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Gynecologic Oncology 133 (2014) 624631

Contents lists available at ScienceDirect

Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno

Review

Platinum resistant ovarian cancer: What is it, who to treat and how to
measure benet?
Alison Davis a,, Anna V. Tinker b, Michael Friedlander c
a
b
c

The Canberra Hospital and The Australian National University, Canberra, Australia
Vancouver Centre, British Columbia Cancer Agency, Vancouver, Canada
The Prince of Wales Clinical School, University of New South Wales, Sydney, Australia

H I G H L I G H T S
Platinum resistant ovarian cancer is comprised of a heterogeneous and complex spectrum of diseases.
Detailing time to progression, method of determining progression, histotype and genomic information may all improve interpretation of clinical trial results.
More active agents and better methods of assessing benet are needed.

a r t i c l e

i n f o

Article history:
Received 21 December 2013
Accepted 25 February 2014
Available online 4 March 2014
Keywords:
Platinum resistant
Ovarian cancer
Histotype
Genotype
Treatment

a b s t r a c t
Platinum resistant ovarian cancer was historically dened as disease recurrence within 6 months of completion
of rst-line platinum-based chemotherapy, although this is now more broadly applied to also include patients
progressing within 6 months after multiple lines of chemotherapy. However, this denition ignores the heterogeneity and complexity of the spectrum of diseases that comprise platinum resistant ovarian cancer (PROC) and is
innately awed as it was initially derived using methods of detection of recurrence that would now be regarded as
outdated. The outcome of patients with PROC is generally poor, with low response rates to further chemotherapy
and a median survival of less than 12 months, but this is unpredictable and can be quite variable from study to
study. This review outlines the complexity of PROC, examines how this impacts on the interpretation of the results
of clinical trials, and explores how the denition may be improved. We also briey describe the mechanisms of
platinum resistance, the results of clinical trials to date as well as treatment options for patients with PROC and
highlight the need for better methods of assessing clinical benet in this poor prognostic sub group of patients.
Crown Copyright 2014 Published by Elsevier Inc. All rights reserved.

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .
Platinum resistant disease: what is it? . . . . . . . . . . . . . . .
Relationship between specic histotype and response to chemotherapy
The Role of BRCA Mutations . . . . . . . . . . . . . . . . . . . .
The BRCAness prole . . . . . . . . . . . . . . . . . . . . . .
Mechanisms of resistance . . . . . . . . . . . . . . . . . . . . .
Tumor heterogeneity . . . . . . . . . . . . . . . . . . . . . . .
Platinum resistant disease: outcomes of therapy . . . . . . . . . . .
Who to treat, how to treat and for how long? . . . . . . . . . . . .
Chemotherapy-response assays . . . . . . . . . . . . . . . . . .
How long to treat and how many lines of therapy? . . . . . . . . .
What to measure . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest statement . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author at: Medical Oncology Unit, The Canberra Hospital, Yamba Drive, Canberra ACT 2606, Australia.
E-mail addresses: Alison.davis@act.gov.au, Alison_davis90@hotmail.com (A. Davis).

http://dx.doi.org/10.1016/j.ygyno.2014.02.038
0090-8258/Crown Copyright 2014 Published by Elsevier Inc. All rights reserved.

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A. Davis et al. / Gynecologic Oncology 133 (2014) 624631

Introduction
Globally, approximately 224,000 women are diagnosed with ovarian, primary peritoneal or fallopian tube cancer (henceforth referred to
as ovarian cancer) annually with 140,000 deaths [1]. At the time of
diagnosis, most patients have advanced stage disease and despite
debulking surgery and platinum-based chemotherapy, the majority
will experience disease recurrence requiring further treatment. The
most widely used predictor of the likelihood of response to subsequent
platinum-based chemotherapy has been the platinum free interval. Patients with recurrent ovarian cancer are typically categorized as having
either platinum resistant or platinum sensitive disease, based on a
platinum-free interval of less than or greater than 6 months, but some
studies use progression free interval (PFI) to dene PROC. Although
PFI is often considered to be synonymous with platinum-free interval,
it is important to note that these can be different. The PFI is generally dened as the interval from diagnosis to recurrence/progression, which
would include the period on treatment. Clinical studies in ovarian
cancer often use platinum-free interval to dene patient eligibility or
subgroup ie platinum sensitive or resistant, but PFI to measure outcome.
However, it is arguably more useful to think of the probability of platinum response as a continuum rather than xating on arbitrary time
points to dene patient subsets and determine treatment approaches.
The aim of this review is to explore the complexity and heterogeneity of patients with platinum-resistant ovarian cancer (PROC), the potential impact this has on interpretation of clinical trial results and
outline the Gynecologic Cancer InterGroups' (GCIG) recommendations
for better categorizing patients with recurrent ovarian cancer in clinical
trials. We also briey review the mechanisms of platinum resistance,
and treatment options as well as outcomes. Given that the prognosis
for most patients with PROC is poor, and treatment to date has had minimal effect on overall survival, one of the main goals of therapy is palliation and symptom improvement. We discuss the international efforts
that are underway to measure the impact of chemotherapy on symptom
benet, which despite its importance, has mostly been neglected in
measured outcomes of clinical trials to date.

625

detectable disease and/or radiological evidence of disease recurrence


[2,6,7]. These studies were carried out in an era prior to the widespread
use of CA125 to detect recurrence and when radiological techniques
were relatively crude compared to the high resolution CT, MRI and
PET scans now available. It is very likely that the patients in the original
studies were quite different to asymptomatic patients with a rising
CA125 who may be found to have recurrent disease on a CT or PET CT
within 6 months of completing rst line chemotherapy. As both a
CA125 rise and radiologic ndings may precede the clinical recurrence
of ovarian cancer by several months [8], these patients would have historically been considered platinum-sensitive, but are now classied as
platinum-resistant.
The platinum-free interval may therefore be inuenced by the frequency and types of investigations a patient receives during follow up
and this has several important implications. Firstly, patients with early
recurrence of disease detected by PET/CT or high resolution CT may
not be treated with platinum-based therapy due to being inappropriately classied as platinum-resistant. Secondly, this could impact on the
interpretation of results of clinical trials conducted in PROC patients
due to the heterogeneous mix of patients included in these studies.
There is a progressively higher likelihood of response to second-line
platinum-based therapy, and also to non-platinum agents, as the
platinum-free interval increases, see Table 2 [2,9]. Therefore the activity
of new drugs or drug combinations in PROC could appear falsely high if
studies include greater numbers of asymptomatic patients diagnosed
with PROC based purely on a rising Ca125 or with low volume disease
on imaging, as these patients may have inherently more chemotherapy
sensitive disease compared to patients who have symptomatic progression within 6 months of completing rst-line chemotherapy. To complicate matters further, the denition of platinum resistance has been
extended to include patients who relapse within 6 months after second
or multiple lines of chemotherapy and thus patients classied as
platinum resistant are a very heterogeneous group.
To avoid confusion and improve clarity in clinical trials, the GCIG
has proposed that all future trials specify how the recurrence was
established (rising CA125, radiologically or symptomatically) and describe the populations in terms of the interval since last line of platinum,
rather than labeling patients as platinum sensitive or resistant [10].

Platinum resistant disease: what is it?


Patients who initially respond to platinum-based chemotherapy and
who subsequently relapse 6 months or more after their initial treatment have been classied as platinum sensitive and most will respond
to further platinum-based chemotherapy with response rates ranging
from 30% to 90% [25]. The median survival of patients with platinum
sensitive recurrent ovarian cancer is 2 years, but can range from only
a few months to more than a decade. Many patients will receive multiple lines of treatment over time, but with few exceptions will ultimately
develop platinum resistant disease.
Patients who relapse within 6 months of completing rst-line
therapy have been classied as being platinum resistant and typically
have low response rates to subsequent chemotherapy (b 15%), with a
progression free survival of 34 months and a median survival under
a year, see Table 1. The 3 studies originally used to dene platinum resistance determined recurrence based on clinical symptoms, clinically

Relationship between specic histotype and response


to chemotherapy
The most common form of epithelial ovarian cancer is high grade serous cancer (HGSC). The relationship between time-to-recurrence and
platinum-sensitivity is best applied to patients with HGSC, and possibly
high grade endometrioid cancers (EC). Clear cell carcinoma (CCC),
mucinous carcinoma (MC), low grade endometrioid carcinoma and
low grade serous carcinoma (LGSC) are less common histotypes of ovarian cancer which behave very differently to HGSC, with respect to
presentation, clinical course, response to chemotherapy, genetic risk
factors (e.g not BRCA associated) and molecular aberrations and drivers,
see Table 3. In general, CCC, MC and LGSC tend to be resistant to
platinum-based chemotherapy. Patients with advanced or metastatic
CCC or MC have poor clinical outcomes, with median survivals of 20

Table 1
Denitions of platinum response.
Denition

Comments

Platinum free interval


Platinum refractory
Platinum resistant

last platinum dose until progressive disease is documented


progression during or within 4 weeks of platinum-based rst line chemotherapy
relapse b 6 months after 1st line platinum-based chemotherapy.

Platinum sensitive

relapse 6 months after 1st line platinum-based chemotherapy.

subject to the types and frequency of investigations during follow up


median OS 35 months
median PFI ~ 3 months
median OS 912 months
median PFI 912 months
median OS 2436 months

PFS: progression free interval OS: overall survival.

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A. Davis et al. / Gynecologic Oncology 133 (2014) 624631

Table 2
Relationship between progression free interval and response to second-line therapy [2].
Secondary response rates based on duration of prior response
Duration of prior response
(months)

No. of regimens
(N = 211)

Response rate (%)

b12
1217
18

51
60
100

33
55
75

Includes patients who received multiple courses of second-line, platinum based


therapy.

and 14 months, respectively [11]. Historically, all the subtypes of


ovarian cancer were studied together. The inclusion of patients with
these inherently different subtypes of ovarian cancer in clinical studies
of PROC introduces bias and makes it difcult to interpret the results.
At the very least, patients with different histotypes of ovarian cancer
should be stratied and ideally, should be studied independently as
unique diseases.
The Role of BRCA Mutations
Germ-line mutations in BRCA1 and BRCA2 are established risk
factors for the development of HGSC of the ovary and are present in
approximately 1520% of women with ovarian cancer and an even
higher proportion of those with HGSC [12,13]. BRCA mutation carriers
with ovarian cancer have a more favorable clinical course (longer survival rates) and higher responsiveness to platinum-based therapies
[1417]. A recent paper by Alsop et al noted that BRCA mutation carriers
with early recurrence of ovarian cancer (relapse occurring b6 months
following primary therapy including CA125 and radiological imaging
to diagnose recurrence) had a higher chance of response to second-line
chemotherapy with platinum based chemotherapy compared to
BRCA1/2 wildtype cases [12]. While intriguing, this study included
only 17 patients with BRCA mutations and PROC, therefore the ndings need to be conrmed in a larger cohort.
However, knowing the BRCA status could have an impact on clinical
decision-making and based on Alsops' ndings it seems reasonable to
consider retreating patients with BRCA mutations and early recurrence
with platinum-based therapy rather than assuming that they have platinum resistant disease. Clinical trial results may also be inuenced by
the proportion of patients included who have BRCA mutations and to
date this has not been readily available information. The GCIG consensus paper suggested that it would be important to report the proportion
of patients that are germ-line BRCA mutation carriers in clinical trials
and document their response to the preceding platinum treatment
(in addition to time since last platinum treatment) as this could help
interpret the activity of new therapies.
The BRCAness prole
Many sporadic HGSC share phenotypic characteristics with tumors
associated with germ-line BRCA mutations. This so-called BRCAness
phenotype may be due to a variety of mechanisms associated with

defective homologous recombination (HR) which include epigenetic


hypermethylation of the BRCA1 promoter [18,19], somatic mutation of
BRCA1/2 [20,21], amplication of EMSY [22] resulting in BRCA silencing,
loss of function mutations or methylation of the FANCONI anemia
complex [23] and hypermethylation of RAD51C, amongst others.
A correlation between disruption of HR and response to platinum
and other DNR repair targeted therapies including poly(ADP-ribose)
polymerase (PARP) inhibitors, has been shown in several in vitro
studies [2426]. More recently, a BRCAness gene expression prole
based on samples of BRCA1/2-mutated tumors was able to predict platinum and PARP inhibitor responsiveness [27]. This study also found that
BRCAness was of independent prognostic value in a small group of patients with sporadic ovarian cancers, most of whom had HGSC. If this, or
other gene expression proles, can be validated it would be a useful tool
for stratication and patient selection in clinical trials of treatment for
recurrent ovarian cancer. In addition to BRCA mutation status, reporting
the proportion of patients with a BRCAness phenotype in clinical
studies of PROC may also be important, as this may also impact on the
likelihood of response to platinum-based chemotherapy. Combined, patients with BRCA mutations and BRCAness phenotype could represent
over 50% of patients with HGSC [28].
Mechanisms of resistance
The variability in response to platinum chemotherapy of patients
with PROC is probably due to multiple factors including the heterogeneity of patients entered into clinical trials, how recurrence was determined and is also likely to be related to the differing mechanism/s of
resistance. Despite an improved understanding of the complex interplay between clonal selection and the microenvironment of resistant
tumors we still have much to learn about the mechanisms of platinum
resistance, which are complex and multiple [29].
The cytotoxic effect of cisplatin (and its analogs) involves active uptake into cells and subsequent binding to DNA, forming adducts which
then leads to the production of intra-strand and inter-strand crosslinks,
and in turn single or double strand DNA breaks. This DNA damage can
result in activation of the apoptosis cascade and cell death unless the
cell can repair the DNA. Platinum may also cause mitochondrial damage,
which is associated with decreased ATPase activity and cell death [30].
Factors associated with resistance to platinum include those that
limit the formation of cytotoxic platinum-DNA adducts and those that
prevent cell death occurring after platinum-adduct formation [31].
The former may result from either reduced uptake of cisplatin into
cells or increased efux via alterations to transport proteins or by
inactivation of intracellular cisplatin by conversion into cisplatin- thiol
conjugates. The latter form of resistance may occur by increased DNA
repair after adduct formation. There are ve major DNA repair mechanisms including nucleotide excision repair (NER), mismatch repair
(MMR), homologous recombination (HR), base excision repair (BER)
and translesion synthesis. Alterations in various proteins associated
with these repair mechanisms have been associated with platinum resistance, for example high levels of excision repair cross-complementation
group 1 (ERCC1) protein [32], mutations or down-regulation of MLH1,
MSH2 and MSH1 [33] and secondary mutations of BRCA1 or 2, which

Table 3
Clinical features of the different ovarian cancer histotypes.

Portion of cases (%)


Genetic Risk Factors
Precursor Lesions/Cell of Origin
Common stage at presentation
Response to Platinum-based therapy
Molecular aberrations

HGSC

CCC

EC

MC

LGSC

70
BRCA1/2
STIC, p53 signatures
advanced
Chemo-sensitive
p53, BRCA1, BRCA2, HR defects

12
HNPCC
Endometriosis
early
Chemo-resistant, radiosensitive
PI3K, ARID1A, MSI

11
HNPCC/BRCA
Endometriosis
early
Chemo-sensitive
PTEN, bcatenin, ARID1A, MSI

3
none known
not known
early
Chemo-resistant
KRAS, HER2

3
none known
SBT
advanced.
Chemo-resistant
BRAF, KRAS, NRAS

HGSC: high grade serous carcinoma, CCC: clear cell carcinoma, EC: endometrioid carcinoma, MC: mucinous carcinoma, LGSC: low grade serous carcinoma, HNPCC: hereditary nonpolyposis colorectal cancer, STIC: serous tubal intraepithelial carcinoma, HR: homologous recombination, SBT: serous borderline tumor, MSI: microsatellite instability.

A. Davis et al. / Gynecologic Oncology 133 (2014) 624631

can cause reversion to the BRCA genotype and reestablishment of BRCA


function, hence increasing HR [34,35]. These various factors may either
be present at diagnosis or acquired over time.
Recently two models, the cancer stem cell (CSC) model and the environment mediated drug resistance model (EMDR) have been proposed to explain the origin of chemotherapy resistant cells [36]. The
CSC model proposes that genetic and/or epigenetic alterations occurring
in the multi-potent tissue-specic adult stem cells may result in malignant transformation into cancer stem cells. As these cells possess stem
cell-like properties, including the ability for self renewal and cell
division, they multiply forming tumors and with further genetic or epigenetic alterations may develop invasive properties allowing the tumor
to metastasize to distant sites [37,38]. CSC appear to be intrinsically resistant to chemotherapy for a variety of different reasons and may represent a major source of chemoresistant cells within tumors [3941]. In
the EMDR model, resistance emerges as the cancer cells interact with
their surrounding microenvironment and enter a quiescent state due
to the complex interplay between tumor and its microenvironment. It
is recognized that tumors that develop a prominent desmoplastic reaction have a poor prognosis and are associated with platinum resistance
[42].
Patients with primary platinum refractory disease have intrinsic
drug resistance and either do not respond or progress very early on
treatment. Primary platinum refractory ovarian cancers are quite uncommon and are usually seen with non-serous ovarian cancers such
as CCC or MC rather than the more common HGSC. It is likely that the
mechanisms of resistance between these various histotypes are very
different and beyond the scope of this review. Patients who have an initial response to platinum chemotherapy are believed to have tumors
with a heterogeneous population of both intrinsically platinum resistant
cells and also sensitive cells. The sensitive cells undergo apoptosis
following chemotherapy (tumor response) but the resistant subpopulation of cells persist and expand leading to early recurrence in platinum resistant disease. Platinum sensitive patients may respond
recurrently to platinum, due to the regrowth of the sensitive population.
Ultimately however, the sensitive cells may alter or mutate, rendering
them resistant, or the resistant cell population will outgrow the
sensitive population.
Tumor heterogeneity
Beyond the recognition of different histotypes of ovarian cancer, the
genomic heterogeneity within tumors of the same histotype has recently been described. The Cancer Genome Atlas (TCGA) Research Network
recently completed a thorough genomic analysis involving 489 HGSC
[28]. They found p53 mutations were almost universal (96%) and
BRCA mutations common (22%, both germ line and somatic mutations),
but other mutations were uncommon (26%). However, there was a
striking degree of genomic instability with frequent somatic copy
number alterations. Gene expression arrays demonstrated at least
four distinct subtypes based on gene clustering, which they termed immunoreactive, differentiated, proliferative and mesenchymal. They conrmed the ndings by Bowtell's group who performed gene expression
arrays on 285 serous and endometrioid ovarian cancers and identied 6
separate molecular subtypes associated with different molecular, histological characteristics as well as patient outcomes [43]. The subgroups
identied by the two groups were shown to correlate [28]. Further
work is required to determine the impact of the different molecular
subtypes on likelihood of response to chemotherapy.
Heterogeneity also exists spatially within the primary tumor and between the primary and the metastases and has also been shown to exist
temporally, when repeat biopsies are taken at different time points during the disease course [44,45]. This heterogeneity adds signicantly to
the complexity of assessing or interpreting response to treatments
and outcomes in patients. This is supported by anecdotal clinical observations of patients with a differential response to treatment with

627

progression in one site and response in other sites. There are currently
no established mechanisms for capturing how common this is, and no
guidance or consensus on appropriate management of these patients.
In future studies, particularly of targeted therapies, repeat biopsies
both at the time of recurrence and following further treatment will
be essential to gain a better understanding of the mechanisms of
resistance.
Platinum resistant disease: outcomes of therapy
There have been numerous phase 2 studies conducted in patients
with PROC. Table 4 summarizes the published Gynecologic Oncology
Group (GOG) phase 2 studies of chemotherapy in this patient population. These studies appear to show an incremental increase in the response rate (dened by the RECIST criteria) over time, which may be
explained in several ways. Firstly, this may represent real improvements in therapy, with more effective agents being studied over time.
More likely, this observation may be an artifact of patient selection
and the changing population of PROC, for the reasons described in detail
earlier. Furthermore, it is uncertain how many patients with germ-line
BRCA mutations or somatic impairment in HR (BRCAness) were
included, which as discussed, may also affect likelihood of response.
To date, Phase 2 results involving targeted therapies have been disappointing, with the exception of bevacizumab, with response rates
b10% in most studies (see Table 5). Bevacizumab, a recombinant humanized monoclonal antibody that targets vascular endothelial growth
factor (VEGF)-A has single agent activity in recurrent ovarian cancer of
between 16 and 21% [46,47] and also has shown encouraging activity
in PROC when combined with oral cyclophosphamide or weekly
paclitaxel [4850].
Phase 3 studies involving combinations of non-platinum chemotherapy agents or combinations of chemotherapy and targeted agents
have often included PROC patients as a subgroup only. Until recently,
none had shown a signicant improvement in PFI or overall survival
(OS), with a consistent median PFI of 34 months and OS approximately 12 months, see Table 6. Two recently presented studies, involving
chemotherapy plus and an anti-angiogenic agent, have shown an improved PFI in PROC. The AURELIA study (involving chemotherapy
combined with bevacizumab) showed an almost doubling of the
PFI (3.4 vs 6.7 months, HR 0.48, p b 0.001) with the addition of
Table 4
Published GOG Phase 2 clinical trials with chemotherapy conducted in platinum-resistant
ovarian cancer.
RR (%)

Year of
publication

Study

Agent

2011

GOG-126R

Nanoparticle, albumin-bound
(nab) paclitaxel
Docetaxel + trabectidin
Ixabepilone
Irofulven
Pemetrexed
Paclitaxel poliglumex
Karenitecin
Cisplatin + gemcitabine
Paclitaxel weekly
Capecitabine
9-aminocampthothecan
Docetaxel
Oxaliplatin
Paclitaxel + valspodar (PSC833)
CI-958
Altretamine
(hexamethylmelamine)

47^

2010
2009
2008
2006
2005
2003
2001
2000
1998

GOG-186 F
GOG 126 M
GOG 146O
GOG 126Q
GOG 186C
GOG 186D
GOG 126 L
GOG 126 N
GOG 146 L
GOG 126I
GOG 126 J
GOG 126 K
GOG 126E
GOG 126G
GOG 126C

response rate calculated for all evaluable patients.


^
Patients with platinum free interval b 6 months.
#
b12 months.
612 months.
^^
Platinum refractory.

23
#

53 /71
49^
61^^
51^
25^/49#
18^/26
57^
48^
27
58^
60^
23^
58^^
25^
36^

30
14.3
12.7
21
16
12
16
20.9
8
14
22.4
4.3
8.6
4
10

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A. Davis et al. / Gynecologic Oncology 133 (2014) 624631

Table 5
Published GOG phase 2 clinical trials with targeted therapies conducted in platinum resistant ovarian cancer (generally dened as platinum free interval b12 months).
Year of publication

Study

Agent

RR (%)

PFS 6# (%)

2012

GOG 126 T
GOG 170G
GOG170M
GOG 170 N
GOG 170I
GOG 170 F
GOG 170 J
GOG 170 K
GOG 170H
GOG 170E
GOG 170D
GOG 170C
GOG 126B

Belinostat/carboplatin
Lapatinib
Dasatinib
Urokinase-derived peptide (A6)
Temsirolimus
Sorafenib
Enzastaurin
Mifopristone
Vorinostat
Imatinib
Bevacizumab
Getinib
Cisplatin + cyclosporine A

29
28
34
31
40^/54
50^/59
16^/27
24
27
56
26^/62
27
26^

7.4
0
0
0
9.3
3.4
7
4.5
3.7
1.8
21
4
11.5

8
20.6
6.5
24.1
24
11

7.4
16
40.3
14.8

2011

2010
2008
2007
2005
1998

Based on evaluable patients and includes all those with platinum free interval b12 months.
^
patients with platinum free interval b6 months.
#
PFS: progression free survival.

bevacizumab, but no improvement in OS (13.3 vs 16.6 months, HR 0.85,


p = 0.171 [51]. Of note, 40% of patients in the chemotherapy alone
arm received bevacizumab on progression. The TRINOVA 1 study
(paclitaxel chemotherapy combined with an angiopoietin 1/2 inhibitor,
trebananib) also showed an improvement in PFI (5.4 vs 7.2 months, p
b 0.001) [52]. Also, a randomized Phase 2 study, PRECEDENT, examining the addition of EC145, a folate targeted vinca alkaloid to liposomal
doxorubicin has shown an improved PFI (2.7 vs 5 months, p = 0.031)
with the addition of EC145 [70] and the subsequent Phase 3 study
(PROCEED) is still accruing.
Who to treat, how to treat and for how long?
Using the widely accepted denition of platinum resistant disease
ie. recurrence diagnosed within 6 months of completion of rst or

subsequent-line platinum-based chemotherapy, this will include


asymptomatic patients with no detectable disease on imaging and a rising CA125, those with small volume recurrence who are also usually
asymptomatic and patients with rapidly progressive, larger volume,
symptomatic disease. Within this heterogeneous group of patients
there will be a subset that will respond to further platinum therapy,
but predicting who will benet is very difcult and based on best
guess rather than objective criteria. Until such time when we can better
determine if a patient will derive benet from further platinum it seems
reasonable to consider platinum therapy either as a single agent or in
combination with other agents on a case by case basis, particularly
when patients fall into a grey zone, for example prior response to platinum based chemotherapy and progress within 46 months after last
platinum treatment. Carboplatin is generally well tolerated but recurrent lines of therapy are known to increase the risk of a hypersensitivity

Table 6
Phase 3 clinical trials in platinum resistant ovarian cancer.
Drugs

RR (%)

PFS
(months)

OS
(months)

Comments and References

Paclitaxel
Topotecan
Paclitaxel
Weekly paclitaxel
Topotecan
PLD
Paclitaxel
Paclitaxel + epidoxorubicin
PLD
Gemcitabine
Topotecan
Treosulfan
PLD or Topotecan
Canfosfamide
PLD
PLD/Trabectedin
PLDPatupilone

59
60
57
51
124
130
90
91
96
99
57
57
229
232
117
115
417
412
72
70

6.7
13.3
26
19
6.5
12.3
46.9
37.4
8.3
6.1
19.3
7
10.9
4.3

9.5a
8.2a

7.9
15.5
1
0

3.1a
2.1a
6
6
3.1
3.6
4.2a
2.2a
4.3
2.3
3.7
4
3.7
3.7
4.6a
3.5a

Subgroup data
[60]
Subgroup data
[61]
Subgroup data
[62]
Partial platinum resistance (73% b6mo)
[63]
[64]

182
179

12
31

3.4
6.7

13.3
16.6

PFS p = 0.001
OS p = 0.17
[51]

919 total

30
38

5.4
7.2

17.3
19

PFS p b 0.001
OS NS
[52]

OVATURE
weekly carboplatin
+/phenoxodiol
AURELIA
PLD/Topotecan/
weekly Paclitaxel
+/bevacizumab
TRINOVA 1
weekly paclitaxel
+/trebananib

RR: response rate, PFS: progression free survival, OS: overall survival.
PLD: pegylated liposomal doxorubicin.
a
converted from weeks to months.

13.5
12.7
11.2a
7.3a
13.5
8.5

12.7
13.2
10.5a
8.8a

Pre-planned sub-stratum of platinum resistant [65]


A trial of 3rd line therapyexperimental arm inferior [66]
Subgroup analysis
[67]
[68]
Closed early
[69]

A. Davis et al. / Gynecologic Oncology 133 (2014) 624631

reaction and combination therapy is generally more toxic than single


agent therapy. As there is no evidence for a survival benet from early
reintroduction of chemotherapy in asymptomatic patients with early
recurrence, as determined by Ca125 progression alone [53], treatment
should be delayed until patients are symptomatic or based on imaging
ndings expected to become symptomatic in the near future.
Determining which patients with clearly platinum-resistant or
platinum-refractory ovarian cancer will benet from treatment and
how to select patients for treatment is complex and is not clinically
well dened. Clinicians typically rely on patient factors to direct such
decisions including patient performance status and desire for additional
therapy, presence/persistence of toxicity from prior lines of treatment,
and symptoms needing palliation. On average, 1015% of patients
with PROC have an objective response to treatment and therefore a
trial of therapy in appropriately selected, and informed, patients with
an ECOG PS of 02 is reasonable and includes selecting patients who
would meet the eligibility criteria for inclusion into clinical trials. It is
less certain what the benet of treatment is in patients with a poor performance status and rapidly progressive disease and good palliative care
is probably the most important intervention in this setting.
Chemotherapy is most often given as single agents, used sequentially in suitably selected patients. Commonly used chemotherapy drugs include paclitaxel, liposomal doxorubicin, topotecan, gemcitabine and
etoposide, amongst others. The choice of agent for an individual patient
is dependent on the history of prior treatment, residual toxicities,
patient preferences in terms of toxicity and the availability, cost and
convenience of treatments. Consideration should be given to adding
bevacizumab to chemotherapy in select patients, although this requires
an open discussion with the patient regarding the lack of proven survival benet, added toxicities and practical concerns such as potential cost.
Whether other targeted agents will have a role in the future remains to
be determined.
Chemotherapy-response assays
Currently it is not possible to condently predict the likelihood of an
individual patient's response to chemotherapy or targeted therapy.
There have been a number of retrospective studies examining the correlation between chemo-response assays and patient outcomes in ovarian
cancer but results have been inconsistent [5456]. More recently, a prospective, multi-institutional study involving 262 women with recurrent
or persistent ovarian cancer, found that patients treated with an assay
sensitive regimen had signicantly improved PFS and OS, while no difference in outcomes was seen between the intermediate and resistant
groups [57]. The majority of the patients (68%) had HGSC and 45%
were platinum resistant. Patients were treated with one of 15 prospectively specied protocol treatments, determined by the treating oncologist, who was blinded to the results of the assay during the initial
treatment phase, but was able to review assay results at disease
progression. The association with assay response was consistent in platinum sensitive and platinum resistant tumors. These results are interesting and if conrmed in prospective studies may provide a very
useful tool for individualizing drug selection.
How long to treat and how many lines of therapy?
The likelihood of clinical benet or response to second-line platinum
based chemotherapy correlates with the time interval between primary
chemotherapy and relapse. With subsequent lines of therapy it is recognized that the likelihood of response and the duration of response reduces signicantly. Hoskins et al retrospectively reviewed 120 women
with recurrent ovarian cancer (both platinum sensitive and resistant)
and determined that an interval of b6 months between two consecutive relapses was predictive of poor survival, and might be used to
determine whom not to treat or when to stop [58]. Grifths et al subsequently reviewed 274 women with PROC and conrmed that efcacy

629

declined rapidly with successive lines of therapy, in particular when


the patient had primary platinum refractory disease. Patients were unlikely to benet from further chemotherapy after failure of two lines
of therapy. Given the high likelihood that further chemotherapy will
be ineffective in heavily pretreated patients with resistant/refractory
disease and the inevitable toxicities associated with treatment, it is
important that clinicians discuss the option of supportive care alone as
this may well provide the best palliation.
What to measure
Standard endpoints for clinical trials of new agents or combinations
include RECIST and CA125 response as well as PFS and OS. Clinical trials
generally include patients with good performance status and younger
age, which may not be representative of the general patient population.
As most studies have shown only a minority of patients with PROC will
have an objective response by RECIST or CA125 and that the median PFS
is only 34 months, how can we determine whether patients are
obtaining a symptomatic or palliative benet from treatment?
There have been very few studies in PROC that have included a measure of quality of life (QoL), and none that have shown improved QoL or
symptom palliation, despite this being the main goal of treatment. There
is a general perception among oncologists that more patients appear to
subjectively benet from treatment than are shown to meet criteria for
response, but this has been poorly studied. In a small study, 5060% of
patients appeared to benet in terms of quality of life and emotional
well being, while objective responses were seen in only 7 of 27 (26%)
[59]. There is general consensus that we need an accurate measure of
the palliative benet of treatment to weigh against the toxicity of treatment, particularly in the setting of platinum resistant disease where response rates are low and of short duration. However, before we can
assess changes in QoL and symptom benet we need to better understand what the cancer related symptoms are, how frequently they
occur, how important they are to the patient and whether we can
reliably measure them. There are a number of validated QoL tools available. Some are generic (SF-36, SF-12), others cancer specic (QLQ-C30,
FACT-G, CARES-SF), disease specic (QOL-OVCA, QLQ-OV28, FACT-O for
ovarian) or symptom specic (FACT-Anemia and FACIT-Fatigue), but
none have been designed to specically measure symptom benet in
the recurrent disease setting. The GCIG Symptom Benet study, is currently recruiting, and aims to validate a measure of symptom benet
that can be used as an endpoint in trials in PROC as well as prognostic
models to predict which patients are most likely to benet from further
chemotherapy.
Conclusion
Platinum resistant ovarian cancer patients should not be regarded as
a homogeneous and distinct population dened simply by the interval
from the last platinum chemotherapy or the time to recurrence. Ovarian
cancer is a complex malignancy and is comprised of multiple histological subtypes, with numerous genotypes and phenotypes within each
histotype, which all potentially impact on biological behavior and
response to chemotherapy. It is also a dynamic disease process with genetic and epigenetic alterations occurring and evolving both over time
and at different metastatic sites of disease.
The GCIG has proposed that, rather than making assumptions about
likelihood of response to treatment and labeling or categorizing recurrent ovarian cancer as platinum sensitive or resistant, it is more
important to specify the time from last platinum therapy and use this
to categorize patients included in clinical trials as well as stratifying
for the various histotypes. Information about BRCA, BRCAness phenotype and any future relevant genomic information, should also be documented where-ever possible, given the potential impact on response to
platinum-based chemotherapy.

630

A. Davis et al. / Gynecologic Oncology 133 (2014) 624631

In the future it may be possible to determine whether a patient is


likely to be sensitive or resistant to platinum or other agents, but until
then we must rely on clinical parameters such as ECOG performance
status, previous treatment history and residual toxicities when selecting
treatment. Importantly, we also need to ensure that patients with PROC
are deriving a meaningful benet from palliative treatment, particularly
given their poor prognosis.
Conict of interest statement
MF has received an honorarium for participation on a Roche advisory board. The other
authors declare that they have no conicts of interest to disclose.

References
[1] GLOBOCAN 2008 v1.2 Cancer Incidence and Mortality Worldwide [Internet]; 2010.
[2] Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Secondline platinum therapy in patients with ovarian cancer previously treated with
cisplatin. J Clin Oncol 1991;9(3):38993.
[3] Rose PG, Fusco N, Fluellen L, Rodriguez M. Second-line therapy with paclitaxel and
carboplatin for recurrent disease following rst-line therapy with paclitaxel and
platinum in ovarian or peritoneal carcinoma. J Clin Oncol 1998;16(4):14947.
[4] Balbi G, Di Prisco L, Musone R, Menditto A, Cassese E, Balbi C, et al. Second-line with
paclitaxel and carboplatin for recurrent disease following rst paclitaxel and platinum compounds in ovarian carcinoma. Eur J Gynaecol Oncol 2002;23(4):3479.
[5] Hoekstra AV, Hurteau JA, Kirschner CV, Rodriguez GC. The combination of monthly
carboplatin and weekly paclitaxel is highly active for the treatment of recurrent
ovarian cancer. Gynecol Oncol 2009;115(3):37781.
[6] Blackledge G, Lawton F, Redman C, Kelly K. Response of patients in phase II studies of
chemotherapy in ovarian cancer: implications for patient treatment and the design
of phase II trials. Br J Cancer 1989;59(4):6503.
[7] Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of
the ovary with cisplatin or carboplatin following initial treatment with these
compounds. Gynecol Oncol 1990;36(2):20711.
[8] Goonewardene TI, Hall MR, Rustin GJ. Management of asymptomatic patients on
follow-up for ovarian cancer with rising CA-125 concentrations. Lancet Oncol
2007;8(9):81321.
[9] Bookman MA, Malmstrom H, Bolis G, Gordon A, Lissoni A, Krebs JB, et al. Topotecan
for the treatment of advanced epithelial ovarian cancer: an open-label phase II study
in patients treated after prior chemotherapy that contained cisplatin or carboplatin
and paclitaxel. J Clin Oncol 1998;16(10):334552.
[10] Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, et al.
Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011;21(4):7715.
[11] Mackay HJ, Brady MF, Oza AM, Reuss A, Pujade-Lauraine E, Swart AM, et al. Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial
ovarian cancer. Int J Gynecol Cancer 2010;20(6):94552.
[12] Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive
women with ovarian cancer: a report from the Australian Ovarian Cancer Study
Group. J Clin Oncol 2012;30(21):265463.
[13] Schrader KA, Hurlburt J, Kalloger SE, Hansford S, Young S, Huntsman DG, et al.
Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histologybased referral strategy. Obstet Gynecol 2012;120(2 Pt 1):23540.
[14] Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, et al. Effect
of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol
2002;20(2):4636.
[15] Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in
women with BRCA-associated ovarian carcinoma. Cancer 2003;97(9):218795.
[16] Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. BRCAness
syndrome in ovarian cancer: a casecontrol study describing the clinical features
and outcome of patients with epithelial ovarian cancer associated with BRCA1 and
BRCA2 mutations. J Clin Oncol 2008;26(34):55306.
[17] Vencken PM, Kriege M, Hoogwerf D, Beugelink S, van der Burg ME, Hooning MJ, et al.
Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after rst-line chemotherapy compared with sporadic ovarian cancer patients.
Ann Oncol 2011;22(6):134652.
[18] Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, et al. BRCA1 promoter
region hypermethylation in ovarian carcinoma: a population-based study. Cancer
Res 2000;60(19):532933.
[19] Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, et al. Promoter
hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors.
J Natl Cancer Inst 2000;92(7):5649.
[20] Foster KA, Harrington P, Kerr J, Russell P, DiCioccio RA, Scott IV, et al. Somatic and
germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res
1996;56(16):36225.
[21] Hilton JL, Geisler JP, Rathe JA, Hattermann-Zogg MA, DeYoung B, Buller RE. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 2002;94(18):1396406.
[22] Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, et al. EMSY links the
BRCA2 pathway to sporadic breast and ovarian cancer. Cell 2003;115(5):52335.
[23] Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, et al.
Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian
tumors. Nat Med 2003;9(5):56874.

[24] McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deciency in
the repair of DNA damage by homologous recombination and sensitivity to
poly(ADP-ribose) polymerase inhibition. Cancer Res 2006;66(16):810915.
[25] D'Andrea AD. The Fanconi Anemia/BRCA signaling pathway: disruption in cisplatinsensitive ovarian cancers. Cell Cycle 2003;2(4):2902.
[26] Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, Curto J, et al. CpG island methylation of DNA damage response genes in advanced ovarian cancer. Cancer Res
2005;65(19):89617.
[27] Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N,
et al. Gene expression prole of BRCAness that correlates with responsiveness to
chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin
Oncol 2010;28(22):355561.
[28] Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian
carcinoma. Nature 2011;474(7353):60915.
[29] Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular
mechanisms of cisplatin resistance. Oncogene 2012;31(15):186983.
[30] Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance.
Oncogene 2003;22(47):726579.
[31] Tapia G, Diaz-Padilla I, editors. Molecular Mechanisms of Platinum resistance in
Ovarian cancer; 2013.
[32] Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E. Messenger RNA levels of
XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinumbased chemotherapy. J Clin Invest 1994;94(2):7038.
[33] Helleman J, van Staveren IL, Dinjens WN, van Kuijk PF, Ritstier K, Ewing PC, et al. Mismatch repair and treatment resistance in ovarian cancer. BMC Cancer 2006;6:201.
[34] Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1
mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer
Res 2008;68(8):25816.
[35] Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary
mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature
2008;451(7182):111620.
[36] Zahreddine H, Borden KL. Mechanisms and insights into drug resistance in cancer.
Front Pharmacol 2013;4:28.
[37] Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer
2005;5(4):27584.
[38] Massard C, Deutsch E, Soria JC. Tumour stem cell-targeted treatment: elimination or
differentiation. Ann Oncol 2006;17(11):16204.
[39] Mimeault M, Hauke R, Mehta PP, Batra SK. Recent advances in cancer stem/progenitor
cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med 2007;11(5):9811011.
[40] Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer
chemoresistance by preferential expression of the Akt/PKB survival pathway.
Oncogene 2008;27(12):174958.
[41] Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct
populations of cancer stem cells determine tumor growth and metastatic activity
in human pancreatic cancer. Cell Stem Cell 2007;1(3):31323.
[42] Helleman J, Jansen MP, Burger C, van der Burg ME, Berns EM. Integrated genomics of
chemotherapy resistant ovarian cancer: a role for extracellular matrix, TGFbeta and
regulating microRNAs. Int J Biochem Cell Biol 2010;42(1):2530.
[43] Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular
subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.
Clin Cancer Res 2008;14(16):5198208.
[44] Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):88392.
[45] Bashashati A, Ha G, Tone A, Ding J, Prentice LM, Roth A, et al. Distinct evolutionary
trajectories of primary high-grade serous ovarian cancers revealed through spatial
mutational proling. J Pathol 2013;231(1):2134.
[46] Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al.
Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer
or peritoneal serous cancer. J Clin Oncol 2007;25(33):51806.
[47] Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in
persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a
Gynecologic Oncology Group Study. J Clin Oncol 2007;25(33):516571.
[48] Chura JC, Van Iseghem K, Downs Jr LS, Carson LF, Judson PL. Bevacizumab plus cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Gynecol
Oncol 2007;107(2):32630.
[49] Sanchez-Munoz A, Mendiola C, Perez-Ruiz E, Rodriguez-Sanchez CA, Jurado JM,
Alonso-Carrion L, et al. Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Oncology
2010;79(12):98104.
[50] Markman M. Addition of bevacizumab to weekly paclitaxel signicantly improves
progression-free survival in heavily pretreated recurrent epithelial ovarian cancer.
Gynecol Oncol 2012;124(1):171 [author reply -2].
[51] Witteveen P, Lortholary A, Fehm T, Poveda A, Reuss A, Havsteen H, et al. FInal overall
survival (OS) results from AURELIA, an open-label randomised phase III trial of
chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant
recurrent ovarian cancer (OS). European Cancer Congress LBA 5. Eur J Cancer
2013;49(Suppl. 3):S3.
[52] Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae DS, et al. A phase III, randomized, double-blind trial of weekly paclitaxel plus the angiopoeitin 1 and 2 inhibitor, trabananib, or placebo in women with recurrent ovarian cancer: TRINOVA-1.
European Cancer Congress LBA 41. Eur J Cancer 2013;49(Suppl. 2):S18.
[53] Rustin GJ, van der Burg ME, Grifn CL, Guthrie D, Lamont A, Jayson GC, et al. Early
versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a
randomised trial. Lancet 2010;376(9747):115563.

A. Davis et al. / Gynecologic Oncology 133 (2014) 624631


[54] Holloway RW, Mehta RS, Finkler NJ, Li KT, McLaren CE, Parker RJ, et al. Association
between in vitro platinum resistance in the EDR assay and clinical outcomes for
ovarian cancer patients. Gynecol Oncol 2002;87(1):816.
[55] Gallion H, Christopherson WA, Coleman RL, DeMars L, Herzog T, Hosford S, et al.
Progression-free interval in ovarian cancer and predictive value of an ex vivo
chemoresponse assay. Int J Gynecol Cancer 2006;16(1):194201.
[56] Herzog TJ, Krivak TC, Fader AN, Coleman RL. Chemosensitivity testing with
ChemoFx and overall survival in primary ovarian cancer. Am J Obstet Gynecol
2010;203(1) [68 e1-6].
[57] Rutherford T, Orr Jr J, Grendys Jr E, Edwards R, Krivak TC, Holloway R, et al. A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. Gynecol Oncol
2013;131(1):276.
[58] Hoskins PJ, Le N. Identifying patients unlikely to benet from further chemotherapy:
a descriptive study of outcome at each relapse in ovarian cancer. Gynecol Oncol
2005;97(3):8629.
[59] Doyle C, Crump M, Pintilie M, Oza AM. Does palliative chemotherapy palliate?
Evaluation of expectations, outcomes, and costs in women receiving chemotherapy
for advanced ovarian cancer. J Clin Oncol 2001;19(5):126674.
[60] ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, et al.
Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.
J Clin Oncol 1997;15(6):218393.
[61] Rosenberg P, Andersson H, Boman K, Ridderheim M, Sorbe B, Puistola U, et al.
Randomized trial of single agent paclitaxel given weekly versus every three weeks
and with peroral versus intravenous steroid premedication to patients with ovarian
cancer previously treated with platinum. Acta Oncol 2002;41(5):41824.
[62] Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial
ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin
versus topotecan. J Clin Oncol 2001;19(14):331222.
[63] Buda A, Floriani I, Rossi R, Colombo N, Torri V, Conte PF, et al. Randomised controlled
trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients
with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the Mario Negri Institute, Milan, G.O.N.O.

[64]

[65]

[66]

[67]

[68]

[69]

[70]

631

(Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo)
group. Br J Cancer 2004;90(11):21127.
Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, et al.
Randomized phase III trial of gemcitabine compared with pegylated liposomal
doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol
2007;25(19):28118.
Meier W, du Bois A, Reuss A, Kuhn W, Olbricht S, Gropp M, et al. Topotecan versus
treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse
within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie
Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2009;114(2):199205.
Vergote I, Finkler N, del Campo J, Lohr A, Hunter J, Matei D, et al. Phase 3 randomised
study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or
topotecan as third-line therapy in patients with platinum-refractory or -resistant
ovarian cancer. Eur J Cancer 2009;45(13):232432.
Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al.
Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer.
J Clin Oncol 2010;28(19):310714.
Colombo N, Kutarska E, Dimopoulos M, Bae DS, Rzepka-Gorska I, Bidzinski M, et al.
Randomized, open-label, phase III study comparing patupilone (EPO906) with
pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with
recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer.
J Clin Oncol 2012;30(31):38417.
Fotopoulou C, Vergote I, Mainwaring P, Bidzinski M, Vermorken JB, Ghamande SA,
et al. Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with
or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III
OVATURE multicenter randomized study. (published online ahead of print Dec 10,
2013) Ann Oncol; 2013. http://dx.doi.org/10.1093/annonc/mdt515.
Naumann RW, Coleman R, Burger C, Sausville EA, Kutarska E, Ghamande SA, et al.
PRECEDENT: A randomised phase II trial comparing Vintafolide (EC145) and
pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients
with platinum-resistant ovarian cancer. J Clin Oncol 2013;31(35):44008.