clinical practice guidelines Annals of Oncology 24 (Supplement 6): vi24vi32, 2013

doi:10.1093/annonc/mdt333

Newly diagnosed and relapsed epithelial ovarian

carcinoma: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
J. A. Ledermann1, F. A. Raja1, C. Fotopoulou2, A. Gonzalez-Martin3, N. Colombo4 & C. Sessa5, on
behalf of the ESMO Guidelines Working Group*
1
UCL Cancer Institute, University College London, London; 2Imperial College, London, UK; 3MD Anderson Cancer Centre, Madrid, Spain; 4European Institute of Oncology,
University of Milan Bicocca, Milan, Italy; 5Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland

These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO)

incidence and epidemiology with a rst-degree relative have more than a twofold increase in
risk of ovarian cancer compared with women with no family
The estimated number of new ovarian cancer cases in Europe in history. However, only 10% of ovarian cancer cases have an
2012 was 65 538 with 42 704 deaths [1]. There is variation in the identiable genetic mutation, e.g. the known susceptibility genes
incidence rate across the continent with a higher incidence in BRCA 1 and BRCA 2. An inherited BRCA 1 mutation confers a
northern European countries. In the USA, there were 20 400 15%45% lifetime risk of developing ovarian cancer and 85%
clinical practice

newly diagnosed cases and 14 400 deaths in 2009 [2]. Ovarian risk of developing breast cancer. A BRCA 2 mutation increases
guidelines

cancer is the fth most common type of cancer in women and the lifetime risk of ovarian cancer to 10%20% and breast
the fourth most common cause of cancer death in women. The cancer risk of 85%. Women with hereditary ovarian cancer
estimated lifetime risk for a woman developing ovarian cancer is tend to develop the disease 10 years earlier than women with
about 1 in 54. non-hereditary ovarian cancer. There are no clear guidelines for
Ovarian cancer is predominantly a disease of older, referral of ovarian cancer patients for testing. Referral is made
postmenopausal women with the majority (>80%) of cases being on the basis of a family history and ethnic background. The
diagnosed in women over 50 years. The exact cause of ovarian importance of identifying BRCA mutations has increased as, in
cancer remains unknown but many associated risk factors have addition to risk-reducing surgery and surveillance for breast
been identied. A womans reproductive history appears to cancer in the patient and in family members, there are new
contribute signicantly to her lifetime risk of ovarian cancer. treatments emerging specically for BRCA-related cancers.
Those women who have had multiple pregnancies have a lower
risk than those with fewer pregnancies, who in turn have a lower
risk than nulliparous women. Early menarche and late
menopause also seem to contribute to a greater risk of ovarian pathology
cancer, while use of the oral contraceptive pill, tubal ligation, The majority of cases of ovarian cancer are of epithelial origin
breastfeeding and suppression of ovulation offer protection (90%). The World Health Organisation histological typing of
against ovarian cancer. All of these risk factors point to ovulation epithelial ovarian tumours recognises the following distinct
being correlated with the development of ovarian cancer. Further subtypes [4]:
risk factors are obesity and possibly the use of talcum powder.
Family history plays a very important role in the development serous
of ovarian cancer, although in a recent study 44% patients with endometrioid
high-grade serous ovarian cancer and a germline BRCA clear cell
mutation did not report a family history of cancer [3]. Women mucinous
Brenner (transitional cell)
mixed epithelial tumours
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Ofce, Via undifferentiated
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland. unclassied
E-mail: [email protected]

Clinical trials have demonstrated that the subtype has
Approved by the ESMO Guidelines Working Group: April 2002, last update July 2013.
This publication supersedes the previously published versionAnn Oncol 2010; 21
prognostic importance [5] [I]. Grade is an additional prognostic
(Suppl. 5): v23v30. determinant and a number of grading systems currently exist

The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
Annals of Oncology clinical practice guidelines
which are derived from reviewing the following tumour other carcinomas
characteristics: architectural features, mitotic counts and nuclear Mixed carcinomas are diagnosed when a tumour consists of
atypia. Based on these, a grade of 13 is most commonly more than one histological type and the minor component
assigned [6]. There is no single universally accepted grading forms >10%. Undifferentiated carcinomas are rare and are likely
system. Some use a two-tier staging [7]; moreover, it is being to represent one end of the high-grade serous spectrum [13].
recognised increasingly that different grading systems for
different histological subtypes should be employed. The
borderline tumours (tumours of low malignant
complexity of subclassication below and its affect on treatment
choice underline the importance of the role of an expert in
potential)
gynaecological pathology in typing tumours. Borderline tumours comprise about 10%15% of ovarian
tumours and do not t into the category of benign or malignant.
As most ovarian tumours are serous in origin, borderline serous
serous carcinomas
tumours are the most common type but borderline mucinous
Invasive serous carcinomas are the most common histological and endometrioid tumours also occur. Borderline serous
type accounting for up to 80% of advanced ovarian cancers. In tumours form part of the spectrum of low-grade serous cancers.
recent years, convincing data have been presented that high- They are managed primarily by surgery and respond poorly to
grade serous and low-grade serous ovarian cancers are two chemotherapy.
distinct disease entities [8, 9]. Tumours with mild to moderate
cytologic atypia and low mitotic rates are classied as low-grade,
whereas patients with severe cytologic atypia and high mitotic molecular pathogenesis
rates are considered high-grade serous tumours. There are also Ovarian cancer is recognised as a heterogeneous disease, and in
distinct mutations present in each type, and the cell of origin the last few years a dualistic model for the pathogenesis of this
may also be different, as discussed in the next section. Clinically, disease has emerged which divides epithelial tumours into type 1
women with low-grade serous tumours, which account for and type 2 ovarian carcinomas. This classication is not intended
10% of serous cancers tend to present at a younger age and to replace histological subtypes but provides a parallel
have a longer survival compared with women with high-grade terminology pertaining to the broad mechanism of cancer
tumours [10]. There is an increasing realisation that low-grade development [13]. Type 1 cancers tend to be low-grade and
serous tumours do not respond to traditional chemotherapy indolent tumours and include low-grade serous, endometrioid,
regimens [11] and that alternative approaches are required mucinous, clear-cell and malignant Brenner tumours. These
particularly for the treatment of recurrent tumours. tumours are characterised by mutations of KRAS, BRAF, ERBB2,
PTEN, PIK3CA and ARID1A and are relatively genetically stable.
endometrioid These mutations occur early in the evolution of type 1 ovarian
The majority of endometrioid ovarian cancers are usually early tumours and are also observed in borderline tumours and
stage (stage 1) and low grade. The prevalence of endometrioid endometriosis. A stepwise sequence of tumour development is
ovarian cancers has decreased in recent years, likely due to now well recognised from benign precursor lesions (e.g.
better pathological diagnosis, and currently they account for borderline tumour) to malignant lesions in type 1 cancers.
10% of ovarian cancers. Endometriosis and in particular Conversely, there is no clear precursor lesion for type 2 cancers.
endometriotic cysts have been implicated as putative precursor These are high-grade, aggressive tumours comprising high-grade
lesions to endometrioid ovarian cancer. ARID1A mutations serous, high-grade endometrioid, malignant mixed mesodermal
have been detected in endometriotic cysts and in endometrioid tumours and undifferentiated tumours. Type 2 tumours are very
ovarian cancer, suggesting a causative role [12]. frequently associated with TP53 mutations, and one landmark
study found that 97% of high-grade serous cancers were
clear-cell cancers associated with a TP53 mutation. Approximately 20% of these
tumours also carried a BRCA1/2 mutation due to a combination
Clear-cell cancers account for 5% of ovarian cancers, although of germline and somatic mutations [14].
the incidence varies worldwide. Japanese women develop clear- In recent years, accumulating evidence has shown that the
cell ovarian cancers more commonly. The prognosis for stage 1 majority of high-grade serous ovarian and peritoneal tumours
clear-cell cancers is relatively good. However, advanced stage originate in the mbria of the fallopian tube (serous tubal
clear-cell cancers have a worse prognosis than serous ovarian intraepithelial carcinoma) [15, 16]. These malignant cells then
cancers as the tumours tend to be resistant to the standard metastasise to the ovaries and the peritoneal cavity.
chemotherapeutic agents used in ovarian cancer. Clear-cell
cancers are also strongly associated with endometriosis and a
signicant proportion carry ARID1A mutations [12]. diagnosis
Patients with ovarian cancer conned to the ovary may have few
transitional carcinoma or no symptoms, making clinical diagnosis of early ovarian
Primary ovarian transitional carcinomas are rare but cancer more difcult. Symptoms are most commonly seen with
carcinomas with transitional features are quite common. The advanced disease. Recognised symptoms of all stages include
majority of the latter are variants of high-grade serous abdominal or pelvic pain, constipation, diarrhoea, urinary
carcinomas and exhibit WT1 positivity. frequency, vaginal bleeding, abdominal distension and fatigue.

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clinical practice guidelines Annals of Oncology

In advanced ovarian cancer, ascites and abdominal masses lead can be calculated from clinical factors, ultrasound and CA 125
to increased abdominal girth, bloating, nausea, anorexia, and can be used to refer patients to a specialist gynaecological
dyspepsia and early satiety. Extension of disease across the oncology team. Computed tomography (CT) scans are routinely
diaphragm to the pleural cavities can produce pleural effusions used to determine the extent of disease and to aid in surgical
and the development of respiratory symptoms. Patients may planning. Imaging of the chest with CT or chest X-ray should be
become aware of an abdominal or nodal mass either in the done to look for pleural effusions and disease above the
inguinal region, axillae or the supraclavicular fossa. diaphragm. A pleural effusion cannot be regarded as malignant
Following a full clinical assessment, measurement of serum CA and indicative of FIGO stage IV disease without conrmation of
125 is routinely used to aid diagnosis. However, its utility to positive cytology. Magnetic resonance imaging (MRI) scans do
detect early disease is questionable as it is elevated only in about not form part of routine investigations.
50% of patients with the International Federation of Gynecology
and Obstetrics (FIGO) stage I disease. In advanced disease, CA staging and risk assessment
125 is elevated in about 85% of patients. It is not specic for
ovarian cancer and raised CA 125 levels may be found in non- FIGO staging remains the most powerful indicator of prognosis
gynaecological malignancies (e.g. breast, lung, colon and (see Table 1). Although surgically dened, preoperative
pancreatic cancer) and benign disease (e.g. endometriosis, pelvic assessment with cross-sectional imaging (CT or MRI) is essential
inammatory disease and ovarian cysts). Serum as it guides surgery and the pathway of intervention. Given the
carcinoembryonic antigen (CEA) and CA 199 levels are variation in histological subtypes and evolving different patterns
sometimes measured in situations where it is unclear whether an of care, reliance on a cytological diagnosis should be avoided and
ovarian mass is of gastrointestinal origin, or a primary mucinous a histological diagnosis should be obtained if at all possible.
ovarian tumour. Similarly, in these situations, colonoscopy Primary surgery remains the most common and preferred
and/or gastroscopy are sometimes considered, particularly when approach, but where this is deemed not feasible, an image-
CA 125/CEA ratio is 25. Ultrasonography of the abdomen and guided or laparoscopic biopsy should be carried out.
pelvis is usually the rst imaging investigation recommended for
women in whom ovarian cancer is suspected. Transvaginal treatment plan
ultrasonography has improved the visualisation of ovarian
structures, thus improving the differentiation of malignant versus surgical management of early primary disease
benign conditions [17]. A number of morphological variables The aim of surgery for early ovarian cancer is to resect the
have been identied as being strongly associated with ovarian tumour and to undertake adequate staging. This will provide
cancer. The presence of a large lesion, multi-locular cysts, solid prognostic information and will dene whether chemotherapy
papillary projections, irregular internal septations and ascites are is needed. The diagnosis may be made preoperatively, but
highly suggestive of ovarian cancer. A risk of malignancy index sometimes a tumour is an incidental nding. The availability of

Table 1. Staging of cancer of the ovary

Stage I Growth limited to the ovaries

IA Growth limited to one ovary; no ascites present containing malignant cells. No tumour on the external surface; capsule intact
IB Growth limited to both ovaries; no ascites present containing malignant cells. No tumour on the external surfaces; capsules intact
ICa Tumour either stage IA or IB, but with tumour on surface of one or both ovaries, or with capsule ruptured, or with ascites present containing
malignant cells, or with positive peritoneal washings

Stage II Growth involving one or both ovaries with pelvic extension

IIA Extension and/or metastases to the uterus and/or tubes
IIB Extension to other pelvic tissues
IICa Tumour either stage IIA or IIB, but with tumour on surface of one or both ovaries, or with capsule(s) ruptured, or with ascites present containing
malignant cells, or with positive peritoneal washings

Stage III Tumour involving one or both ovaries with histologically conrmed peritoneal implants outside the pelvis and/or positive regional lymph nodes.
Supercial liver metastases equal stage III. Tumour is limited to the true pelvis, but with histologically proven malignant extension to small
bowel or omentum
IIIA Tumour grossly limited to the true pelvis, with negative nodes, but with histologically conrmed microscopic seeding of abdominal peritoneal
surfaces, or histologically proven extension to small bowel or mesentery
IIIB Tumour of one or both ovaries with histologically conrmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2
cm in diameter; nodes are negative
IIIC Peritoneal metastasis beyond the pelvis >2 cm in diameter and/or positive regional lymph nodes

Stage IV Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to stage
IV. Parenchymal liver metastasis equals stage IV
a
In order to evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know whether rupture of the
capsule was spontaneous, or caused by the surgeon and whether the source of malignant cells detected was peritoneal washings or ascites.
Reprinted from the International Journal of Gynecology and Obstetrics [57]. Copyright 2006, with permission from Elsevier.

vi | Ledermann et al. Volume 24 | Supplement 6 | October 2013

Annals of Oncology clinical practice guidelines
a frozen section to identify a malignant epithelial cancer may improvements in the rate of cytoreduction, with no increase in
allow the necessary surgical staging to be done, without the need morbidity as a result of this process [26]. Thus, women with
for a second operative procedure. Accurate surgical staging is advanced disease are advised to undergo surgery in specialised
important as it may unmask occult advanced disease. centres with adequate infrastructure and training [B]. Optimal
Depending on the histological grade and subtype, 30% of the cytoreduction is dened as total macroscopic tumour clearance
patients with apparently early epithelial ovarian cancer will be with no residual visible disease. A recent meta-analysis evaluating
upstaged after comprehensive surgical staging [18, 19]. Cass the surgical outcome of more than 3120 patients showed that
et al. showed that, in 96 patients with grade 3 tumours and gross residual tumour is a more powerful prognostic determinant than
disease conned to one ovary, 15% had microscopically positive FIGO stage; patients with suboptimally debulked stage IIBIIIB
lymph nodes [20]. Among these patients, 50% had positive tumours had a worse outcome that those with completely
pelvic nodes, 36% had positive para-aortic node and both were debulked stage IIIC tumours [23]. The value of systematic pelvic
positive in 14% of the cases. Maggioni et al. reported on a and para-aortic lymphadenectomy in advanced disease remains
prospective randomised trial of systematic lymphadenectomy in controversial. A retrospective analysis of more than 1900 patients
patients with ovarian cancer macroscopically conned to the found that lymphadenectomy was associated with a prolonged
pelvis. Positive nodes were detected in 22% of patients survival in patients with no gross residual disease [27]. However, a
undergoing systematic lymphadenectomy, compared with only prospective randomised trial of lymphadenectomy versus removal
9% of patients who underwent merely a sampling (P = 0.007). of bulky nodes in patients with <2 cm residual tumour showed an
Although a trend for improved progression-free survival (PFS) improvement in PFS but not OS for the lymphadenectomy group
and overall survival (OS) was observed for the [28]. A large multi-centre, prospectively randomised trial of
lymphadenectomy group when compared with the control lymphadenectomy in this group of patients just completed accrual
group, the study lacked the statistical power to be conclusive in (LION Trial, AGO-OVAR OP.3 [NCT00712218]). Until the
this respect [21]. Thus, there is currently no evidence to suggest results of such trials become available, systematic
that lymphadenectomy per se improves survival. Bulky lymph lymphadenectomy should not be regarded as a standard
nodes should be resected in an effort to remove all visible procedure. Currently, the removal of bulky lymph nodes is carried
residual disease. Adequate, non-fertility-sparing surgery should out as part of an attempt to achieve maximum cytoreduction.
consist of peritoneal washings, ideally taken before The timing of surgical cytoreduction in relation to
manipulation of the tumour, bilateral salpingo-oophorectomy, chemotherapy is still debated. A large prospective trial showed
hysterectomy, multiple peritoneal biopsies of all abdominal [25] that in advanced bulky stage IIIC or IV disease, three cycles
elds, at least infracolic omentectomy, appendectomy in case of of platinum-based neoadjuvant chemotherapy followed by
mucinous histology and pelvic and para-aortic lymph node interval debulking surgery was not inferior to primary
dissection up to the renal veins. debulking surgery followed by chemotherapy [I, A]. Surgical
When young women are affected, fertility-sparing surgery morbidity had a non-signicant trend to be lower in the
could be considered in early-stage disease, but always after neoadjuvant arm. As a result of these data, the use of primary
thoroughly informing the patient about the potential risks. chemotherapy with interval surgery is becoming more widely
Patients with stage IA or stage IC with unilateral ovarian accepted and is offered to patients with poor performance status
involvement and favourable histology, that is mucinous, serous, at presentation, low albumin levels and in those with very
endometrioid or mixed histology and grade 1 or 2, would be extensive tumour dissemination. Validation of the results of this
amenable to organ-preserving surgery, but only in combination approach may come from further trials that are ongoing. The
with complete surgical staging. This would include a place of secondary interval debulking surgery after primary
lymphadenectomy to exclude more advanced disease. In large surgery with suboptimal cytoreduction and three cycles of
retrospective analyses, women with G3 disease or stage IC with chemotherapy is less clear. Improved survival following
clear-cell histology had a higher risk of recurrence. However, this secondary surgery was seen in the European Organisation for
increased risk is mainly related to a higher incidence of Research and Treatment of Cancer (EORTC) trial [24], but it
extraovarian spread observed in grade 3 tumours, rather than to a was not conrmed by another trial conducted by the
higher relapse rate in the preserved ovary [22]. Therefore, these Gynaecological Oncology Group (GOG) [29]. However,
patients should be carefully informed about their prognosis to differences in the extent of primary cytoreduction and the use of
enable them to make a personalised and thorough choice. paclitaxel with platinum may account for the discordant results.
A second look diagnostic laparoscopy or laparotomy after
completion of treatment to assess intraperitoneal status is
surgical management of primary advanced obsolete and should not be carried out, as its impact on survival
ovarian cancer has never been demonstrated.
In advanced epithelial ovarian cancer, the aim is complete
cytoreduction of all macroscopic visible disease, since this has
been shown to be associated with a signicantly increased OS and surgical management of relapsed ovarian cancer
PFS [2325]. In order to achieve this, a maximal surgical effort is and surgery for palliation
required, including intestinal resection, peritoneal stripping, The value of surgical cytoreduction in relapsed epithelial
diaphragmatic resection, removal of bulky para-aortic lymph ovarian cancer remains controversial and is not regarded as a
nodes and splenectomy. There is an increasing body of evidence standard of care, as the evidence for this approach has not been
that suggests specialist training and surgical expertise results in demonstrated in prospective trials. In retrospective analyses,

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clinical practice guidelines Annals of Oncology

surgery at rst relapse appears to be associated with a survival Standard chemotherapy consists of a combination of
benet only when a complete tumour resection can be obtained paclitaxel 175 mg/m2 and carboplatin AUC 6-5, both
[30, 31]. Patients with two of three of the following criteria: administered intravenously every 3 weeks [I, A] [3638]. This
complete resection at rst surgery, good performance status and has been the standard treatment of more than 15 years, and
absence of ascites had the best survival [III, C]. There are clinical trials in the last decade adding a third drug, such as the
currently two prospective multi-centre randomised trials large Gynaecologic Cancer InterGroup (GCIG) ICON-5/GOG
evaluating the value of surgery at relapse. The European trial, 182 trial [39], have not been shown to improve PFS or OS in
DESKTOP III [NCT01166737] uses selection criteria based on these patients. The combination of cisplatin and paclitaxel is
the above. The other study GOG 213 [NCT00565851] also equally effective but is more toxic and less convenient to
incorporates the addition of bevacizumab to chemotherapy. administer. Usually six cycles of treatment are given; no
The value of surgery to improve palliation at later relapse is less evidence exists to suggest that more than six cycles results in a
clear. The largest multi-centre retrospective analysis on tertiary better outcome. While survival benets are seen in trials with
cytoreduction included more than 400 patients in 14 centres platinum-based therapy, many women undergo several lines of
worldwide [32]. This analysis showed that residual tumours retain treatment, making dissection of the contribution of individual
a positive effect on survival even in the tertiary setting of epithelial therapies, particularly rst-line therapy, more complex.
ovarian cancer, attenuating the impact of other well-established For those patients who develop an allergy to or do not
negative prognostic predictors of survival such as ascites, tolerate paclitaxel, the combination of docetaxel-carboplatin or
advanced FIGO stage and peritoneal carcinomatosis [IV, C]. pegylated liposomal doxorubicin (PLD)-carboplatin can be
considered an alternative, based on two randomised clinical
adjuvant chemotherapy for early-stage trials that showed similar efcacy [II, A] [40, 41].
Alternative schedules of administration of paclitaxel and
disease platinum chemotherapy have included intraperitoneal delivery
A recent Cochrane meta-analyses of ve large prospective and dose-dense regimens.
clinical trials (4 of 10 with platinum-based chemotherapy) Intraperitoneal chemotherapy has a solid pharmacokinetic
showed that chemotherapy is more benecial than observation background and consists of administration of part of the
in patients with early-stage ovarian cancer [33]. Patients who chemotherapy, usually the platinum agent, directly into the
received platinum-based adjuvant chemotherapy had better OS peritoneal cavity through a catheter. One randomised clinical
[hazard ratio (HR) 0.71; 95% condence interval (CI) 0.53 trial carried out by the GOG (GOG-172) demonstrated a benet
0.93] and PFS (HR 0.67; 95% CI 0.530.84) than patients who in PFS and OS for a regimen that included not only
did not receive adjuvant treatment. Even though two-thirds of intraperitoneal cisplatin on day 2 and intravenous paclitaxel on
the patients included in the two major studies were day 1, but also intraperitoneal paclitaxel on day 8 [42].
suboptimally staged, some benet for chemotherapy in Additionally a meta-analysis of ve clinical trials conrmed a
optimally staged patients cannot be excluded. Long-term benet for intraperitoneal chemotherapy in OS [43]. This led to
follow-up of the ICON 1 trial conrms the benet of adjuvant a National Cancer Institute alert in 1996 recommending that
chemotherapy, particularly in those patients at higher risk of intraperitoneal therapy should be considered in patients with
recurrence (stage 1B/C grade 2/3, any grade 3 or clear-cell small volume (<1 cm) or no residual disease after surgery.
histology) [34]. Therefore, adjuvant chemotherapy should be However, this treatment has not been adopted as a standard of
offered not only to suboptimally staged patients but also to care in the majority of institutions and countries due to its
those optimally staged at higher risk of recurrence [I, A]. greater toxicity and difculty in delivering all of the
The optimal duration of treatment remains controversial; planned treatment. The absence of the current standard
there has been only one randomised trial (GOG 157) which intravenous control arm in these trials has further inuenced
showed that six cycles of carboplatin and paclitaxel were not scepticism, and many clinicians still regard intraperitoneal
associated with longer PFS or OS, but with a signicantly therapy as experimental, recommending its use only in the
greater toxicity than with three cycles [35]. There are no data to context of randomised trials. Several of these are in progress
demonstrate that the addition of paclitaxel to carboplatin is [I, B].
superior. Some clinicians feel that separating the choice of Dose-dense scheduling to improve the effectiveness of
treatment between FIGO stage IC and stage IIIV is articial, paclitaxel chemotherapy has also been explored in ovarian
and therefore choose to offer combination chemotherapy to cancer. A Japanese study (NOVELJGOG 3062) compared 3-
women with stage IC. However, evidence of a benet of weekly paclitaxel and carboplatin with the same dose of
combination therapy in this group is lacking; therefore, it is carboplatin every 3 weeks (AUC 6) and paclitaxel administered
reasonable to consider single-agent carboplatin to all women in a weekly dose of 80 mg/m2. Signicant benets in PFS and
with intermediate and high-risk stage I disease. OS were seen at 3 years, and a recent update with longer follow-
up has conrmed this benet in women with small volume and
front-line chemotherapy for epithelial >2 cm residual disease [44, 45]. However, 36% of patients had to
stop this regimen prematurely due to side-effects, especially
ovarian cancer (FIGO stage IIIV) myelotoxicity. This is a potentially practice-changing trial, but
The risks of recurrence for disease spread beyond the ovary are the possibility that this is a chance nding or is due to a
signicant, and chemotherapy is recommended for all patients pharmacogenomic difference between Japanese and Caucasian
with FIGO stage IIIV disease post surgery. populations makes it necessary to conrm these results in a

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Annals of Oncology clinical practice guidelines
Caucasian population. Two trials are in progress (GOG 262 interval debulking surgery or at the end of rst-line
[NCT01167712] and ICON 8 [NCT01654146]) and one was chemotherapy, to conrm the disease status. If the CA 125 does
recently completed (MITO 7 [NCT00660842]), but in the not reach the normal range before the end of chemotherapy, or
absence of conrmatory data, dose-dense administration of if there is residual disease on CT, the disease status would be
paclitaxel currently can only be considered an option, and not regarded as a partial response to front-line treatment.
as a standard of care [I, B].

targeted therapy chemotherapy in recurrent ovarian

Angiogenesis is an important component driving the growth of cancer
ovarian cancer. Two large randomised clinical trials (GOG-218
Despite optimal upfront surgery and the administration of
and ICON-7) have assessed the addition of bevacizumab to the
front-line paclitaxelcarboplatin chemotherapy, 70% of
combination of paclitaxel and carboplatin in front-line therapy
patients will relapse in the rst 3 years.
[46, 47]. Bevacizumab is a monoclonal antibody targeting
The prognosis and probability of response to second-line
vascular endothelial growth factor. In both trials patients in the
therapy and subsequent lines depends in great part on the
experimental arm received bevacizumab intravenously every 3
progression-free interval after the last dose of the preceding line
weeks during the chemotherapy phase, followed by a limited
of chemotherapy. These categories are based on the response to
period of maintenance with the same schedule of bevacizumab.
a rechallenge with platinum-based drugs but probably apply to
GOG-218 included a second experimental arm of bevacizumab
non-platinum therapies as well. A categorisation, recently
with chemotherapy, followed by maintenance with a placebo.
updated and conrmed by the GCIG 4th Ovarian Cancer
There were signicant differences in both trials in terms of dose
Consensus Meeting, denes platinum-refractory as patients
(7.5 mg/kg in the ICON-7 versus 15 mg/kg in the GOG-218),
progressing during therapy or within 4 weeks after the last dose;
duration (12 months in the ICON-7 versus 15 months in the
platinum-resistant patients progressing within 6 months of
GOG-218) and patient characteristics (GOG-218 included only
platinum-based therapy; partially platinum-sensitive, patients
patients with stage IIIIV and macroscopic residual disease after
progressing between 6 and 12 months; and platinum-sensitive
surgery, but ICON-7 included patients also with high-risk early
patients progressing with an interval of more than 12 months
stage, and patients in a more advanced stage but without
(GCIG Consensus) [49]. It should be noted that these categories
macroscopic residual disease after surgery). Both trials met their
are based on observational studies and that the categorisation is
primary end point, which was PFS for the two bevacizumab
probabilistic, with the likelihood of response being a continuous
maintenance arms. The test for interaction in the ICON-7 trial
variable. Furthermore, the category of platinum-resistant/
showed that a greater benet was observed in the high-risk
refractory comprises patients whose disease recurs after one or
population, dened as those patients with stage IIIIV and
several lines of treatment. The biological behaviour of the
residual disease >1 cm. In an interim analysis, OS was
tumour in these groups may be very variable, with differing
prolonged in this group. No survival difference was observed in
growth rates and distribution of symptoms requiring different
GOG-218 and mature survival results from ICON-7 are awaited.
approaches to treatment.
Bevacizumab has been licensed by the European Medicines
Treatment of patients with platinum-resistant or refractory
Agency (EMA) at 15 mg/kg, with carboplatin and paclitaxel and
disease should be focused on quality of life and control of
for 15 months or until progression. Bevacizumab is not
symptoms. Traditionally, this is a poor prognosis population with
licensed for ovarian cancer in the USA, and it is not consistently
a short expected OS, usually <12 months. Four different agents,
used in Europe. Some clinicians restrict the use of the drug to
weekly or 3-weekly paclitaxel, topotecan, PLD and gemcitabine,
the subgroup of higher risk patients as dened in the ICON-7
have been shown to have some activity in phase III trials, with
trial, and some are awaiting the mature survival data from
overall response rates no >15% and a median PFS of 34 months.
ICON 7, while others use the drug in its licensed dose and
Occasionally, platinum drugs continue to be used in the
indication or use the drug in patients with recurrent ovarian
platinum-resistant population with, for example, a dose-dense
cancer. The addition of bevacizumab is recommended for
regimen. However, as no agent has proven to be superior to
patients with advanced ovarian cancer with poor prognostic
another, the selection of therapy should be based on toxicity,
features such as stage IV or suboptimal debulking as dened in
clinical situation of the patient and convenience of
the ICON-7 trial [I, B]. Bevacizumab should be given with
administration. Randomised trials of combination chemotherapy
paclitaxel or carboplatin with a treatment duration of one year.
have shown no advantage in this population; it compounds
Trials with other anti-angiogenic drugs and extended therapy
toxicity. Accordingly, sequential single-agent therapy is the
with bevacizumab are ongoing.
recommended management for this group of patients [I, A].
For those patients with a later relapse, over 6 months and
evaluating the response to treatment especially over 12 months, carboplatin-doublet should be the
As CA 125 is elevated in most patients with advanced disease, treatment of choice [I, A]. Trials have included carboplatin
serial measurement is a useful marker to assess the response to compared with the same drug combined with paclitaxel,
chemotherapy according to GCIG criteria [48]. Where there is gemcitabine or an anthracycline. All have shown an
visible disease on CT at the beginning of chemotherapy, some improvement in PFS but a survival benet was only seen with
clinicians will formally evaluate a response on CT halfway the carboplatinpaclitaxel combination (ICON 4/OVAR 2.2)
through chemotherapy. A CT should be carried out before [50]. A meta-analysis including four randomised trials

Volume 24 | Supplement 6 | October 2013 doi:10.1093/annonc/mdt333 | vi

clinical practice guidelines Annals of Oncology

conrmed an improvement in PFS with a HR of 0.68 (95% CI bevacizumab at some point during progression) [I, A].
0.570.81) and OS with a HR of 0.8 (95% CI 0.641.0) [51]. However, bevacizumab in combination with this chemotherapy
Additionally, the CALYPSO trial demonstrated that the has been licensed by the EMA and is a recommended treatment
combination of carboplatinPLD was not inferior to paclitaxel for patients with platinum-sensitive relapsed ovarian cancer
carboplatin in terms of PFS, but was better tolerated because of who have not previously received bevacizumab.
the minimal incidence of alopecia, neuropathy, and arthralgias The second (AURELIA) trial was carried out in patients with
and fewer hypersensitivity reactions [52]. Again, the selection platinum-resistant ovarian cancer. This was a selected group
between the different options of platinum-based doublets who had received no more than two previous lines of treatment
should be based on the toxicity prole and convenience of and who did not have evidence of bowel obstruction or tumour
administration [I, B]. involvement of the serosa of the rectosigmoid colon. Patients
Several choices of treatment exist for patients with platinum- received standard chemotherapy according to physician choice
sensitive relapse. As this can occur on more than one occasion, (weekly paclitaxel, PLD or topotecan), and were randomised to
it allows for different combinations to be selected. Most of these receive bevacizumab or no additional treatment, together with
combinations involve platinum, but in the partially platinum- chemotherapy and then as maintenance until progression.
sensitive group, a survival benet was seen in a subgroup Patients receiving bevacizumab had a longer PFS (HR 0.48, 95%
analysis of the OVA-301 trial when trabectedin was combined CI 0.380.60) and an increment in response rate measured by
with PLD, when compared with PLD alone [I, B] [53, 54]. It has Response Evaluation Criteria in Solid Tumors (RECIST) of 15%
been hypothesised that this benet is due to the restoration of (11.8% versus 27.3%) [I, B] [56]. However, quality of life and OS
platinum-sensitivity by articially prolonging the platinum- data are still pending.
free interval. This is now being explored in two prospective
randomised trials.
follow-up
Relapse may be dened according to CA 125 criteria even if this
targeted therapy does not directly lead to a change in treatment. More often, a
Bevacizumab has shown to improve the PFS of recurrent rising CA 125 triggers further imaging. According to GCIG
ovarian cancer in two randomised phase III trials. The rst criteria, progression or recurrence based on serum CA 125
(OCEANS trial) included patients with measurable recurrent levels is dened on the basis of a progressive serial elevation of
ovarian cancer after rst-line and a platinum-free interval serum CA 125 [48]. Elevated values must be conrmed by two
longer than 6 months. All patients received a combination of separate measurements obtained at least one week apart. CA
carboplatin and gemcitabine at standard doses and were 125 progression will be assigned the date of the rst
randomised to receive bevacizumab (15 mg/kg) or placebo measurement that meets the criteria as noted.
administered every 3 weeks until progression. The addition of The value and type of follow-up after primary therapy has a
bevacizumab to chemotherapy increased signicantly the PFS weak evidence base and as a result practice varies. Clinical
(HR 0.48, 95% CI 0.380.60) and produced an increment in the evaluation with or without pelvic examination and
response rate of 21% (ORR 78.5% versus 57.4%, P < 0.0001)] measurement of CA 125 is often carried out every 3 months for
[55]. A more mature survival analysis has not proven any 2 years, then every 6 months during years 4 and 5 or until
additional benet in OS, probably due to the high rate of progression occurs. While the benet of monitoring CA 125
crossover (41% of patients in the control arm received during therapy is clear, the value of its measurement following

Table 2. Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service
Grading Systema)

Levels of evidence
I Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-
conducted randomised trials without heterogeneity
II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of
trials with demonstrated heterogeneity
III Prospective cohort studies
IV Retrospective cohort studies or casecontrol studies
V Studies without control group, case reports, experts opinions
Grades of recommendation
A Strong evidence for efcacy with a substantial clinical benet, strongly recommended
B Strong or moderate evidence for efcacy but with a limited clinical benet, generally recommended
C Insufcient evidence for efcacy or benet does not outweigh the risk or the disadvantages (adverse events, costs,...), optional
D Moderate evidence against efcacy or for adverse outcome, generally not recommended
E Strong evidence against efcacy or for adverse outcome, never recommended
a
Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001;
33: 139144. By permission of the Infectious Diseases Society of America.

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Annals of Oncology clinical practice guidelines
the completion of treatment is less certain. A phase III references
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clinical practice guidelines Annals of Oncology

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