9 0.45
Non- BRCA HRD+12 .9 3.8 0.38
ARIEL 310 4
gBRCA 16. 6 5.4 0.23
HRD+ (includes
W T/g BR C A )
13.6 5.4 0.32
|
73
BEREK Et al .
and attention to any symptoms that could suggest recurrence; a
physical and pelvic examination should be performed. This is an
opportunity to refer appropriate patients for genetic testing if it
was not done at diagnosis or during treatment. CA125 has tra-
ditionally been checked at regular inter vals, but there has been
debate regarding the clinical benefit of using CA125 progression
alone as a trigger for initiating second- line chemotherapy. A large
MRC OV05- EORTC 55955 study showed that treating asymptom-
atic patients with recurrent ovarian cancer with chemotherapy on
the basis of CA125 progression alone did not improve survival and
early treatment in asymptomatic patients had a negative impact
on quality of life.112 This study has generated considerable debate
regarding the use of CA125 for follow- up, but most agree that it
is reasonable not to immediately initiate treatment unless there is
a clear clinical indication to do so. The timing of treatment should
be based on symptoms as well as clinical and radiological findings.
Imaging tests such as ultrasonography of the pelvis, CT, MRI, and/
or positron emission tomography (PET) scans should be performed
only when the clinical findings or the tumor markers suggest pos-
sible recurrence.
There appears to be no benefit to initiating chemotherapy in an
asymptomatic patient with recurrent disease based only on rising
CA125 levels in the absence of clinical symptoms or radiological ev-
idence of recurrence. In asymptomatic patients with small volume
disease and no radiological evidence of recurrence, close observa-
tion is a reasonable option, as well as entr y into an appropriate clini-
cal trial or possibly a trial of tamoxifen may be considered.
A Cochrane database systematic review of tamoxifen in unse-
lected women with recurrent ovarian cancer repor ted a 10% objective
response and a 32% disease stabilization rate.113 The patients treated
were heterogeneous and included asymptomatic patients with rising
CA125 levels, and symptomatic patients with chemotherapy- resistant
disease who had been heavily pretreated and had a poor performance
status. GOG 198 compared tamoxifen and thalidomide in women with
recurrent Stage III or IV epithelial ovarian, tubal, or peritoneal cancer
who had completed first- line chemotherapy, and who subsequently
had Gynecologic Cancer InterGroup (GCIG) documented CA125 pro-
gression. The study reported that women who received thalidomide
had a 31% increased risk of disease progression (HR 1.31), compared
with those who were given tamoxifen.114 The median progression- free
survival was 3.2 months in the thalidomide group versus 4.5 months
in the tamoxifen group. This suggests that tamoxifen may have a
role in selected patients with a rising CA125 level, and the relation-
ship between estrogen receptor positivity and benefit of tamoxifen
in this patient population is being evaluated in current studies. In the
PARAGON trial the role of anastrozole in 54 asymptomatic patients
with rising CA125 was investigated in a phase 2 design.115 The primary
endpoint was clinical benefit at 3 months and this was observed in 18
patients (34.6%; 95% CI, 23%– 48%). The median duration of clinical
benefit was 6.5 months (95% CI, 2.8– 11.7). Most patients progressed
within 6 months of starting anastrozole but 12 (22%) continued treat-
ment for longer than 6 months. The role of hormonal therapy in this
setting remains uncertain.
9 | CHEMOTHERAPY FOR RECURRENT
EPITHELIAL CANCER OF THE OVARY,
FALLOPIAN TUBE, AND PERITONEUM
The majority of patient s who present with advanced epithelial can-
cers of the ovary, fallopian tube, and peritoneum will relapse with
a median time to recurrence of 16 months. Patients with recurrent
ovarian cancer constitute a heterogeneous group with a variable
prognosis, and a variable response to further treatment. The most
widely used clinical surrogate for predicting response to subse-
quent chemotherapy and prognosis has been the progression- free
interval or the “platinum- free interval,” which is defined as the time
from cessation of primar y platinum- based chemotherapy to dis-
ease recurrence or progression.116,117 This has been useful to define
specific patient populations, but it has a number of limitations and
depends on how patients are followed. In particular, it depends on
how recurrence is detected and defined. Patients with a treatment-
free inter val of less than 6 months are classified as platinum resist-
ant and generally treated with nonplatinum- based chemotherapy,
while those with a treatment- free interval of more than 6 months
are considered to be platinum sensitive and commonly treated with
platinum- based chemotherapy. Patients who progress while on
treatment or within 4 weeks of stopping chemotherapy are classi-
fied as platinum refrac tory.116,117
There have been modifications to these definitions, and time
to progression or recurrence rather than treatment- free interval
or platinum- free interval has been used to define specific patient
populations. There has been significant change in practice over the
last 20 years and patients have been routinely followed with regu-
lar CA125 testing after completion of chemotherapy. For example,
the “platinum- resist ant” subgroup may include asymptomatic pa-
tients with CA125 progression alone at 3 months post chemother-
apy or radiological evidence of recurrence as well as those who are
symptomatic with clinical recurrence. The Fourth Ovarian Cancer
Consensus Conference reached agreement that distinct patient
populations should be based on the inter val from last platinum ther-
apy and the time to progression. The progression- free interval is de-
fined from the last date of platinum dose until progressive disease is
documented.116,117
For patients whose disease is considered platinum sensitive, the
ICON4 study showed advantage in terms of overall survival and
progression- free survival for a combination of carboplatin and pacli-
taxel versus single- agent carboplatin.118 Level of Evidence A.
For patient s with neurotoxicity, gemcitabine119 or liposomal
doxorubicin120 may be substituted for paclitaxel. A large GCIG study
(CALYPSO) compared carboplatin and liposomal doxorubicin (CD)
with carboplatin and paclitaxel (CP) in 976 patients.121 The CD arm
had statistically superior progression- free sur vival compared with
the CP arm, with a median progression- free survival of 11.3 months
versus 9.4 months, respectively. There was no significant differ-
ence in the overall survival between the treatment groups. Median
overall sur vival was 33 months versus 30.7 months for the CP and
CD arms, respectively. The CD arm was better tolerated with less
74
|
BE REK Et al.
severe toxicities, and this combination is now widely used. Level of
Evidence A.
There is evidence that the addition of bevacizumab to the reg-
imen of carboplatin and gemcitabine improves progression- free
survival compared with carboplatin and gemcitabine in platinum-
sensitive disease. In the OCEANS study,122 484 patients with
platinum- sensitive disease were randomly assigned to carbo-
platin (AUC 4 on day 1) and gemcitabine 1000 mg/m2 on days 1
and 8) with or without bevacizumab (15 mg/kg on day 1) every
21 days cycles. Bevacizumab could be given concurrently with
chemotherapy for a maximum of 10 cycles followed by bevaci-
zumab alone until progression of disease or toxicity. The addi-
tion of bevacizumab to carboplatin and gemcitabine resulted
in an improvement in progression- free survival (12 months vs
8 months; HR 0.48; 95% CI, 0.39– 0.61); however, there was no
difference in overall survival between the two arms. Treatment
with bevacizumab was associated with higher rates of serious hy-
pertension (17% vs <1%), proteinuria grade 3 or higher (9% vs
1%), and noncentral nervous system bleeding (6% vs 1%).122 The
OV21 trial randomized 682 patients with platinum- sensitive re-
current ovarian cancer to 6 intravenous cycles of bevacizumab
(15 mg/kg, day 1) plus carboplatin (AUC 4, day 1) plus gemcit-
abine (1000 mg/m2, days 1 and 8) every 3 weeks (standard group)
or 6 cycles of bevacizumab (10 mg/kg, days 1 and 15) plus car-
boplatin (AUC 5, day 1) plus peg ylated liposomal doxorubicin
(30 mg/m2, day 1) ever y 4 weeks (experimental group), both fol-
lowed by maintenance bevacizumab (15 mg/kg ever y 3 weeks in
both groups) until disease progression or unacceptable toxicity.
The median progression- free survival was 13.3 months (95% CI,
11.7– 14.2) in the experimental group versus 11.6 months (95% CI,
11.0– 12.7) in the standard group (HR 0.81; 95% CI, 0.68– 0.96;
P = 0.012).123 The results of this trial support the experimental
regimen in clinical practice.
For patient s with definite platinum- resistant disease, enroll-
ment on available clinical trials or treatment with nonplatinum
chemotherapy should be considered. There are a number of
chemotherapy options including liposomal doxorubicin,124 topo-
tecan,124 etoposide,125,126 and gemcitabine.127,128 The reported
response rates are low, about 10%, with a median time to progres-
sion of 3– 4 months and a median survival of 9– 12 months. There
have been many trials carried out with new agents in patients with
platinum- resistant ovarian cancer, including epothilones,129 tra-
bectedin,130 and pemetrexed,131 among others, with no significant
increase in response rates or progression- free survival. More re-
cently there have been encouraging reports of novel new agents
or combinations including Wee1 (WEE1hu) inhibitor adavosertib
combined with gemcitabine,132 as well as mir vetuximab soravtan-
sine in patients with high folate receptor alpha expression,133 and
these drugs are actively being investigated. There are many clin-
ical trials in progress for patients with platinum- resistant ovarian
cancer and these are listed on ClinicalTrials.gov. No new cytotoxic
agent has been approved to treat recurrent ovarian cancer for
many years.
There is a role for angiogenesis inhibitors in platinum- resistant
ovarian cancer. In the AURELIA trial, women with recurrent
platinum- resistant ovarian cancer were randomized to standard of
care, i.e. weekly topotecan, weekly paclitaxel, or monthly liposo-
mal doxorubicin versus these agents combined with bevacizumab
(10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks).134 Patients
in the experimental arm had a longer progression- free survival of
6.7 months versus 3.4 months and a higher overall response rate
of 30.9% versus 12.6%. An exploratory subgroup analysis noted
an increase in overall survival for weekly paclitaxel plus bevaci-
zumab from 13.4 months to 22.4 months (with and without bevaci-
zumab).135 The findings in the AURELIA trial changed the standard
of care.
9.1 | Immune checkpoint inhibitors in recurrent
ovarian cancer
There has been much interest in exploring the role of immune check-
point inhibitors in patients with recurrent ovarian cancer including
those with platinum resistance. However, in general the results of
these studies have been disappointing with low response rates re-
ported. For example, KEYNOTE- 100 evaluated pembrolizumab, an
anti- PD- 1 antibody, in patients with recurrent ovarian cancer af ter
multiple prior lines.136 The overall response rate was 8%, with a com-
bined positive score (CPS, quantifying the number of PD- L1 positive
cells) over 10 the objective response rate was 11%– 18%. Similarly,
the response rate with avelumab, an anti- PD- L1 antibody, was 10%
in recurrent ovarian cancer.137 However, there may be a role for
combination regimens, which are being explored. For example, the
phase 1/2 TOPACIO trial using niraparib and pembrolizumab in re-
current platinum- resistant ovarian cancer showed a response rate of
18%.138 The combination of the CTLA- 4 antibody ipilimumab with
nivolumab, an anti- PD- 1 antibody induction, followed by nivolumab
maintenance had an objective response rate of 31.4% compared
with 12.2% with nivolumab alone in a recently reported randomized
phase 2 trial.139 Although the median progression- free survival was
longer with combination, it was only 3.9 months versus 2 months,
and the benefit questionable given the increased toxicity. The multi-
cohort Leap- 005 trial recently reported preliminary data on another
combination treatment using pembrolizumab and the multityrosine
kinase inhibitor lenvatinib. In 31 patients with recurrent ovarian
cancer the response rate was 29%.140 There are still more trials in
progress that are likely to provide results over the next few years. It
will take time to define the role of immune checkpoint inhibitors in
patients with recurrent ovarian cancer, but it seems likely that only a
small subset of patients benefits and the challenge is to identify who
these patients are.
The optimal management of a patient with platinum- resistant or
refractory disease is complex and requires a careful assessment of
the patient's performance status, symptoms, and extent of disease.
Attention to symptom control and good palliative care is an essential
component of management.
|
75
BEREK Et al .
With very few exceptions, recurrent disease is not curable
and the aim of treatment is to maintain quality of life and palliate
symptoms particularly in patients with platinum- resistant ovarian
ca ncer.141 There are many potential treatment options, including
chemotherapy, angiogenesis inhibitors, radiation therapy, or sur-
gery in selected patients and inclusion in clinical trials. There is
a subset of patients who may benefit from secondary surgical
debulking.
9.2 | PARP inhibitors as monotherapy in patients
with recurrent ovarian cancer
Olaparib is US Food and Drug Administration (FDA) approved for the
treatment of patients with germline BRC A- mutated recurrent ovar-
ian cancer who have received three or more prior lines of chemo-
therapy. The FDA granted approval on the basis of the response rate
in a single- arm study of olaparib in patients with BRCA mutations
and with a wide range of different cancers. The response rate was
34% in heavily pretreated BRCA- positive patients with platinum-
resistant recurrent ovarian cancer and the median progression- free
survival was 7.9 months.142
Rucaparib is also approved for treatment of BRCA- mutation-
associated advanced ovarian cancer after completion of treatment
with two or more chemotherapy regimens regardless of whether
patients are platinum sensitive or resistant. Rucaparib's approval
was based primarily on ef ficacy data from 206 patients with BRCA-
associated recurrent ovarian cancer who had prior treatment with
two or more chemotherapy regimens and safety data from 377
patients with ovarian cancer treated with 600 mg rucaparib orally
twice daily.143 Investigator- assessed objective response rate was
54% and the median duration of response was 9.2 months.143
10 | MANAGEMENT OF LOW- GRADE
SEROUS CANCERS
Low- grade serous cancers (LGSCs) comprise 5%– 10% of serous
ovarian cancers and up to 8% of all ovarian cancers.144 They are
typically diagnosed at a younger age than in women with high- grade
serous ovarian cancer (HGSOC), with a median age of 47– 54 years at
diagnosis , and are characterized by a relatively indolent behavior and
resistance to cytotoxic chemotherapy.145 In contrast to HGSOC they
do not have TP53 mutations, but may have KRAS or BRAF mutations,
and activation of the Ras- Raf- MEK- ERK signaling pathway.146,147
Most patients with low- grade serous ovarian cancer (LGSOC) have
advanced stage disease at initial diagnosis and the surgical manage-
ment is similar to patients with high- grade cancers, with attempts at
total res ection of tumor— w ith the exception of f ertility- sparing surger y
in younger women with tumors confined to the ovary. Neoadjuvant
platinum- based chemotherapy for advanced stage LGSOC was asso-
ciated with a radiological response rate of 4%, which is much lower
than resp onse rates of up to 80% in patients with HGSOC.148 Similarly,
the response rates to chemotherapy have been reported to be low in
a number of studies and the rate was only 3.7% (4.9% in patients with
platinum- sensitive disease and 2.1% in those with platinum- resistant
disease) in a r eport of patient s with recurre nt LGSC.145 A retrospective,
exploratory, case– control analysis of over 5000 patients receiving ad-
juvant che motherapy in clinic al trials include d 145 patients (2.8%) with
LGSOC, of whom 37 had suboptimal debulking and were evaluable
for response evaluation.149 The response rate was higher than other
studies at 23.1% in this small subset of patients with LGSOC compared
with 90.1% in patients with HGSOC.
Hormonal therapy has been reported to be associated with clini-
cal benefit in recurrent and metastatic LGSC. Hormonal therapy was
reported to have a response rate of 9% in a retrospective analysis of
64 patients with recurrent LGSC.150 In 26 patients with LGSC of the
ovary or peritoneum, adjuvant hormone therapy following debulking
surgery was associated with a median progression- free survival of
22 months and a recurrence rate of 14.8%.151 In this small study, sur-
vival of the patients treated with adjuvant hormonal therapy was not
significantly different to an age- and stage- matched control group
of patients with LGSC treated with surger y and adjuvant chemo-
therapy. A retrospective analysis was reported of 203 patients with
LGSC of the ovar y or peritoneum who received either maintenance/
adjuvant hormonal treatment or observation, based on physician
discretion, following primary cytoreductive surgery and platinum-
based chemotherapy.1 52 Patients who received adjuvant hormonal
therapy had significantly longer median progression- free sur vival
(64.9 months vs 26.4 months) compared with the patients in the ob-
servation group, without significant prolongation of overall survival
(115.7 months vs 102.7 months). The role of maintenance/adjuvant
hormonal therapy in patients with LGSC will soon be tested in a large
NRG Oncology trial.
LGSCs commonly show mutations in the MAP kinase pathway,
particularly in BRAF, KRAS and NRAS. In view of this there have
been a number of studies exploring targeted therapy with MEK in-
hibitors (MEKi). In a GOG phase 2 trial (GOG 0239) of the MEKi
selumetinib in 52 women with recurrent LGSC, the overall re-
sponse rate was 15%, with one complete response and seven par-
tial responses with 65% of patients having stable disease.153 The
median progression- free survival was 11.0 months. The MILO trial
was an open- label phase 3 trial that randomized patients with re-
current LGSC to either chemotherapy (physician's choice of pe-
gylated liposomal doxorubicin, paclitaxel, or topotecan) or MEK162
(binimetinib). This trial was stopped after a planned interim analysis
showed that the hazard ratio for progression- free survival crossed
the predefined futility boundary.154 The median progression- free
survival was 9.1 months (95% CI, 7.3– 11.3) for binimetinib and
10.6 months (95% CI, 9.2– 14.5) for chemotherapy (HR1.21; 95%
CI, 0.79– 1.86), resulting in early study closure after 341 patients
had enrolled. Secondary efficacy end points were similar in the two
groups: overall response rate 16% versus 13% and median overall
survival 25.3 months versus 20.8 months for binimetinib and che-
motherapy, respectively. More recently a randomized trial (NRG-
GOG 0281) of the MEK inhibitor trametinib versus chemotherapy
76
|
BE REK Et al.
reported an improved objective response rate of 26.2% versus
6.2% in recurrent LGSC of trametinib compared with standard
chemotherapy. In addition, the median progression- free survival
increased from 7.2 months with chemotherapy to 13 months with
trametinib and overall survival was also increased, although this
was not statistically significant.155 This remains an area of active
investigation.
Follow- up of patient s with no evidence of disease is the same as
for those with malignant epithelial carcinomas, but at less frequent
intervals. Level of Evidence C.
10.1 | Management of low malignant potential
(borderline) tumors
Compared with invasive epithelial cancers, borderline tumors tend
to affect a younger population and constitute 15% of all epithelial
tumors of the ovary.156 Nearly 75% of these are Stage I at the time of
diagnosis. The following can be said for these tumors157:
• The diagnosis must be based on the pathology of the primary
tu mor.
• Extensive sectioning of the tumor is necessary to rule out invasive
ca ncer.
• The prognosis of these tumors is extremely good, with a 10- year
survival of about 95%.
• Invasive cancers that arise in borderline tumors are often in-
dolent and generally have a low response to platinum- based
chemotherapy.
• S pontaneou s regression of per itoneal implan ts has been obse rved.
• Early stage, serous histolog y, and younger age at diagnosis are
associated with a more favorable prognosis.
• Although gross residual disease after primary laparotomy is asso-
ciated with poorer prognosis, mortality from the disease remains
low.
• Those patients who have invasive implants in the omentum or
other distant sites are more likely to recur earlier. The role of cy-
totoxic chemotherapy is questionable as the response rates are
low.
The causes of death include complications of disease (e.g.
small bowel obstruction) or complications of therapy, and only
rarely malignant transformation. The mainstay of treatment is
primar y surgical staging and cytoreduc tion. For patients with
Stage I disease who want to preserve fertility, conservative
surgery with unilateral salpingo- oophorectomy can be consid-
ered after intraoperative inspec tion of the contralateral ovary
to exclude involvement.158 For patients with only one ovary, or
bilateral cystic ovaries, a partial oophorec tomy or cystectomy
can be considered for fer tility preservation. For all other pa-
tients, total hysterectomy and bilateral salpingo- oophorectomy
are recommended, with maximal cytoreduction if the disease is
metastatic.
Patients with borderline tumors in all stages of disease should
be treated with surgery. A small percentage of patients with in-
vasive implants may respond to chemotherapy but the response
to chemotherapy is low. Uncommonly, some patient s recur early
and have higher- grade invasive cancers and may benefit from
chemotherapy.159
In patient s with late recurrence of the disease, secondary cy-
toreduction should be considered, and chemotherapy given only if
invasive disease is present histologically.
Follow- up of patient s with no evidence of disease is the same as
for those with malignant epithelial carcinomas, but at less frequent
intervals. If the contralateral ovar y has been retained, it should be
followed by transvaginal ultrasonography, at least on an annual
basis.1,157,160 Level of Evidence C.
11 | MANAGEMENT OF GRANULOSA CELL
TUMORS
Granulosa cell tumors account for about 70% of sex- cord stromal
tumors and 3%– 5% of all ovarian neoplasms. 2 There are two types
of granulosa cell tumors: the juvenile and the adult types. Because
of the high estrogen production, the juvenile type typically presents
with sexual precocity, while the adult type may present with post-
menopausal bleeding. The majority of patients are diagnosed with
Stage I tumors. The peak incidence is in the first postmenopausal
decade.2,161
Granulosa cell tumors are generally indolent (i.e. with a ten-
dency to late recurrence). Stage at diagnosis is the most important
prognostic factor. Other prognostic factors include age at diagnosis,
tumor size, and histologic features. If metastatic, adequate cy tore-
duction is the mainstay of treatment. If the patient is young and the
disease is confined to one ovary, conservative surgery should be
performed.162,163
Infrequency of the dise ase and its protra cted course has resulted in
a lack of prospective studies. There is no evidence that adjuvant che-
motherapy or radiotherapy improves the results of surgery alone for
Stage I disease. The value of postoperative adjuvant chemotherapy for
higher- risk St age I disease (tumor size >10 cm, capsule rupture, high mi-
totic count) is uncertain, and has not been tested in randomized stud-
ies. Platinum- based chemotherapy is used for patients with advanced
or recurrent disease, with an overall response rate of 63%– 80%.163– 165
Bleomycin/etoposide/cisplatin (BEP) has been widely used to treat
patients with metastatic granulosa cell tumors; however, there is sig-
nificantly increased toxicity of bleomycin in patients over the age of
40 years a nd there were a numbe r of deaths associated with bleomycin
in early GOG trials, which led them to reduce the bleomycin dose to
20 units/m2 intravenously every 3 weeks (x 4) to reduce toxicity.166
Carboplatin and paclitaxel appear to have a similar response rate and
less toxicity than BEP.165 The optimal chemotherapy regimen is an
open question and is being addressed in GOG- 0264 (NCT01042522),
which is randomizing patients with recurrent/metastatic granulosa cell
tumors to BEP or carboplatin and paclitaxel.
|
77
BEREK Et al .
Bevacizu mab has also been rep orted to have single - agent ac tivity
with a response rate of 16% in 36 patients with granulosa cell tumors
and measurable disease.167 ALIENOR/ENGOT- ov7 is a randomized
phase 2 trial that compared weekly paclitaxel with weekly paclitaxel
in combination with bevacizumab in 60 patients with relapsed gran-
ulosa cell tumors. The overall response rate increased with the ad-
dition of bevacizumab (25% with weekly paclitaxel vs 44% with the
combination), but there was no statistical difference in the primary
endpoint; progression- free survival at 6 months was 71% (55– 84%)
and 72% (55– 87%) in the weekly paclitaxel and weekly paclitaxel
with bevacizumab arms, respectively.168
Hormonal therapies have also been widely used to treat patients
with recurrent granulosa cell tumors. A systematic review of hor-
monal therapies that included retr ospective studies with a total of 31
patients reported overall response rates of 71%.169 A retrospective
single- center series of 15 patients treated with letrozole repor ted a
partial response rate of 41% and a median progression- free survival
of over 20 months. In contrast , a retrospective study that included
22 patient s with evaluable disease reported a response of 18% and
64% had stable disease with an aromatase inhibitor.170 PARAGON
is the only prospective trial and reported a 10.5% par tial response
rate with anastrozole but a high proportion of patients with stable
disease.171 It is not clear if the stable disease is due to treatment or
the indolent biology of granulosa cell tumors.
Follow- up is clinical. For patients with elevated levels of inhibin
B and/or anti- müllerian hormone at initial diagnosis of granulosa
cell tumors, inhibin B and/or anti- müllerian hormone appear to be
reliable markers during follow- up for early detection of residual or
recurrent disease.172
There is no evidence- based preference for inhibin B or anti-
müllerian hormone as a tumor marker.173 Serum inhibin is a useful
tumor marker in postmenopausal women. Level of Evidence C .
12 | MANAGEMENT OF GERM CELL
MALIGNANCIES
This group of ovarian tumors consists of a variety of histologically
different subtypes that are all derived from the primitive germ cells
of the embr yonic gonad. Malignant germ cell tumors represent a
relatively small proportion of all ovarian tumors. Prior to advances in
chemotherapy, the prognosis for these aggressive tumors was poor.
The use of platinum- based chemotherapeutic regimes has made
germ cell malignancies among the most highly curable cancers.161
12.1 | Presentation
These are most common ovarian tumors in the second and third
decades of life. They are frequently diagnosed by finding a palpa-
ble abdominal mass in a young woman who complains of abdominal
pain. The following are the symptoms of germ cell tumors in order
of frequency161:
• Acute abdominal pain.
• Chronic abdominal pain.
• Asymptomatic abdominal mass.
• Abnormal vaginal bleeding.
• Abdominal distention.
12.2 | Histologic classification
The classification of germ cell tumors of the ovary is important to
determine prognosis and for treatment with chemotherapy. Germ
cell tumors are classified as follows2,161:
• Dysgerminoma.
• Embryonal carcinoma
• Teratoma (immature, mature, mature with carcinoma [squamous
cell, carcinoid, neuroectodermal, malignant struma, etc]).
• Extra- embryonal differentiation (choriocarcinoma, endodermal
sinus tumor [yolk sac tumor]).
12.3 | Diagnosis, staging, and surgical management
Ovarian germ cell tumors are staged similarly to epithelial carcino-
mas, although the staging system used for male germ cell tumors is
probably more useful. The approach to treatment is based on the
principles of management of metastatic germ cell tumors of the
testis (i.e. low, intermediate, and poor risk). Dysgerminoma is the
equivalent of seminoma in testicular cancer.174 It is exquisitely sen-
sitive to platinum- based chemotherapy and is radiosensitive. The
cure rate is high irrespec tive of the stage. The other histologic sub-
types are equivalent to nonseminomatous testicular cancer. The
aggressiveness of the disease is dependent on the type— the most
aggressive being endodermal sinus and choriocarcinoma, but with
combination chemotherapy, they are highly curable.17 5– 179
As chemotherapy can cure the majority of patients, even with
advanced disease, conservative surgery is standard in all st ages of all
germ cell tumors. Conservative surgery means laparotomy with careful
examination and biopsy of all suspicious areas, with limited cytoreduc-
tion, thereby avoiding major morbidity. The uterus and the contralat-
eral ovar y should be left intact. Wedge biopsy of a normal ovary is not
recommended as it defeats the purpose of conservative therapy by po-
tentially causing infer tility. Patients with advanced disease may benefit
from 3– 4 cycles of neoadjuvant chemotherapy using BEP (bleomycin,
etoposide, cisplatin [platinum]) regimen with preservation of fertil-
it y.180 Patients who receive conservative surgery with the preservation
of one ovary retain acceptable fertility rates despite adjuvant treat-
ment with chemotherapy. There has been no report of higher adverse
obstetric outcome or long- term unfavorable sequelae in the offspring.
Secondary surger y is of no proven benefit, except in those pa-
tients whose tumor was not completely resected at the initial op-
eration and who had teratomatous elements in their primary tumor.
Surgical resection of residual masses may be beneficial in such
78
|
BE REK Et al.
patients, as there may be mature teratomatous nodules that can
continue to increase in size (growing teratoma syndrome), and more
rarely can undergo malignant transformation over time to an incur-
able malignancy (e.g. squamous cell carcinoma).181
12.4 | Postoperative management and follow- up of
dysgerminoma
Patients with Stage IA disease may be observed after surgery. A
small proportion of patients may recur, but they can be treated suc-
cessfully at the time of recurrence with a high rate of cure. Patients
with disease beyond the ovary should receive adjuvant chemother-
apy. Although radiation therapy is effective, it is no longer used in
view of late effects and chemotherapy is highly effective.
A follow- up surveillance regime for patients with Stage IA dys-
germinoma is outlined in Table 5. This schedule is based on the ex-
perience managing seminomas in males and the reports by Dark
et al.182 and Patterson et al.183 This pragmatic follow- up schedule
and has not been tested in randomized trials.
12.4.1 | Chemotherapy for dysgerminoma
Dysgerminoma is extremely sensitive to chemotherapy and treat-
ment with chemotherapy cures the majority of patients, even with
advanced disease.161,184 The recommended chemotherapy regimen
is as follows:
• Etoposide (E) 100 mg/m2 IV per day for 5 days ever y 3 weeks for
3 cycles.
• Cisplatin (P) 20 mg/m2 IV per day for 5 days every 3 weeks for 3
cycles.
• Bleomycin (B) 30 IU IV/IM on days 1/8/15 for 12 weeks (optional)
(Note: bleomycin is dosed in International Units). If bleomycin is
omitted, then 4 cycles of EP are commonly used. (Note that vari-
ous schedules of bleomycin have been used and the role of bleo-
mycin in dysgerminomas is controversial).
There is increased interest in de- escalation of chemother-
apy in dysgerminomas as they are so chemosensitive. It may be
possible to omit bleomycin and substitute carboplatin for cis-
platin due to the acute adverse effects and potential long- term
adverse effects associated with BEP, which include secondar y
malignancies, cardiovascular disease, hyper tension, Raynaud's
phenomenon, pulmonary toxicity, nephrotoxicity, neurotox-
icity, deafness, decreased fertility, and psychosocial problems
amongst others. GOG 116 is an old trial that investigated carbo-
platin 400 mg/m2 and etoposide 120 mg/m2 on days 1– 3 ever y
4 weeks in 39 patients with Stage IB– III dysgerminoma.185 No
patients relapsed despite the very modest dose of carbopla-
tin and 3 days of etoposide every 4 weeks for 3 cycles only;
but the trial closed early after the results of two trials in males
with nonseminomatous testicular cancer reported inferior out-
comes with carboplatin compared with cisplatin. Shah et al.186
reported the result s of pooled data from six trials (three pediat-
ric and three adult) on behalf of the Malignant Germ Cell Tumor
International Consortium (MaGIC), which included 126 patients
with advanced stage (Stage IC– IV) dysgerminomas who were
treated with either carboplatin- or cisplatin- based chemother-
apy. Survival outcomes were equivalent with a 96% 5- year sur-
vival in both groups with no differences seen according to age
(<25 or >25 years old). Seven patient s relapsed including two
patients treated with carboplatin- based chemotherapy and five
with BEP, and all were salvaged.
When there is bulky residual disease it is common to give 3– 4
courses of BEP or EP chemotherapy.187 Level of Evidence B.
The optimal follow- up schedule has not been clinically investi-
gated in ovarian germ cancers and the frequency of visits and in-
vestigations is controversial. Patient s who have Stage I tumors and
are offered surveillance need to be seen regularly and one option is
to utilize the follow- up regimen presented above.182 Patients who
have had chemotherapy have a lower risk of recurrence and the fre-
quency of CT scans can be reduced, which is similar to the approach
for testicular germ cell tumors.183 Each follow- up visit should involve
TABLE 5 Follow- up regime for Stage I germ cell malignanciesa
Regimen Description
Surveillance Baseline CT chest, abdomen,
and pelvis, if not per formed
preoperatively
Repeat CT or MRI, abdomen and
pelvis at 3 months after surgery
Repeat CT or MRI abdomen plus
pelvis at 12 months
Pelvic ultrasound alternate visits (not
when having CT scan) for 2 years
if nondysgerminoma and for
3 years if dysgerminoma
Chest X- ray at alternate visits
Clinical examination
1 year Monthly
2nd year 2 monthly
3rd year 3 monthly
4th year 4 monthly
Years 5– 10 6 monthly
Tumor marker follow- up Samples: serum AFP and hCG, LDH
and CA 125 (regardless of initial
value)
0– 6 months 2 weekly
7– 12 months 4 weekly
12– 24 months 8 weekly
24– 36 months 12 weekly
36– 48 months 16 weekly
48+ months 6 monthly until year 10
Abbreviations: AFP, alpha- fetoprotein; hCG, human chorionic
gonadotropin; LDH, lactate dehydrogenase.
aAdapted from Patterson et al.183
|
79
BEREK Et al .
taking a medical history, physical examination, and tumor marker de-
termination. Although tumor markers are important, radiological im-
aging is also pertinent, especially for patients whose tumor markers
were not raised at diagnosis. CT or MRI scans should be performed
as clinically indicated.182
Patients who have not received chemotherapy should be fol-
lowed closely. Ninety percent of relapses in these patients occur
within the first 2 years. At relapse, with few exceptions, these pa-
tients can be successfully treated.182 Level of Evidence D.
12.5 | Postoperative management and follow-
up of nondysgerminoma germ cell malignancies
These tumors are highly curable with chemotherapy, even with ad-
vanced disease. Patient s with Stage IA grade 1– 2 immature teratoma
have a very good prognosis and should be only observed af ter pri-
mary conservative surgery. Adjuvant chemotherapy does not appear
to add any sur vival benefit in this subgroup of patients. Although ad-
juvant chemotherapy has been routinely recommended to all other
patients with Stage I nondysgerminomatous ovarian germ cell tu-
mors, this approach has been challenged and there may be a role for
close surveillance and chemotherapy reserved for the subset who
relapse as this is the standard of care in males with apparent Stage 1
testicular cancers. All other patients with nondysgerminomas, and
higher- stage and higher- grade immature teratomas, should receive
postoperative adjuvant chemotherapy.161
The recommended chemotherapy regimen is etoposide 100 mg/
m2 per day for 5 days with cisplatin 20 mg/m2 per day for 5 days, and
bleomycin at 30 IU IM/IV on days 1, 8, and 15 for a total of 12 weeks
of treatment. For patient s with good prognosis disease, 3 cycles of
BEP are recommended, while patients with intermediate/poor risk
disease should receive 4 cycles of BEP.161
Patients who relapse af ter BEP may still attain a durable re-
mission and cure with second- line chemotherapy regimens such
as paclitaxel– ifosfamide– cisplatin (TIP).177 High- dose chemo-
therapy and autologous marrow rescue may be considered in se-
lected patients. These patients should be managed in specialized
units.
After chemotherapy, patients with metastatic immature tera-
tomas can sometimes have residual masses, which are composed
entirely of mature elements. These masses can grow (growing ter-
atoma syndrome), and should be resected after the completion of
chemotherapy.188 Level of Evidence B.
All patients should have alpha- fetoprotein (AFP) and human
gonadotropin (beta hCG) to monitor response to treatment. All pa-
tients treated with chemotherapy should be followed up with med-
ical history, physical examination, and appropriate tumor markers in
the same way as dysgerminomas. CT or MRI scans should be per-
formed as clinically indicated.159
Relapses in patients usually occur within the first 2 years after
diagnosis161,177 Level of Evidence D.
13 | SARCOMA OF THE OVARY
Ovarian sarcomas are rare and occur primarily in postmenopausal
patients.161,189 Nevertheless, accurate diagnosis and dif ferentiation
from other types of primary ovarian cancer are important, as the
prognosis is generally poor.
There are t wo types of sarcoma. Malignant mixed Müllerian tu-
mors (MMMTs) or ovarian carcinosarcomas, the more common of
the two, are biphasic tumors composed of both carcinomatous and
sarcomatous elements.189,19 0 Most authors agree that most MMMTs
are monoclonal in origin and should be thought of and managed as a
high- grade epithelial cancer. The sarcomatous component is derived
from the carcinoma or from a stem cell that undergoes divergent
differentiation. Thus, ovarian carcinosarcomas are best regarded as
metaplastic carcinomas.
Pure sarcomas are very rare and should be treated according to
the specific histologic subtype. These rare sarcomas include fibro-
sarcomas, leiomyosarcomas, neurofibrosarcomas, rhabdomyosar-
comas, chondrosarcomas, angiosarcomas, and liposarcomas. Their
management is not discussed here.
Patients with early stage MMMTs/ovarian carcinosarcomas have
a better outcome than those with advanced stage disease, but the
overall prognosis is poor. They should be managed similarly to high-
grade pelvic serous cancers. Their rarity prohibits any prospective
randomized trials.
The principles of surgical management of ovarian
MMMTS/ovarian carcinosarcomas are the same as for high-
grade pelvic serous cancers. Following surgery, patients
should receive platinum- based chemotherapy.161 The fol-
low- up schedule is as recommended for epithelial malignan-
cies. Level of Evidence C.
AUTHOR CONTRIBUTIONS
JB, MR, SK, LK, and MF reviewed and updated the chapter on cancer
of the ovary, fallopian tube, and peritoneum published in the 2018
Cancer Report.
ACKNOWLEDGMENTS
This chapter updates the information published in the FIGO Cancer
Report 2018,19 1 with approval granted by the original authors.
CONFLICTS OF INTEREST
Outside the submitted work, JSB reports institutional research
funding received from Tesaro and ImmunoGen, and participation
on a Merck Data Safety Monitoring Committee (MK- 7339- 001
ENGOT- ov43). Outside the submitted work, MF reports insti-
tutional research grants received from AstraZeneca, Novartis,
and Beigene; consulting fees from AstraZeneca, GSK, MSD, Lilly,
Novartis, and Takeda; honoraria for lectures from AstraZeneca,
GSK, and ACT Genomics; and participation on an AGITG Data
Safety Monitoring Board. All other authors report no conflicts
of interest.
80
|
BE REK Et al.
REFERENCES
1. Berek JS, Friedlander M, Hacker NF. Epithelial ovarian, fallopian
tube, and peritoneal cancer. In: Berek JS, Hacker NF, Eds. Berek
and Hacker ’s Gynecologic Oncology, 7th edn. Wolters Kluwer
Health; 2020.
2. Scully RE, Young RH, Clements PB. Tumors of the ovar y, maldevel-
oped gonads, fallopian tube, and broad ligaments. Atlas of Tumor
Pathology. Third series. Armed Forces Institute of Pathology;
1998 .
3. Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma
of the fimbria and pelvic serous carcinoma: evidence for a causal
relationship. Am J Surg Pathol. 2 007;31:161- 169.
4. Callahan MJ, Crum CP, Medeiros F, et al. Primary fallopian tube
malignancies in BRCA- positive women undergoing surgery for
ovarian cancer risk reduction. J Clin Oncol. 2007;25:3985- 3990.
5. Kurman RJ, IeM S. Pathogenesis of ovarian cancer: lessons from
morphology and molecular biology and their clinical implications.
Int J Gynecol Pathol. 2008;27:151- 160.
6. Crum CP, Drapkin R, Miron A , et al. The distal fallopian tube: a new
model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol.
2007;19:3- 9.
7. Carlson JW, Miron A, Jarboe EA , et al. Serous tubal intraepithelial
carcin oma: its poten tial role in pri mary perit oneal serous c arcinoma
and serous cancer prevention. J Clin Oncol. 2008;26:4160- 4165.
8. Aziz S, Kupers tein G, Rosen B, et al. A genetic epidemiolog-
ical study of carcinoma of the fallopian tube. Gynecol Oncol.
2001;80:341- 345.
9. Levanon K, Crum C, Drapkin R. New insights into the pathogen-
esis of serous ovarian cancer and its clinical impact. J Clin Oncol.
2008;26:5284- 5293.
10. Deffieux X, Morice P, Thoury A, Camatte S, Duvillard P, Cast aigne
D. Anatomy of pelvic and par a- aortic nodal spread in patients with
primary fallopian tube carcinoma. J Am Coll Surg. 2005;200:45- 48.
11. Baekelandt M, Jorunn Nesbakken A, Kristensen GB, Trope
CG, Abeler VM. Carcinoma of the fallopian tube. Cancer.
2000;89:2076- 2084.
12. Burghardt E, Girardi F, Lahousen M, Tamussino K, Stettner H.
Patterns of pelvic and paraaortic lymph node involvement in ovar-
ian cancer. Gynecol Oncol. 1991;40:10 3- 106.
13. Bankhead CR, Kehoe ST, Austoker J. Symptoms associated
with diagnosis of ovarian cancer: a systematic review. BJOG.
2005;112:857- 865.
14. Lataifeh I, Marsden DE, Robertson G, Gebski V, Hacker NF.
Presenting symptoms of epithelial ovarian cancer. Aust N Z J Obstet
Gynecol. 20 05;45:211- 214.
15. Gilbert L, Basso O, Sampalis J, et al. Assessment of symptomatic
women for early diagnosis of ovarian cancer: results from the pro-
spective DOvE pilot project. Lancet Oncol. 2012;13:285- 291.
16. Gilks CB, Irving J, Köbel M, et al. Incidental nonuterine high- gr ade
serous carcinomas arise in the fallopian tube in most cases: further
evidence for the tubal origin of high– grade serous carcinomas. Am
J Surg Pathol. 2015;39:357- 364.
17. Prat J; FIGO Committee on Gynecologic Oncology. Staging classi-
fication for cancer of the ovary, fallopian tube, and peritoneum. Int
J Gynecol Obstet. 2014;124:1- 5.
18. Berek JS. Lymph- node positive s tage IIIC ovarian cancer: a sepa-
rate entity? Int J Gynecol Cancer. 2009;19(Suppl 2):S18- S20.
19. Kurman R J, Carcangiu ML, Herrington C S, Young RH, Eds. WHO
Classification of Tumours of Female Reproductive Organs. IACR;
2014:11- 40.
20. Bodurka DC, Deavers MT, Tian C, et al. Reclassification of serous
ovarian carcinoma by a 2- tier system: a Gynecologic Oncology
Group Study. Cancer. 2012;118:3087- 3094.
21. Amin MB, G reene FL, Edge SBThe Eighth Edition AJCC
Cancer Staging Manual: Continuing to build a bridge from a
population- based to a more “personalized” approach to cancer
staging. CA Cancer J Clin. 2017;67(2):93- 99.
22. Soslow RA, Han G, Park K J, et al. Mor phologic patterns associ-
ated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod
Pathol. 2012;25:625- 636.
23. Kalloger SE, Köbel M, Leung S, et al. Calculator for ovarian carci-
noma subt ype prediction. Mod Pathol. 2011;24:512- 521.
24. Roh MH, Yassin Y, Miron A, et al. High- gr ade fimbrial- ovarian car-
cinomas are unified by altered p53, PTEN and PAX2 expression.
Mod Pathol. 2010;23:1316- 1324.
25. Ayhan A, Kurman RJ, Yemelyanova A, et al. Defining the cut point
between low- grade and high- grade ovarian serous carcinomas: a
clinicopathologic and molecular genetic analysis. Am J Surg Pathol.
2009;33:1220- 1224.
26. Siegel RL, Miller KD, Jemal A . Cancer s tatistics, 2020. CA Cancer J
Clin. 2020;70:7- 30.
27. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020:
GLOBOCAN estimates of incidence and mortality worldwide for
36 cancers in 185 countrie s. CA Cancer J Clin. 2021;71:209- 249.
28. Negri E, Franceschi S, Tzonou A , et al. Pooled analysis of 3
European case- control studies of epithelial ovarian cancer: I.
Reproductive factors and risk of epithelial ovarian cancer. Int J
Cancer. 1991;49:50- 5 6.
29. Lynch HT, Watson P, Lynch JF, Conway TA, Fili M. Hereditary
ovarian cancer. Heterogeneity in age at onset. Cancer. 1993;71(2
Suppl):573- 581.
30. Struewing JP, Hart ge P, Wacholder S, et al. The risk of cancer as-
sociated with specific mutations of BRCA1 and BRCA2 among
Ashkenazi Jews. N Engl J Med. 1997;336:1401- 1408.
31. Risch HA, McLaughlin JR, Cole DEC, et al. Population BRCA1 and
BRCA2 mutation frequencies and cancer penetrances: a kin- cohort
study in Ontario, Canada. J Natl Cancer Inst. 20 06;98:1694- 1706.
32. Ch etrit A, Hir sh- Yechezke l G, Ben- D avid Y, et al. Effect of B RCA1/2
mutations on long- term survival of patients with invasive ovarian
cancer : the national Israeli study of ovarian c ancer. J Clin Oncol.
2008;26:20- 25.
33. Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred
site for early adenocarcinoma in women with familial ovarian c an-
cer syndrome. Am J Surg Pathol. 20 06;30:230- 236.
34. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in
women with ovarian carcinoma. JAMA Oncol. 2016;2:482- 490.
35. Walsh T, Cas adei S, Lee MK, et al. Mutations in 12 genes for in-
herited ovarian, fallopian tube, and peritoneal carcinoma iden-
tified by massively parallel sequencing. Proc Natl Acad Sci USA.
2011;108:18032- 18037.
36. Ryan NAJ, Bolton J, McVey RJ, Evans DG, Crosbie E J. BRCA and
lynch syndrome- associated ovarian cancers behave differently.
Gynecol Oncol Rep. 2017;22:108- 109.
37. eviQ [website]. http s://w ww.eviq.org.a u. Accessed March 5, 2021.
38. S ociety of Gyn ecologic Onco logy. SGO Clini cal Pract ice Statement :
Genetic testing for ovarian cancer. October 1, 2014. https://www.
sgo.org/clini cal- pract ice/guide lines/ genet ic- testi ng- for- ovari an-
cance r/. Accessed March 5, 2021.
39. Buys SS, Par tridge E, Black A, et al. Effect of screening on ovar-
ian cancer mortality: the Prostate, Lung, Colorec tal and Ovarian
(PLCO) cancer screening randomized controlled trial. JAMA.
2011;305:2295- 2303.
40. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening
and mor tality in the UK Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS): a randomised controlled trial. Lancet.
2016;3 87:945- 956.
41. Hermsen BBJ, Olivier RI, Verheijen RHM, et al. No efficacy of an-
nual gynaecological screening in BRCA1/2 mut ation carriers; an
observational follow- up study. Br J Cancer. 2007;96:1335- 1342.
42. Woodward ER, Sleightholme HV, Considine AM, Williamson
S, McHugo JM, Cruger DG . Annual surveillance by CA125
|
81
BEREK Et al .
and transvaginal ultrasound for ovarian cancer in both
high- risk and population risk women is ineffective. BJOG.
2007;114:1500- 1509.
43. US Preve ntive Servi ces Task Force, G rossman DC, Cu rry SJ, Owens
DK, et al. Screening for ovarian cancer: US preventive services
task force recommendation statement. JAMA. 2018;319:588- 594.
4 4. Rosenthal AN, Fraser LSM, Philpot t S, et al. Evidence of stage shift
in women diagnosed with ovarian cancer during phase II of the
United Kingdom familial ovarian cancer screening study. J Clin
Oncol. 2017;35:1411- 1420.
45. ACOG committee opinion no. 774: opportunistic salpingec tomy as
a strategy for epithelial ovarian cancer prevention. Obstet Gynecol.
2019;133:e279- e284.
46. Trimbos JB, Vergote I, Bolis G, et al. Impact of adjuvant chemo-
therapy and surgical staging in early stage ovarian carcinoma:
European Organisation for Research and Treatment of Cancer-
Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer
Inst. 2003;95:113- 125.
47. Zanetta G, Chiari S, Rota S, et al. Conservative surgery for stage
I ovarian carcinoma in women of childbearing age. Br J Obstet
Gynaecol. 1997;10 4:1030 - 1035.
48. Young V, O'Connell PR , Keane FB. The role of adjuvant therapy
in the management of node negative breast cancer. Ir Med J.
1990;83:34- 35.
49. Bell J, Brady M, Lage J, et al. A randomized phase III trial of three
versus six cycles of carboplatin and aclitaxel as adjuvant treat-
ment in ear ly stage ovarian epithelial carcinoma: a Gynecologic
Oncology Group study. Gynecol Oncol. 2006;102:432- 439.
50. Nagle CM, Francis JE, Nelson AE, et al. Reducing time to diagnosis
does not improve outcomes for women with symptomatic ovarian
cancer : a report from the Australian Ovarian Cancer Study Group.
J Clin Oncol. 2011;29:2253- 2258.
51. Sørensen SS, Mosgaard BJ. Combination of cancer antigen 125
and carcinoembryonic antigen can improve ovarian cancer diag-
nosis. Dan Med Bull. 2011;58:A4331.
52. Hacker NF, Berek JS, L agasse LD, Nieberg RK, Elashoff RM.
Primary cytoreductive surgery for epithelial ovarian cancer. Obstet
Gynecol. 1983;61:413- 420.
53. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ.
Survival effect of maximal cytoreductive surgery for advanced
ovarian carcinoma during the platinum era: a met a- analysis. J Clin
Oncol. 2002;20:1248- 1259.
54. Harter P, Sehouli J, Lor usso D, et al. A randomized trial of lymph-
adenectomy in patients with advanced ovarian neoplasms. N Engl J
Med. 2019;380:822- 832.
55. Vergote I, Tropé CG , Amant F, et al. Neoadjuvant chemotherapy
or primary surger y in stage IIIC or IV ovarian c ancer. N Engl J Med.
2010;363:943- 953.
56. Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy ver-
sus primary surger y for newly diagnosed advanced ovarian cancer
(CHORUS): an open- label, randomised, controlled, non- inferiority
trial. Lancet. 2015;386:249- 257.
57. Vergote I, Coens C, Nankivell M, et al. Neoadjuvant chemother-
apy versus debulking surgery in advanced tubo- ovarian cancers:
pooled analysis of individual patient data from the EORTC 55971
and CHORUS trials. Lancet Oncol. 2018;19:1680- 1687.
58. Kumar L, Pramanik R, Kumar S, Bhatla N, Malik S. Neoadjuvant
chemotherapy in gynaecological cancers – implications for stag-
ing. Best Pract Res Clin Obstet Gynaecol. 2015;29:790- 801.
59. van der Burg ME, van Lent M, Buyse M, et al. The effect of
debulking surgery after induction chemotherapy on the progno-
sis in advanced epithelial ovarian cancer. Gynecological Cancer
Cooperative Group of the European Organization for Research
and Treatment of C ancer. N Engl J Med. 1995;332:629- 634.
60. Ferron JG, Uzan C, Rey A, et al. Histological response is not a prog-
nostic factor after neoadjuvant chemotherapy in advanced- stage
ovarian cancer with no residual dise ase. Eur J Obstet Gynecol
Reprod Biol. 2 009;147:101- 105.
61. Böhm S , Faruqi A, Said I, et al. Chemotherapy Response Score: de-
velopment and validation of a system to quantify histopathologic
response to neoadjuvant chemotherapy in Tubo- ovarian high-
grade serous carcinoma. J Clin Oncol. 2015;33:2457- 2463.
62. Coghlan E, Meniawy TM, Munro A, et al. Prognostic role of his-
tological tumor regression in patients receiving neoadjuvant che-
motherapy for high- grade serous Tubo- ovarian carcinoma. Int J
Gynecol Cancer. 20 17;27:708- 713.
63. Chan JK, Tian C, Fleming GF, et al. The potential benefit of 6
vs. 3 cycles of chemotherapy in subsets of women with early-
stage high- risk epithelial ovarian cancer: an exploratory anal-
ysis of a Gynecologic Oncology Group study. Gynecol Oncol.
2010;116:301- 306.
64. Young RC, Walton L A, Ellenberg SS, et al. Adjuvant therapy in
stage I and stage II epithelial ovarian cancer. Results of two pro-
spective randomized trials. N Engl J Med. 1990;322:1021- 1027.
65. Aabo K, Adams M, Adnitt P, et al. Chemotherapy in advanced
ovarian cancer: four s ystematic meta- analyses of individual pa-
tient data from 37 randomized trials. Advanced Ovarian Cancer
Trialists’ Group. Br J Cancer. 199 8;78:1479- 1487.
66. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and
cisplatin versus paclitaxel and cisplatin: a phase III randomized
trial in patients with suboptimal stage III/IV ovarian cancer (from
the Gynecologic Oncology Group). Semin Oncol. 1996;23(5 Suppl
12 ):4 0- 4 7.
67. Vasey PA, Paul J, Birt A , et al. Docetaxel and cisplatin in combi-
nation as first- line chemotherapy for advanced epithelial ovarian
cancer. Scot tish Gynaecological Cancer Trials Group. J Clin Oncol.
1999;17:2069- 2080.
68. Gemignani M, Hensley M, Cohen R, Venkatraman E, Saigo PE,
Barakat RR. Paclitaxel- based chemotherapy in carcinoma of the
fallopian tube. Gynecol Oncol. 2001;80:16- 20.
69. Ozols RF, Bundy B N, Greer B, et al. P hase III trial of ca rboplatin and
paclitaxel compared cisplatin and paclitaxel in patients with opti-
mally resected stage III ovarian c ancer: a Gynecologic Oncology
Group study. J Clin Oncol. 2003;21:3194- 3200 .
70. Bookman MA , Brady MF, McGuire WP, et al. Evaluation of new
platinum- based treatment regimens in advanced- stage ovarian
cancer : a Phase III Trial of the Gy necologic C ancer Inter Group. J
Clin Oncol. 2 009;27:1419- 1425.
71. Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial
of docetaxel- carboplatin versus paclitaxel- carboplatin as first-
line chemotherapy for ovarian carcinoma. J Natl Cancer Inst.
200 4;96:1682- 1691.
72. Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus pacli-
taxel versus carboplatin plus pegylated liposomal doxorubicin as
first- line treatment for patients with ovarian cancer: the MITO- 2
randomized phase III trial. J Clin Oncol. 2011;29:3628- 3635.
73. Calver t AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage:
prospective evaluation of a simple formula based on renal func-
tion. J Clin Oncol. 1989;7:1748- 1756.
74. Nagao S, Fujiwara K, Imafuku N, et al. Dif ference of carbo-
platin clearance estimated by the Cockroft- Gault, Jelliffe,
Modified- Jelliffe, Wright or Chatelut formula. Gynecol Oncol.
2005;99:327- 333.
75. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin
plus intravenous cyclophosphamide versus intravenous cisplatin
plus intr avenous cyclophosphamide for stage III ovarian cancer. N
Engl J Med. 19 96;335:1950 - 1955.
76. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of
standard- dose intravenous cisplatin plus paclitaxel versus moder-
ately high- dose intravenous paclitaxel and intraperitoneal cispla-
tin in small- volume stage III ovarian cancer: an intergroup study
of the Gynecologic Oncology Group, Southwestern Oncolog y
82
|
BE REK Et al.
Group, and the Eastern Cooperative Oncolog y Group. J Clin Oncol.
2001;19:1001- 1007.
77. Armstrong DK, Bun dy B, Wenzel L, et al. Intraperitoneal cisplatin
and paclitaxel in ovarian cancer. N Engl J Med. 20 06;354:34- 43.
78. Jaaback K, Johnson N, Lawrie TA. Intraperitoneal chemotherapy
for the initial management of primar y epithelial ovarian cancer.
Cochrane Database Syst Rev. 2011;(11) :CD005340 .
79. Walker JL , Brady MF, Wenzel L, et al. Randomized trial of intra-
venous versus intraperitoneal chemotherapy plus bevacizumab
in advanced ovarian carcinoma: an NRG Oncology/Gynecologic
Oncology Group study. J Clin Oncol. 2019;37:1380- 1390.
80. Katsumata N, Yasuda M , Takahashi F, et al. Dose- dense paclit axel
once a week in combination with carboplatin every 3 weeks for
advanced ovarian cancer: a phase 3, open- label, randomised con-
trolled trial. Lancet. 20 09;374:1331- 1338.
81. Katsumata N, Yasuda M, Isonishi S, et al. Long- term re sults of
dose- dense paclitaxel and carboplatin versus conventional pa-
clitaxel 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.
82 . Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel
once a week versus every 3 weeks in patients with advanced ovar-
ian cancer (MITO- 7): a randomised, multicentre, open- label, phase
3 trial. Lancet Oncol. 2014;15:396- 405.
83. Clamp AR, James EC, McNeish IA, et al. Weekly dose- dense che-
motherapy in first- line epithelial ovarian, fallopian tube, or primary
peritoneal carcin oma treatment (ICO N8): primary progression f ree
survival analysis results from a GCIG phase 3 randomised con-
trolled trial. Lancet. 2019;394:2084- 2095.
84. Clamp AR , James EC, McNeish I, et al. ICON8: Overall survival re-
sults in a G CIG phase III r andomised con trolled tria l of weekly dose-
dense chemotherapy in first line epithelial ovarian, fallopian tube
or primary peritoneal carcinoma treatment. Paper 8050. ESMO
Virtual Congress 2020. Ann Oncol. 2020;31(suppl4):S551- S589.
85. Fuh KC, Shin JY, Kapp DS, et al. Survival differences of Asian and
Caucasian epithelial ovarian cancer patients in the United States.
Gynecol Oncol. 2015;136:491- 497.
86. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevaci-
zumab in ovarian cancer. N Engl J Med. 2011;365:2484- 2496.
87. Burger RA , Brady MF, Book man MA, et al. Incorpor ation of beva-
cizumab in the primar y treatment of ovarian cancer. N Engl J Med.
2011;365:2473- 2483.
88. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with
or without bevacizumab for women with newly diagnosed ovarian
cancer (ICON7): overall survival results of a phase 3 randomised
trial. Lancet Oncol. 2 015;16:928- 936.
89. Tewari KS , Burger RA, Enserro D, et al. Final overall survival of a
randomized trial of bevacizumab for primary treatment of ovarian
cancer. J Clin Oncol. 2019;37:2317- 2328.
90. van Driel WJ, Koole SN, Sikorska K, et al. Hyper thermic in-
traperitoneal chemotherapy in ovarian cancer. N Engl J Med.
2018;378:230- 240.
91. Falandry C, Savoye AM , Stefani L, et al. EWOC- 1: A randomized
trial to evaluate the feasibility of three different first- line chemo-
therapy regimens for vulnerable elderly women with ovarian can-
cer (OC): A GCIG- ENGOT- GINECO study. J Clin Oncol. 2019;37(15
suppl):5508.
92. Onda T, Satoh T, Ogawa G, et al. Comparison of survival between
primary debulking surgery and neoadjuvant chemotherapy for
stage III/IV ovarian, tubal and peritoneal cancers in phase III ran-
domised trial. Eur J Cancer. 2020;130:114- 125.
93. Fagotti A, Ferrandina MG, Vizzielli G, et al. Randomized trial of
primary debulking surgery versus neoadjuvant chemotherapy for
advanced epithelial ovarian cancer (SCORPION- NCT01461850).
Int J Gynecol Cancer. 2020;30:1657- 1664.
94. Machida H, Tokunaga H, Matsuo K, et al. Survival outcome and
perioperative complication related to neoadjuvant chemother-
apy with carboplatin and paclitaxel for advanced ovarian can-
cer: A systematic review and meta- analysis. Eur J Surg Oncol.
2020;46:868- 875.
95. Mei L, Chen H , Wei DM, et al. Maintenance chemotherapy for
ovarian cancer. Cochrane Database Syst Rev. 2013;(6):CD007414.
96. Moore K, Colombo N, Scambia G , et al. Maintenance olaparib in
patient s with newly diagnosed advanced ovarian cancer. N Engl J
Med. 2018;379:2495- 2505.
97. Go nzález- Mart ín A, Pothuri B, Vergote I, et al. Niraparib in patients
with newly diagnosed advanced ovarian cancer. N Engl J Med.
2019;381:2391- 2402.
98. Ray- Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevaci-
zumab as first- line maintenance in ovarian cancer. N Engl J Med.
2019;381:2416- 2428.
99. Coleman RL , Fleming GF, Brady MF, et al. Veliparib with first- line
chemotherapy and as maintenance therapy in ovarian cancer. N
Engl J Med. 2019;381:2403- 2415.
10 0. Ledermann J, Har ter P, Gourley C, et al. Olaparib maintenance
therapy in platinum- sensitive relapsed ovarian cancer. N Engl J
Med. 2012;366:1382- 1392.
101. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance ther-
apy in patients with platinum- sensitive relapsed serous ovarian can-
cer: a preplanned retrospective analysis of outcomes by BRCA status
in a randomised phase 2 trial. Lancet Oncol. 2014;15:852- 861.
102. Pujade- Lauraine E, Ledermann JA , Selle F, et al. Olaparib tablets as
maintenance therapy in patients with platinum- sensitive, relapsed
ovarian cancer and a BRC A1/2 mutation (SOLO2/ENGOT- Ov- 21):
a double- blind, randomised, placebo- controlled, phase 3 trial.
Lancet Oncol. 2017;18:1274- 1284.
103. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance
therapy in platinum- sensitive, recurrent ovarian cancer. N Engl J
Med. 2016;375:2154- 2164.
104. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance
treatment for recurrent ovarian carcinoma after response to
platinum therapy (ARIEL3): a randomised, double- blind, placebo-
controlled, phase 3 trial. Lancet. 2017;390 :1949- 1961.
105. Basu P, Mukhopadhyay A, Konishi I. Targeted therapy for gyneco-
logic cancers: toward t he era of precision medicine. Int J Gynecol.
2018;143(Suppl 2) :131- 136.
106. Ledermann JA, Colombo N, Oza AM, et al. Avelumab in combina-
tion with and/or following chemotherapy vs chemotherapy alone
in patients with previously untreated epithelial ovarian cancer:
Results from the phase 3 javelin ovarian 100 trial. Gynecol Oncol.
2020;159(Suppl 1):13- 14.
107. Dowdy SC , Constantinou CL, Hartmann LC, et al. Long term fol-
low- up of women with ovarian c ancer after positive second- look
laparotomy. Gynecol Oncol. 20 03;91:563- 568.
108. Tay EH, Grant P T, Gebski V, Hacker NF. Secondary cytoreductive
surger y for recurrent epithelial ovarian cancer. Obstet Gynecol.
200 2;99:10 08- 1013.
109. Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection
criteria for secondary cytoreductive surgery in patients with re-
current, platinum- sensitive epithelial ovarian carcinoma. Cancer.
20 06;10 6:1933 - 1939.
110. Bois AD, Sehouli J, Vergote I, et al. Randomized phase III study
to evaluate the impact of secondary cytoreductive surgery in
recurrent ovarian cancer: Final analysis of AGO DE SKTOP III/
ENGOT- ov20. J Clin Oncol. 2020;38(15 suppl):6000.
111. Coleman RL, Spir tos NM, Enserro D, et al. Secondary sur gi-
cal cy toreduction for recurrent ovarian c ancer. N Engl J Med.
2019;381:19 29- 1939.
112. Rustin GJS, van der Burg MEL , Griffin CL, et al. Early versus de-
layed treatment of relapsed ovarian cancer (MRC OV05/EORTC
55955): a randomised trial. Lancet. 2010;376:1155- 1163 .
|
83
BEREK Et al .
113. Williams C, Simera I, Bryant A. Tamoxifen for relapse of ovarian
cancer. Cochrane Database Syst Rev. 2010;(3):CD001034.
114. Hurteau JA, Blessing JA, DeCesare SL, et al. Evaluation of recom-
binant human interleukin- 12 in patients with recurrent or refrac-
tory ovarian cancer: a gynecologic oncology group study. Gynecol
Oncol. 2001;82:7- 10.
115. Kok PS, Beale P, O'Connell RL , et al. PARAGON (ANZGOG- 0903):
a phase 2 study of anastrozole in asymptomatic patients with es-
trogen and progesterone receptor- positive recurrent ovarian can-
cer and CA125 progression. J Gynecol Oncol. 2019;30:e86.
116. Markman M, Rothman R, Hakes T, et al. Second- line platinum ther-
apy in patients with ovarian cancer previously treated with cispla-
tin. J Clin Oncol. 1991;9:389- 393.
117. Friedlander M, Trimble E , Tinker A, et al. Clinical trials in recurrent
ovarian cancer. Int J Gynecol Cancer. 2011;21:771- 775.
118. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus
platinum- based chemotherapy versus conventional platinum-
based chemotherapy in women with relapsed ovarian cancer: the
ICON4/AGO- OVAR- 2.2 trial . Lancet. 2003;361:2099- 2106.
119. Pf isterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin
compared with carboplatin in patients with platinum- sensitive re-
current ovarian cancer: an intergroup trial of the AGO- OVAR, the
NCIC CTG , and the EORTC GCG. J Cli n Oncol. 200 6;24:46 99 - 4 70 7.
120. Pfisterer J, Ledermann JA. Management of platinum- sensitive re-
current ovarian cancer. Semin Oncol. 2006;33(2 Suppl 6):S12- S16.
121. Wagner U, Marth C, Largillier R, et al. Final overall survival result s
of phase III GCIG CALYPSO trial of pegylated liposomal doxoru-
bicin and carboplatin vs paclitaxel and carboplatin in platinum-
sensitive ovarian cancer patients. Br J Cancer. 2012 ;107:588- 591.
122. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized,
double- blind, placebo- controlled phase III trial of chemotherapy
with or without bevacizumab in patients with platinum- sensitive
recurrent epithelial ovarian, primary peritoneal, or fallopian tube
cancer. J Clin Oncol. 2012;30:2039- 2045.
123. P fisterer J, Shannon CM, Baumann K, et al. Bevacizumab and
platinum- based combinations for recurrent ovarian cancer: a ran-
domised, open- label, phase 3 trial. Lancet Oncol. 2020;21:699- 709.
124. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lac ave
AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III
study of pegylated liposomal doxorubicin versus topotecan. J Clin
Oncol. 20 01;19:3312- 3322 .
125. Hoskins PJ, Swenerton KD. Oral etoposide is active against
platinum- resistant epithelial ovarian cancer. J Clin Oncol.
1994;12:60- 63.
126. Rose PG, Blessing JA, Soper JT, Barter JF. Prolonged oral etopo-
side in recurrent or advanced leiomyosarcoma of the uterus: a gy-
necologic oncology group study. Gynecol Oncol. 1998;70:267- 271.
127. Friedlander M, Millward MJ, Bell D, et al. A phase II study of gem-
citabine in platinum pre- treated patients with advanced epithelial
ovarian cancer. Ann Oncol. 1998;9:1343- 1345.
128. Shapiro JD, Millward MJ, Rischin D, et al. Activit y of gemcitabine in
patients with advanced ovarian cancer: responses seen following
platinum and paclitaxel. Gynecol Oncol. 1996;63:89- 93.
129. Colombo N, Kutarska E, Dimopoulos M , et al. Randomized, open-
label, phase III study comparing patupilone (EPO906) with pe-
gylated liposomal doxorubicin in platinum- refractory or - resistant
patients with recurrent epithelial ovarian, primary fallopian tube,
or primary peritoneal cancer. J Clin Oncol. 2012;30:3841- 3847.
130. Monk BJ, Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated
liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol.
2010; 28:3107- 3114.
131. Miller DS, Blessing JA, Krasner CN, et al. Phase II evaluation of
pemetrexed in the treatment of recurrent or persistent platinum-
resistant ovarian or primary peritoneal carcinoma: a study of the
Gynecologic Oncology Group. J Clin Oncol. 2009;27:2686- 2691.
132. Lheureux S, Cristea MC, Bruce JP, et al. Adavosertib plus gem-
citabine for platinum- resis tant or platinum- refractor y recurrent
ovarian cancer: a double- blind, randomised, placebo- controlled,
phase 2 trial. Lancet. 2021;397:281- 292.
133. O'Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of
mirvetuximab soravtansine, a folate receptor alpha (FRalpha)-
targeting antibody- drug conjugate ( ADC), in combination with
bevacizumab in patients with platinum- resistant ovarian cancer.
Gynecol Oncol. 2020;157:379- 385.
134. Pujade- Lauraine E, Hilpert F, Weber B, et al. Bevacizumab com-
bined with chemotherapy for platinum- resistant recurrent ovarian
cancer : The AURELIA op en- label randomized phase III trial. J Clin
Oncol. 2014;32:13 02- 1308.
135. Poveda AM, Selle F, Hilpert F, et al. Bevacizumab combined with
weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan
in platinum- resistant recurrent ovarian cancer: analysis by chemo-
therapy cohort of the randomized p hase III AURELIA trial. J Clin
Oncol. 2015;33:38 36- 3838.
136. Matulonis UA, Shapira R, Santin A, et al. Final results from the
KEYNOTE- 100 trial of pembrolizumab in patients with advanced
recurrent ovarian cancer. J Clin Oncol. 2020;38(15 suppl):6005.
137. Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of ave-
lumab for patients wit h recurrent or refractory ovarian c ancer:
phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol.
2019;5:393- 401.
138. Konstantinopoulos PA, Waggoner S, Vidal GA , et al. Single- arm
phases 1 and 2 trial of niraparib in combination with pembroli-
zumab in patients with recurrent platinum- resistant ovarian c arci-
noma. JAMA Oncol. 2019;5:1141- 1149.
139. Zamarin D, Burger RA , Sill MW, et al. Randomized phase II trial
of nivolumab versus nivolumab and ipilimumab for recurrent or
persistent ovarian cancer: an NRG oncology study. J Clin Oncol.
2020;38:1814- 1823.
140. Lwin Z, Gomez- Rocan C , Saada- Bouzid E, et al. LE AP- 005: Phase II
study of lenvatinib (len) plus pembrolizumab (pembro) in patient s
(pts) with previously treated advanced solid tumours. Ann Oncol.
2020;31:S1170.
141. Friedlander M, Butow P, Stockler M , et al. Symptom control in pa-
tients with recurrent ovarian cancer: measuring the benefit of pal-
liative chemotherapy in women with platinum refractory/resistant
ovarian cancer. Int J Gynecol Cancer. 2009;19(Suppl 2):S44- S48.
142. Kaufman B, Shapira- Frommer R , Schmutzler RK, et al. Olaparib
monotherapy in patients with advanced cancer and a germline
BRCA1/2 mutation. J Clin Oncol. 2015;33:244- 250.
143. Swisher EM, Lin KK , Oza AM, et al. Rucaparib in relapsed,
platinum- sensitive high- grade ovarian carcinoma (ARIEL2 Part
1): an international, multicentre, open- label, phase 2 trial. Lancet
Oncol. 2 017;18:75 - 87.
144. Gershenson DM, Sun CC , Lu KH, et al. Clinical behavior of stage
II- IV low- grade serous carcinoma of the ovary. Obstet Gynecol.
2006;108:361- 368.
145. Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low- grade
serous ovarian carcinoma is relatively chemoresistant. Gynecol
Oncol. 20 09;114:48 - 52.
146. Wong K- K, Tsang Y TM, Deavers MT, et al. BR AF mutation is r are in
advanced- stage low- grade ovarian serous carcinomas. Am J Pathol.
2010;177:1611- 1617.
147. Hsu C- Y, Bristow R, Cha MS, et al. Characterization of active
mitogen- activated protein kinase in ovarian serous carcinomas.
Clin Cancer Res. 2004;10:6432- 6436.
148. Schmeler KM, Sun CC, Bodurka DC, et al. Neoadjuvant chemo-
therapy for low- grade serous carcinoma of the ovary or perito-
neum. Gynecol Oncol. 20 08;10 8: 510- 514.
149. Grabowski JP, Harter P, Heitz F, et al. Operability and chemother-
apy responsiveness in advanced low- grade serous ovarian cancer.
84
|
BE REK Et al.
An analy sis of the AGO Study Group metadat abase. Gynecol On col.
2016;140:457- 462.
150. Gershenson DM, Sun CC, Iyer RB, et al. Hormonal therapy for re-
current low- grade serous carcinoma of the ovary or peritoneum.
Gynecol Oncol. 2012;125:661- 666.
151. Fader AN, Bergstrom J, Jernigan A, et al. Primary cy toreduc-
tive surgery and adjuvant hormonal monotherapy in women
with advanced low- grade serous ovarian carcinoma: reducing
overtreatment without compromising survival? Gynecol Oncol.
2017;147:85- 91.
152. Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A ,
Sun CC. Hormonal maintenance therapy for women with low-
grade serous cancer of the ovary or peritoneum. J Clin Oncol.
2017;3 5:1101- 1111.
153. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women
with recurrent low- grade serous carcinoma of the ovary or peri-
toneum: an open- label, single- arm, phase 2 study. Lancet Oncol.
2013 ;14:134- 140.
154. Monk BJ, Grisham RN, Banerjee S, et al. MILO/ENGOT- ov11:
binimetinib versus physician's choice chemotherapy in re-
current or persistent low- grade serous carcinomas of the
ovary, fallopian tube, or primary peritoneum. J Clin Oncol.
2020;38:3753- 3762.
155. Ger shenson D, Miller A, Brady W, et al. A randomized phase II/III
study to assess the efficacy of trametinib in patients with recur-
rent or progressive low- grade serous ovarian or peritoneal cancer.
in ESMO. Ann Oncol. 2019;30:v897- v898.
156. Lalwani N, Shanbhogue AK, Vikram R, Nagar A , Jagirdar J, Prasad
SR. Current update on borderline ovarian neoplasms. AJR Am J
Roentgenol. 2010;194:330- 336.
157. Kennedy AW, Hart WR. Ovarian papillary serous tumors of low
malignant potential (serous borderline tumors). A long- term fol-
low- up study, including patients with microinvasion, lymph node
metastasis, and transformation to invasive serous carcinoma.
Cancer. 1996;78:278- 286.
158. Morice P, Denschlag D, Rodolakis A , et al. Recommendations of
the fertility task force of the European Society of Gynecologic
Oncology about the conservative management of ovarian malig-
nant tumors. Int J Gynecol Cancer. 2011;21:951- 963.
159. Shih KK, Zhou QC, Aghajanian C, et al. Pat terns of recurrence and
role of adju vant chemotherapy in stage II- IV serous ovarian bor-
derline tumors. Gynecol Oncol. 2010;119:270- 273.
160. Zanetta G, Rota S, Chiari S, Bonazzi C , Bratina G , Mangioni C .
Behavior of borderline tumors with particular interest to per-
sistence, recurrence, and progression to invasive carcinoma: a pro-
spective study. J Clin Oncol. 20 01;19:2658- 2664.
161. Berek JS, Friedlander M, Hacker NF. Germ cell and nonepithe-
lial ovarian cancers. In: Berek JS, Hacker NF, Eds. Gynecologic
Oncology. Wolters Kluwer; 2021:477- 502 .
162. Colombo N, Parma G, Zanagnolo V, Insinga A. Management of
ovarian stromal cell tumors. J Clin Oncol. 2007;25:2944- 2951.
163. Schumer ST, Cannistra SA. Gr anulosa cell tumors of the ovary. J
Clin Oncol. 2 003;21:118 0- 1189.
164. Pautier P, Gutier rez- Bonnaire M, Rey A , et al. Combinati on of bleo-
mycin, etop oside, and cispl atin for the treat ment of advanced ov ar-
ian granulosa cell tumors. Int J Gynecol Cancer. 2008;18:446- 452.
165. Brown J, Shvartsman HS, Deavers MT, et al. The activity of tax-
anes compared with bleomycin, etoposide, and cisplatin in the
treatment of sex cord- stromal ovarian tumors. Gynecol Oncol.
2005;97:489- 496.
166. Homesley HD, Bundy BN, Hur teau JA, et al. Bleomycin, etoposide,
and cisplatin combination therapy of ovarian granulosa cell tumors
and other stromal malignancies: a Gynecologic Oncology Group
study. Gynecol Oncol. 1999;72:131- 137.
167. Brown J, Brady WE, Schink J, et al. Efficacy and safet y of bev-
acizumab in recurrent sex cord- stromal ovarian tumors: result s
of a phase 2 trial of the Gynecologic Oncology Group. Cancer.
2014;120:344- 351.
168. Ray- Coquard I, Harter P, Lorusso D, et al. Effect of weekly pa-
clitaxel with or without bevacizumab on progression- free rate
among patients with relapsed ovarian sex cord- stromal tumors:
the ALIENOR/ENGOT- ov7 randomized clinical trial. JAMA Oncol.
2020;6:1923- 1930.
169. van Meurs HS, van Lonkhuijzen LRCW, Limpens J, et al. Hormone
therapy in ovarian granulosa cell tumors: a systematic review.
Gynecol Oncol. 2014;134:196- 205.
170. van Meurs HS, van der Velden J, Buist MR , et al. Evaluation of
response to hormone therapy in patients with measurable adult
granulosa cell tumors of the ovary. Acta Obstet Gynecol Scand.
2015;94:1269- 1275.
171. Banerjee SN, Tang M, O'Connell R, et al. PAR AGON: A phase 2
study of anastrozole (An) in patient s with estrogen receptor (ER)
and / progesterone receptor (PR) positive recurrent/metastatic
granulosa cell tumors/sex- cord stromal tumors (GCT) of the ovary.
J Clin Oncol. 2018;36(15 suppl):5524.
172. Lappöhn RE, Burger HG, Bouma J, et al. Inhibin as a marker for
granulosa- cell tumors. N Engl J Med. 1989;321:790- 793.
173. Geer ts I, Vergote I, Neven P, Billen J. The role of inhibins B and
antimüllerian hormone for diagnosis and follow- up of granulosa
cell tumors. Int J Gynecol Cancer. 20 09;19:847- 855.
174. Winter C , Albers P. Testicular germ cell tumors: pathogenesis, di-
agnosis and treatment. Nat Rev Endocrinol. 2011;7:43- 5 3.
175. Kondagunta GV, Motzer RJ. Chemotherapy for advanced germ cell
tumors. J Clin Oncol. 2006;24:5493- 5502.
176. Williams S, Blessing JA, Liao SY, Ball H, Hanjani P. Adjuvant ther-
apy of ovarian germ cell tumors with cisplatin, etoposide, and
bleomycin: a trial of the Gynecologic Oncology Group. J Clin Onco l.
1994;12:701- 706.
177. Williams SD, Blessing JA , Hatch KD, Homesley HD. Chemother apy
of advanced dysgerminoma: trials of the Gynecologic Oncology
Group. J Clin Oncol. 1991;9:195 0- 1955.
178. G ershenson DM, Morris M, Cangir A, et al. Treatment of malignant
germ cell tumors of the ovary with bleomycin, etoposide, and cis-
platin. J Clin Oncol. 1990;8:715- 720.
179. Williams SD, Blessing JA, DiSaia PJ, Major FJ, Ball HG 3rd, Liao SY.
Second- look laparotomy in ovarian germ cell tumors: the gyneco-
logic oncology group experience. Gynecol Onc ol. 19 94; 52: 287- 2 91.
180. Talukdar S, Kumar S, Bhatla N, Mathur S, Thulkar S, Kumar L . Neo-
adjuvant chemother apy in the treatment of advanced malignant
germ cell tumors of ovar y. Gynecol Oncol. 2014;132:28- 32.
181. Mathew GK , Singh SS, Swaminathan RG , Tenali SG. Laparotomy
for post chemotherapy residue in ovarian germ cell tumors. J
Postgrad Med. 2006;52:262- 265.
182. Dar k GG, Bower M, Newlands ES, Paradinas F, Rustin GJ.
Surveillance policy for stage I ovarian germ cell tumors. J Clin
Oncol. 1997;15:620- 624.
183. Patterson DM, Murugaesu N, Holden L, Seckl MJ, Rustin GJ. A
review of the close surveillance policy for stage I female germ
cell tumors of the ovary and other sites. Int J Gynecol Cancer.
2008;18:43- 50.
184. Huddar t RA, Purkalne G; E SMO Guidelines Task Force. ESMO
Minimum Clinical Recommendations for diagnosis, treatment
and follow- up of mixed or non- seminomatous germ cell tumors
(NSGCT). Ann Oncol. 2005;16(Suppl 1):i37- i39.
185. Williams SD, Kauderer J, Burnett AF, et al. Adjuvant therapy of
completely resected dysgerminoma with carboplatin and etopo-
side: a trial of the Gynecologic Oncology Group. Gynecol Oncol.
200 4;95:496- 499.
186. Shah R, Xia C, Kr ailo M, et al. Is carboplatin- based chemotherapy
as effec tive as cisplatin- based chemotherapy in the treatment of
advanced- stage dysgerminoma in children, adolescents and young
adults? Gynecol Oncol. 2018;150:253- 260.
|
85
BEREK Et al .
187. Ray- Coquard I, Morice P, Lorusso D, et al. Non- epithelial ovarian
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow- up. Ann Oncol. 2018;29(Suppl 4):iv1- iv18.
188. Hariprasad R, Kumar L, Janga D, Kumar S, Vijayaraghavan M. Growing
teratoma syndrome of ovary. Int J Clin Oncol. 2008;13:83- 87.
189. Le T, Krepart GV, Lotocki RJ, Hey wood MS. Malignant mixed me-
sodermal ovarian tumor treatment and prognosis: a 20- year expe-
rience. Gynecol Oncol. 199 7;65:2 37- 24 0.
190. Sood AK, Sorosky JI, Gelder MS, et al. Primary ovarian sarcoma:
analysis of prognostic variables and the role of surgical cy toreduc-
tion. Cancer. 1998;82:1731- 1737.
191. Berek JS, Kehoe ST, Kumar L, et al. Cancer of the ovary, fallo-
pian tube, and peritoneum. Int J Gynecol Obstet. 2018;143(Suppl
2) :5 9- 7 8.
How to cite this article: Berek JS, Renz M, Kehoe S, Kumar L,
Friedlander M. Cancer of the ovary, fallopian tube, and
peritoneum: 2021 update. Int J Gynecol Obstet.
2021;155(Suppl. 1):61– 85. https://doi.org/10.1002/ijgo.13878
Available via license: CC BY
Content may be subject to copyright.