Você está na página 1de 8

Clinical trial results continue to

clarify optimal management of

patients with ovarian cancer.

J. L. Munro. Sandy Neck Light House, Cape Cod. Mixed media on canvas, 18 24.

Current and Future Directions of

Clinical Trials for Ovarian Cancer
Ginger J. Gardner, MD, and Elizabeth L. Jewell, MD
Background: The management of ovarian cancer includes a combination of surgery and chemotherapy. The
majority of clinical trials have historically addressed questions pertaining to the selection, dosing, and schedule
of chemotherapy agents.
Methods: In this report, a comprehensive review of the major clinical trials in ovarian cancer is performed. The
increasing data and clinical experience in the management of ovarian cancer, as it sets the stage for currently
active protocols and future clinical trial design, are emphasized.
Results: Paclitaxel plus carboplatin is the primary intravenous treatment strategy in the front-line setting.
Recent data show an improvement in overall survival for intravenous dose-dense treatment. Multiple randomized
controlled trials support the use of intraperitoneal treatment. For recurrent disease, a growing number of new
agents including targeted therapeutics are now available. Increasingly, surgical approach, biologic targets, and
quality of life endpoints are included in clinical trial design.
Conclusions: Over the last several decades, clinical trials have defined the current therapeutic approach for ovarian
cancer. Paclitaxel with a platinum-based agent is currently the preferred front-line therapy, with encouraging data
to support either dose-dense or intraperitoneal drug delivery. Future trials will determine the role of biologic agents
and vaccine therapies, as well as their impact on quality of life.

The management of ovarian cancer encompasses a combination of surgical resection and chemotherapy. Over
the last several decades, clinical trial results have led to
an evolution in the management of ovarian cancer. In
From the Gynecology Service, Department of Surgery at the Memorial Sloan-Kettering Cancer Center, New York, New York.
Submitted June 28, 2010; accepted August 13, 2010.
Address correspondence to Ginger J. Gardner, MD, Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer
Center, 1275 York Avenue, H-1313, New York, NY 10065. E-mail:
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
44 Cancer Control

2006, for the first time, a median overall survival (OS)

of greater than 5 years was reported among advancedstage ovarian cancer patients treated in a randomized
controlled trial setting.1
Clinical trials continue to address important questions pertaining to the combination of surgery and
chemotherapy, the identification of new targeted therapeutics, and the route and timing of chemotherapy administration. In addition, there is a growing interest in
trial design that incorporates quality of life endpoints
as well as tissue acquisition for translational studies to
further identify the underlying mechanisms of ovarian
cancer growth, metastasis, and development of chemoresistance. This report discusses current and future directions of ovarian cancer clinical trials, with an emphasis
January 2011, Vol 18, No.1

on the prioritization of future research efforts for this

challenging disease.

Primary Treatment
Intravenous Treatment
Landmark studies have established paclitaxel plus carboplatin as the primary intravenous (IV) treatment strategy
for epithelial ovarian cancer. A study by the Gynecologic
Oncology Group (GOG 111) demonstrated a survival
benefit of cisplatin and paclitaxel in comparison to cisplatin and cyclophosphamide.2 This was followed by GOG
158, which demonstrated that carboplatin plus paclitaxel
is at least as effective as cisplatin plus paclitaxel, but with
less renal toxicity.3 These results prompted the Gynecologic Cancer Intergroup (GCIG) to publish consensus
guidelines that favor carboplatin and paclitaxel as the
comparator arm for future clinical trials.4
As new chemotherapy agents have been identified
and shown activity for recurrent disease, GOG 182ICON5 was established to determine if additional cytotoxic agents in the front-line setting would further
extend progression-free survival (PFS) or OS.5 This 5-arm
randomized controlled trial utilized paclitaxel and carboplatin IV every 3 weeks for 8 cycles as the control arm.
Topotecan, gemcitabine, and pegylated liposomal doxorubicin were each evaluated either as a part of triple drug
therapy or in sequential doublets. Interim analysis failed
to demonstrate superiority of any of the experimental
arms, and the trial was closed in 2004. Paclitaxel plus
carboplatin remains the standard front-line IV therapy.
Despite its negative results, this study was significant in
its large-volume global accrual, and it sets the stage for
future international cooperative group trials.
Recent studies have addressed the frequency of IV
treatment. In a randomized phase III trial, a dose-dense
regimen of weekly paclitaxel in combination with carboplatin every 3 weeks showed a statistically significant
improvement in PFS: 28.0 months compared to a PFS
of 17.2 months in patients receiving a standard 3-week
dosing of both agents.6 OS at 3 years was also higher in
the dose-dense group: 72.1% compared to 65.1% in the
conventional treatment group (hazard ratio [HR] = 0.75;
confidence interval [CI], 0.570.98). These results favor
a dose-dense regimen; however, patient dropout due to
toxicity was higher in the dose-dense group, primarily
related to hematologic side effects.
During a similar study period, the GOG evaluated the
addition of a targeted therapeutic, bevacizumab, to the
standard IV paclitaxel/carboplatin regimen administered
every 3 weeks. Bevacizumab is a monoclonal antibody
that neutralizes the vascular endothelial growth factor
(VEGF)-A, the predominantly active species of VEGF, and
thereby inhibits angiogenesis. In GOG 218, paclitaxel and
carboplatin IV every 3 weeks served as the control arm.
The experimental arms included concurrent bevacizumab
at 15 mg/kg, with one arm continuing bevacizumab as
January 2011, Vol 18, No.1

maintenance therapy for an additional 16 cycles after the

primary chemotherapy regimen was complete. A preliminary announcement of GOG 218 demonstrated a benefit
of treatment with bevacizumab but only when bevacizumab is continued as maintenance therapy. Results of
this trial presented at the 2010 meeting of the American
Society of Clinical Oncology (ASCO) reported a 3.8-month
improvement in PFS.7 OS results are pending.
Intraperitoneal Treatment
Concurrent with the developments in IV treatment,
intraperitoneal (IP) treatment has also been shown to
be a valuable strategy. IP chemotherapy is designed to
lev-erage the pharmacokinetic profile of chemotherapeutic agents and thereby deliver higher doses into the
anatomic compartment that is at greatest risk for disease
regrowth. The majority of IP treatment stays within
the peritoneal compartment, with limited deep tissue
penetration; therefore, it is indicated only for patients
who have completed an optimal cytoreductive surgery.
To date, three randomized controlled trials have been
conducted by the GOG as well as several international
studies that have shown a benefit of IP treatment among
optimally debulked patients.1,8-13 GOG 172, the most
recent GOG study, evaluated paclitaxel and cisplatin as
either an IV only or as an IV/IP combination. A significant
benefit in OS was identified: 65.6 months in the IP arm
and 49.7 months in the IV only arm (Fig 1). This benefit
in OS was demonstrated despite the fact that only 42% of
patients were able to complete 6 cycles of IP treatment.
Grade 3/4 toxicities were higher in the IP treated group.
The substantial benefit in OS in this study, as well as the
results of multiple prior studies identifying a benefit of IP
treatment, led the NCI to issue a clinical alert that patients
with newly diagnosed optimally debulked ovarian cancer
should be considered for IP treatment.
Subsequent studies have sought to identify a dose
and schedule with less toxicity than the GOG 172 trial.
GOG 9916 and 9917 were opened to evaluate IP carboplatin. Konner et al14 reported on a phase II trial from
Memorial Sloan-Kettering Cancer Center using a modified 172 regimen in combination with bevacizumab. In
comparison with GOG 172, the day 1 IV paclitaxel was
modified from a 24-hour infusion to a 3-hour infusion,
and the day 2 IP cisplatin dose was decreased from 100
mg/m2 to 75 mg/m2. The day 8 IP paclitaxel remained
the same. With cycle 2, bevacizumab at 15 mg/m2 was
included on day 1 of treatment. At interim analysis, 80%
of patients either had completed 6 cycles or were continuing on protocol with this IP regimen. Grade 3/4
toxicities occurred in approximately 10% of patients,
with the exception of neutropenia, which occurred in
26% of patients. These data suggest that the addition of
bevacizumab to this IV/IP regimen is feasible and preliminarily indicates a high rate of successful completion
of IP therapy with limited toxicity.
Cancer Control 45

Taken together, recent clinical trials suggest there

may be a benefit from dose-dense paclitaxel as seen in
the Japanese study and also in the trial design of GOG
172 that included paclitaxel on day 1 and day 8. The
currently open GOG 252 trial takes into account issues
pertaining to dose-dense therapy, IP therapy, and the inclusion of bevacizumab in front-line treatment in order
to establish the most effective approach (Fig 2). It is
anticipated that GOG 262 will open soon; this trial will
address treatment options for suboptimally debulked patients with randomization to IV paclitaxel and carboplatin given every 3 weeks vs weekly paclitaxel. Both arms
will include bevacizumab administered concurrently as
well as maintenance therapy.
Cytoreductive Surgery
Cumulative data from multiple large retrospective studies
have shown that optimal cytoreductive surgery prior to
chemotherapy is associated with an improvement in
OS.15-17 The rationale for this is based on reduction of
tumor burden and thereby the potential for developing
chemoresistant disease, a reduction in poorly perfused
tumor to enhance drug delivery, and an associated increase
in the percent of tumor with a high mitotic index that is
more susceptible to the effects of cytotoxic chemotherapy.

However, there are limitations of the clinical eligibility for

cytoreductive surgery based on a variety of factors including performance status, comorbidities, age, and disease
distribution. For a patient unable to undergo a primary
cytoreductive surgery, neoadjuvant chemotherapy has
been given to reduce the disease burden prior to surgical resection. Recently, the European Organisation for
Research and Treatment of Cancer (EORTC) conducted a
prospective phase III study to evaluate primary debulking
vs neoadjuvant chemotherapy in advanced-stage ovarian
cancer patients and demonstrated no difference in OS.18
Notably, the median survival for both arms was approximately 30 months, much shorter than the 50 months reported for patients who completed optimal debulking in
most prior studies. The potential for an inherent selection
bias in the patient enrollment should be considered. In
other words, patients enrolled in a trial randomized to
undergo surgery or a more conservative approach may
not include the best surgical candidates. The results of
this single study are provocative and would benefit from
confirmatory studies to support these findings. The GOG
is currently discussing a plan to further evaluate the role
of primary surgery vs neoadjuvant chemotherapy with
selection criteria to better define surgical candidates and
thereby allow for stratification of patient outcomes.

Survival by Treatment Group - GOG 172


Rx Group











Months on Study
Fig 1. Survival advantage of IP paclitaxel/cisplatin over IV-only treatment as demonstrated in GOG 172. From Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43. Copyright 2006 Massachusetts Medical Society. All rights reserved.
46 Cancer Control

January 2011, Vol 18, No.1

Maintenance Therapies
At the completion of surgery and chemotherapy, the majority of patients will achieve a complete clinical remission.
Instead of terminating treatment at this point, the concept
of maintenance therapy is to continue a low-toxicity treatment in an effort to maintain the disease remission and
thereby increase PFS and OS. In general, maintenance
therapy involves continuing at least one of the agents
used in the primary treatment strategy, and much focus
has been placed on antiangiogenic strategies.
A study performed by the Southwest Oncology Group
and the GOG examined the use of IV paclitaxel in patients
with a complete response to upfront therapy. Patients
were randomized to receive either 3 cycles or 12 cycles
of maintenance IV paclitaxel. There was a PFS advantage
of 7 months observed in patients receiving the 12-cycle
arm. This study was terminated early and prevented definitive conclusions about the effectiveness of this treatment
approach on OS.19 In Europe, Pecorelli et al20 found no
improvement in PFS or OS in patients who received an
additional 6 cycles of paclitaxel as consolidation treatment after complete response from initial therapy. The
GOG currently has an ongoing study, protocol 212, with

patients randomized to observation or monthly IV paclitaxel or CT-2103, a polyglutamated taxane.21 GOG 218 and
ICON 7 are examining the use of bevacizumab in front-line
therapy followed by a schema of maintenance dosing.22
GOG 218 has demonstrated a 3.8-month improvement
in PFS for patients who received combination paclitaxel,
carboplatin, and bevacizumab followed by maintenance
bevacizumab compared to the study arms without maintenance therapy. It remains to be seen if this difference
in PFS will be enough to offset the side effects and cost
of treatment. OS data are not yet available.
Immunotherapy represents an exciting area of research and has been studied as a potential option for
maintenance therapy. Vaccines have been developed to
target areas of the CA-125 antigen, a protein produced by
most epithelial ovarian cancers. Oregovomab is an immunoglobulin murine monoclonal antibody that binds to
CA-125. Retrospective studies and phase II trials showed
positive results for the use of oregovomab.23,24 However,
a randomized controlled trial of patients in first clinical
remission showed no benefit over placebo.25 A newer
antigen being evaluated is MUC 16. The vaccine using
MUC 16 as the target is an anti-idiotype vaccine. It is hoped

GOG 252
Phase A: Cycles 1- 6*

80 mg/m2 IV over 1 hour days 1, 8 and 15
AUC 6 IV on day 1
15 mg/kg IV on day 1 beginning on cycle 2



80 mg/m2 IV over 1 hour days 1, 8 and 15
AUC 6 IP on day 1
15 mg/kg IV on day 1 beginning on cycle 2

135 mg/m2 IV over 3 hours day 1
75 mg/m2 IP on day 1
60 mg/m2 IP on day 8
15 mg/kg IV on day 1 beginning on cycle 2

Phase B: Cycles 7- 22*

Weekly IV

15 mg/kg IV on day 1 for cycles 7-22
Weekly paclitaxel + q3wk IP carboplatin

Modified q3wk IP

* Continue regimen every 3 weeks for 6 cycles of chemotherapy and a total of 22 cycles including
bevacizumab unless toxicity or progression intervenes.
Fig 2. Schema of the current GOG 252 protocol evaluating IP cisplatin vs IP carboplatin and a comparator arm IV-only dose-dense treatment. All treatment
arms include concurrent and maintenance bevacizumab dosing.
January 2011, Vol 18, No.1

Cancer Control 47

that such anti-idiotype vaccines will increase the immune

response against the presented antigen. An international
randomized phase III trial enrolled patients in a 2:1 fashion
to receive this vaccine, and results are pending.26

Treatment of Recurrent Disease

While increasing numbers of patients with ovarian cancer
are experiencing 5-year survival,1 90% of suboptimally
debulked patients and 70% of optimally debulked patients
relapse 18 to 24 months following primary treatment.27
Given the expanding number of active drugs and treatment regimens available, treatment selection for recurrent
disease can be complex. Several important studies and
ongoing clinical trials can help in guiding management.
Chemotherapy Options
Traditionally, patients with recurrent platinum sensitive
ovarian cancer, defined as a disease-free interval from completion of primary treatment of at least 6 months, have
been re-treated with platinum-based chemotherapy, often
in combination with another chemotherapeutic agent.
In ICON 4, platinum-sensitive patients were randomized
to receive a platinum-based regimen with or without a
taxane. In the conventional platinum-based chemotherapy
arm, 73% of patients received a single-agent platinum. In
the taxane-containing arm, 90% received paclitaxel as part
of a doublet (80% received paclitaxel and carboplatin, 10%
received paclitaxel and cisplatin). Results demonstrated
that patients assigned to receive a taxane, the majority
of whom received this in combination with a platinum
agent, experienced higher response rates, better PFS, and
superior OS compared to those who received re-treatment
with a single-agent platinum.28 Notably, not all patients
had received the combination of paclitaxel and carboplatin in the front-line setting.
Cumulative toxicity from primary therapy, specifically neurotoxicity, can preclude re-treatment with paclitaxel and carboplatin, and therefore other platinum-based
doublets have been explored. The Arbeitsgemeinschaft
Gynkologische Onkologie (AGO) conducted a randomized phase II trial (AGO OVAR 2.5) comparing singleagent carboplatin with the combination regimen of
gemcitabine and carboplatin. The study showed that
patients assigned to the gemcitabine/carboplatin group
experienced a higher response rate and a superior PFS
but no difference in OS. This study concluded that the
doublet of gemcitabine and carboplatin was an acceptable treatment regimen for recurrent disease.29 Currently,
the OCEANS trial is evaluating outcomes of gemcitabine
and carboplatin in combination with bevacizumab.30
As an alternative strategy, the CALYPSO trial randomized patients to receive either the doublet of pegylated liposomal doxorubicin (PLD) and carboplatin
vs paclitaxel and carboplatin.31 The study demonstrated
an improvement in PFS for the PLD/carboplatin arm
(median: 11.3 month vs 9.4 months; HR = 0.82; P =
48 Cancer Control

.005). Interestingly, there was less marrow toxicity and

a decrease in the rate of carboplatin hypersensitivity reactions, which suggests that this drug combination may
allow for a longer duration of platinum-based treatment.
To examine the combination of carboplatin with PLD
vs single-agent carboplatin, Markman et al32 entered 61
patients into a phase III study prior to closure for insufficient accrual. The study initially reported improvement
in outcome associated with the combination regimen.
Longer follow-up continued to show an improvement in
PFS (median: 12 vs 8 months; P = .02) but not OS, albeit
limited in its small sample size. The lower incidence
of platinum-induced hypersensitivity reactions when
combination treatment is administered with PLD was
also identified in this study.32
Whereas combination treatment with a platinum
doublet is frequently used for recurrent platinum-sensitive patients, especially those with a prolonged disease-free interval, numerous agents are available that
can be used as single-agent therapy. Gemcitabine, PLD,
topotecan, paclitaxel, docetaxel, oral etoposide, and hormonal agents represent some of the single-agent treatment options. Single-agent treatment is currently the
preferred approach for platinum-resistant patients or
for platinum-sensitive patients who have a short time to
recurrence, such as a 6- to 12-month disease-free interval.
Also worthy of consideration is the patients anticipated
tolerability and cumulative toxicity from the front-line
therapy in making the individual treatment selection for
recurrent disease.
Secondary Cytoreductive Surgery
In the setting of newly diagnosed ovarian cancer, primary
cytoreductive surgery to improve survival is generally
accepted. In patients with recurrent disease, the role of
cytoreductive surgery continues to evolve. Several series
have suggested the importance of cytoreductive surgery
prior to the initiation of second-line chemotherapy. In
a retrospective analysis, Chi et al33 showed a 41-month
median OS after secondary optimal cytoreduction for
recurrent ovarian cancer. In another study, investigators demonstrated a 61-month median OS with optimal
secondary cytoreductive surgery.34 Given the potential
for selection bias in these retrospective studies, GOG
213 includes an evaluation of surgery for recurrent
disease. This ongoing phase III trial assesses patients
with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer. If patients are surgical
candidates, they are randomized to either surgery or no
surgery. Once debulked, they are further randomized to
carboplatin and paclitaxel chemotherapy or carboplatin,
paclitaxel, and bevacizumab chemotherapy followed by
maintenance bevacizumab. If patients are not surgical
candidates, they are randomized to the chemotherapy
with or without the antiangiogenic agent. The objective of this trial is to examine the impact of secondary
January 2011, Vol 18, No.1

cytoreductive surgery. In addition, this study examines

the role of the antiangiogenic agent bevacizumab with
paclitaxel and carboplatin re-treatment. Accrual for this
study is ongoing and results are pending.35
Phase I/II Trials
Over the past decade an emphasis on understanding
the molecular pathways involved in cancer cell growth,
metastasis, and the development of chemoresistance
has led to the evaluation of numerous drugs to target
these pathways. Targeted therapeutic agents are currently being analyzed in clinical trials at single-institution,
multi-institutional, and consortium levels.Tissue procurement has been included in many of these trials to evaluate
translational endpoints in order to select patients for
enrollment and to monitor therapeutic response.
Antiangiogenic Agents
Bevacizumab is a recombinant humanized anti-VEGF
monoclonal antibody that binds and neutralizes all forms
of VEGF. The use of bevacizumab in recurrent ovarian
cancer has been explored with promising results and
response rates of up to 24%.36-38 As described above,
bevacizumab has been recently investigated with promising results as a component of front-line and maintenance
therapy and is currently undergoing evaluation with gemcitabine and carboplatin for platinum-sensitive recurrent
disease. VEGF-Trap is a potent angiogenesis inhibitor
fusion protein. In a phase II trial using aflibercept, 41% of
patients demonstrated stable disease or a partial response
to therapy at 14 weeks on the drug.39 Rather than neutralizing the VEGF molecule, another therapeutic strategy
for antiangiogenic agents is to block the VEGF receptor.
This can be accomplished with agents such as sorafenib
or sunitinib, which are orally administered, small molecules that block tyrosine kinase activity located in the
cytoplasmic domain of VEGF receptor (VEGFR). Some of
these small molecules block VEGFR specifically, whereas
others, such as sorafenib and sunitinib, block both VEGFR
and the platelet-derived growth factor (PDGFR), thought
to be involved in later phases of tumor angiogenesis relating to vessel maturation. Numerous protocols evaluating
antiangiogenic agents in combination with cytotoxic
chemotherapy for recurrent disease are currently open.40
mTOR Inhibitors
Dysregulation of mTOR signaling occurs in many tumors
and has been found to be activated in gynecologic
cancers. Increased AKT/PI3K activity with constitutive
downstream activation of the mTOR pathway has been
found in ovarian tumor specimens and ovarian cancer
cell lines. Inhibition of mTOR by agents such as temsirolimus (CCI-779), everolimus (RAD001), and deforolimus
(AP23573) are in clinical trials. GOG 170I, a phase II
study for recurrent/persistent ovarian cancers, evaluated
the use of temsirolimus in recurrent/persistent ovarian
January 2011, Vol 18, No.1

and primary peritoneal cancers. Results were presented

at the 2010 meeting of the Society of Gynecologic Oncologists and suggested modest activity of weekly singleagent temsirolimus in persistent or recurrent disease,
with 24.1% PFS at 6 months. Circulating tumor cells
were analyzed pre- and post-treatment to identify predictors for therapeutic response.41
PARP Inhibitors
Inhibition of poly(adenosine diphosphate [ADP]-ribose)
polymerase (PARP), a key enzyme in the repair of DNA,
may lead to the accumulation of breaks in double-stranded DNA and cell death. Therefore, PARP inhibitors have
been developed and are potentially exciting agents in
the treatment of ovarian cancer, especially cancers with
BRCA1 and BRCA2 mutations. In a sentinel article, a phase
I study showed the PARP inhibitor olaparib lacked severe
toxic effects of conventional chemotherapy and resulted
in objective responses of tumors with BRCA mutations.42
An International Collaborative Expertise for BRCA Education and Research through Genetics (ICEBERG) designed
two of the key clinical trials in germline mutation carriers. A phase II trial of the oral PARP inhibitor olaparib
(AZD2281) is an international, multicenter, single-arm
study with treatment consisting of continuous use of oral
olaparib in BRCA-mutation ovarian cancer patients.43 The
interim analysis from October 31, 2008, showed clinical
benefit in 57.6% of patients at 400 mg twice daily. The
use of PARP inhibitors may not be limited to patients with
germline mutations in the BRCA gene.44-47 One molecular
characterization study suggested that more than 50%
of patients with high-grade sporadic epithelial ovarian
cancer had loss of BRCA function, by either genetic or
epigenetic events.48 Therefore, a phase II, randomized,
double-blind, multicenter study is assessing the efficacy
of AZD2281 in the treatment of patients with platinumsensitive serous ovarian cancer following treatment with
two or more platinum-containing regimens.49
Histone Deacetylase Inhibitors
Aberrant histone modifications such as hypoacetylation
have been associated with malignancy through the transcriptional silencing of tumor suppressor genes. Belinostat is a histone deacetylase inhibitor (HDAC) that
can alter the acetylation level of histone and nonhistone
proteins. Such epigenetic modulation may sensitize drugresistant tumor cells to other antineoplastic agents, as
suggested in preclinical studies.50,51 A phase II study by
the GOG (protocol 0126T) is examining the use of belinostat in combination with carboplatin among patients
with recurrent or persistent platinum-resistant disease.52

In addition to exploring treatments for ovarian cancer,
several clinical trials are examining preventive agents.
Along with parity, oral contraceptive use has consistently
Cancer Control 49

been associated with a decreased risk of ovarian cancer.

GOG 214, an ongoing phase II double-blind randomized
trial, is evaluating the effects of levonorgestrel on the
ovarian epithelium in women at high risk for ovarian
cancer.53 The goal of this trial is to develop a pharmacologic prevention strategy. The primary endpoint will
evaluate the frequency of apoptosis of ovarian epithelium, and the secondary endpoint will estimate the impact
of this drug on proliferation and transforming growth
factor-beta expression in ovarian epithelium.
Fenretinide, a synthetic vitamin A analog, was proposed for chemoprevention of ovarian cancer. Fenretinide reduced ovarian carcinoma occurrence during
the 5-year intervention period, but the effects disappeared after treatment.54

Quality of Life Studies

As of this printing, 78 studies on quality of life are registered with http://www.clinicaltrials.gov, a service of the
US National Institutes of Health. The burden of disease
and the effects of ovarian cancer treatment on everyday living have been increasingly recognized. These
include issues pertaining to chronic pain, lymphedema,
neuropathy, fatigue, and sexual function, to name a few.
Many investigators are now studying both the temporary
and sustained effects of ovarian cancer and its associated treatments. Clinical trials are increasingly including quality of life components in trial designs in efforts
to both prolong and improve the quality of life among
ovarian cancer patients.

Clinical trials in ovarian cancer represent a rich area of
investigation. Study design is targeted to address the
optimal treatment and side effect profile at various points
in the disease course. Increasingly, translational endpoints and quality of life considerations are included as
components of these trials. Clinical trials open today
build on the results of prior studies in order to optimize
the outcomes for women with this challenging disease.
Whereas this manuscript focuses on clinical trials
pertaining to the management of epithelial ovarian
cancers, there are only limited studies available for nonepithelial subtypes due to the low frequency of these
tumors. The GOG has recently developed a rare tumor
working group to provide a dedicated focus and increase
the clinical trial effort for these tumors as well.
1. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin
and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43.
2. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and
cisplatin compared with paclitaxel and cisplatin in patients with stage III and
stage IV ovarian cancer. N Engl J Med. 1996;334(1):1-6.
3. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin
and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group
study. J Clin Oncol. 2003;21(17):3194-3200.
4. du Bois A, Quinn M, Thigpen T, et al. 2004 consensus statements on

50 Cancer Control

the management of ovarian cancer: final document of the 3rd International

Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference
(GCIG OCCC 2004). Ann Oncol. 2005;16(suppl 8):viii7-viii12.
5. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase
III trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27(9):14191425. Erratum in: J Clin Oncol. 2009;27(13):2305.
6. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel
once a week in combination with carboplatin every 3 weeks for advanced
ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet.
7. Burger RA, Brady MF, Bookman MA, et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer
(EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): a
Gynecologic Oncology Group study. J Clin Oncol. 2010;28(18 suppl):LBA1.
8. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin
plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med.
9. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standarddose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in
small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern
Cooperative Oncology Group. J Clin Oncol. 2001;19(4):1001-1007.
10. Kirmani S, Braly PS, McClay EF, et al. A comparison of intravenous
versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer. Gynecol Oncol. 1994;54(3):338-344.
11. Polyzos A, Tsavaris N, Kosmas C, et al. A comparative study of intraperitoneal carboplatin versus intravenous carboplatin with intravenous
cyclophosphamide in both arms as initial chemotherapy for stage III ovarian
cancer. Oncology. 1999;56(4):291-296.
12. Gadducci A, Carnino F, Chiara S, et al. Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and
epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer:
a randomized trial of the Gruppo Oncologico Nord-Ovest. Gynecol Oncol.
13. Yen MS, Juang CM, Lai CR, et al. Intraperitoneal cisplatin-based
chemotherapy vs intravenous cisplatin-based chemotherapy for stage III
optimally cytoreduced epithelial ovarian cancer. Int J Gynaecol Obstet.
14. Konner JA, Grabon D, Pezzulli S, et al. A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel, IP cisplatin, and IV bevacizumab as first-line chemotherapy for optimal stage II or III ovarian, primary
peritoneal, and fallopian tube cancer. J Clin Oncol (Meeting Abstracts).
2009;27:5539. Abstract.
15. Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter
of largest residual disease on survival after primary cytoreductive surgery in
patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet
Gynecol. 1994;170(4):974-979; discussion 979-980.
16. Hoskins WJ, Bundy BN, Thigpen JT, et al. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume
stage III epithelial ovarian cancer: a Gynecologic Oncology Group study.
Gynecol Oncol. 1992;47(2):159-166.
17. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of
maximal cytoreductive surgery for advanced ovarian carcinoma during the
platinum era: a meta-analysis. J Clin Oncol. 2002;20(5):1248-1259.
18. Vergote I. Randomized trial comparing primary debulking surgery
with neoadjuvant chemotherapy followed by interval debulking in stage
IIIC-IV ovarian, fallopian tube, and peritoneal cancer. IGCS Presentation,
2008. http://www.multiwebcast.com/igcs/2008/12th/2717/ignace.b.vergote.
19. Markman M, Liu PY, Moon J, et al. Impact on survival of 12 versus
3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with
advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic
Oncology Group phase 3 trial. Gynecol Oncol. 2009;114(2):195-198.
20. Pecorelli S, Favalli G, Gadducci A, et al. Phase III trial of observation
versus six courses of paclitaxel in patients with advanced epithelial ovarian
cancer in complete response after six courses of paclitaxel/platinum-based
chemotherapy: final results of the After-6 protocol 1. J Clin Oncol. 2009;
21. A Randomized Phase III Trial of Maintenance Chemotherapy Comparing 12 Monthly Cycles of Single Agent Paclitaxel or Xyotax (CT-2103)
(IND# 70177), Versus No Treatment Until Documented Relapse in Women
With Advanced Ovarian or Primary Peritoneal or Fallopian Tube Cancer Who
Achieve a Complete Clinical Response to Primary Platinum/Taxane Chemotherapy. NCT00108745. http://clinicaltrials.gov/ct2/show/NCT00108745.
Accessed August 17, 2010.
22. ICON7 - A Randomised, Two-Arm, Multi-Centre Gynaecologic Cancer
InterGroup Trial of Adding Bevacizumab to Standard Chemotherapy (Carboplatin and Paclitaxel) in Patients With Epithelial Ovarian Cancer.

January 2011, Vol 18, No.1

NCT00483782. http://clinicaltrials.gov/ct2/show/NCT00483782?term=NCT00
483782&rank=1. Accessed August 17, 2010.
23. Ehlen TG, Hoskins PJ, Miller D, et al. A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic
agent for recurrent ovarian cancer. Int J Gynecol Cancer. 2005;15(6):10231034.
24. Mbus VJ, Baum RP, Bolle M, et al. Immune responses to murine
monoclonal antibody-B43.13 correlate with prolonged survival of women
with recurrent ovarian cancer. Am J Obstet Gynecol. 2003;189(1):28-36.
25. Berek J, Taylor P, McGuire W, et al. Oregovomab maintenance
monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol. 2009;27(3):418-425.
26. Sabbatini P. Consolidation therapy in ovarian cancer: a clinical update. Int J Gynecol Cancer. 2009;19(suppl 2):S35-S39.
27. Dizon DS, Hensley ML, Poynor EA, et al. Retrospective analysis of
carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of
ovarian cancer. J Clin Oncol. 2002;20(5):1238-1247.
28. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2
trial. Lancet. 2003;361(9375):2099-2106.
29. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin
compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the
EORTC GCG. J Clin Oncol. 2006;24(29):4699-4707.
30. A Phase III, Multicenter, Randomized, Blinded, Placebo-Controlled
Trial of Carboplatin and Gemcitabine Plus Bevacizumab in Patients With
Platinum-Sensitive Recurrent Ovary, Primary Peritoneal, or Fallopian Tube
Carcinoma. NCT00434642. http://clinicaltrials.gov/ct2/show/NCT00434642
?term=NCT00434642&rank=1. Accessed August 17, 2010.
31. A Multi-National,Randomized, Phase III, GCIG Intergroup Study
Comparing Pegylated Liposomal Doxorubicin and Carboplatin Versus Paclitaxel and Carboplatin in Patients With Epithelial Ovarian Cancer in Late
Relapse (> 6 Months). NCT00189553. http://clinicaltrials.gov/ct2/show/
NCT00189553. Accessed August 18, 2010.
32. Markman M, Moon J, Wilczynski S, et al. Single agent carboplatin
versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian
cancer: final survival results of a SWOG (S0200) phase 3 randomized trial.
Gynecol Oncol. 2010;116(3):323-325.
33. Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinumsensitive epithelial ovarian carcinoma. Cancer. 2006;106(9):1933-1939.
34. Benedetti Panici P, De Vivo A, Bellati F, et al. Secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer.
Ann Surg Oncol. 2007;14(3):1136-1142.
35. A Phase III Randomized Controlled Clinical Trial of Carboplatin and
Paclitaxel Alone or in Combination With Bevacizumab (NSC #704865, IND
#7921) Followed by Bevacizumab and Secondary Cytoreduction Surgery
in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian
Tube Cancer. NCT00565851. http://clinicaltrials.gov/ct2/show/NCT005658
51?term=NCT00565851&rank=1. Accessed August 18, 2010.
36. Burger RA, Sill MW, Monk BJ, et al. 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):5165-5171.
37. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital
phase II consortia. J Clin Oncol. 2008;26(1):76-82.
38. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of
bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal
serous cancer. J Clin Oncol. 2007;25(33):5180-5186. Erratum in: J Clin
Oncol. 2008;26(10):1773.
39. Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with
advanced solid tumors. J Clin Oncol. 2010;28(2):207-214.
40. Burger RA. Role of vascular endothelial growth factor inhibitors in the
treatment of gynecologic malignancies. J Gynecol Oncol. 2010;21(1):3-11.
41. Behbakht K, Sill MW, Darcy KM, et al. Phase II trial of the mTOR inhibitor temsirolimus and evaluation of circulating tumor cells in persistent or
recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(3):s1(SGO#7):S5.
42. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose)
polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;
43. A Phase II Open-Label, Non-Comparative, International, Multicentre
Study to Assess the Efficacy and Safety of KU 0059436 Given Orally Twice
Daily in Patients With Advanced BRCA1 or BRCA2 Associated Ovarian Cancer. NCT00494442. http://clinicaltrials.gov/ct2/show/NCT00494442?term=
NCT00494442&rank=1. Accessed August 18, 2010.
44. Gelmon KA, Hirte HW, Robidoux A, et al. Can we define tumors that
will respond to PARP inhibitors? A phase II correlative study of olaparib in
advanced serous ovarian cancer and triple-negative breast cancer. J Clin

January 2011, Vol 18, No.1

Oncol. 2010 ASCO Ann Meet Proc (Post-Meet Ed). 2010;28(15 suppl May
45. Sandhu SK, Wenham RM, Wilding G, et al. First-in-human trial of a
poly(ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer
patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers. J Clin Oncol. 2010 ASCO Ann Meet Proc (Post-Meet Ed).
2010;28(15 suppl May 20):3001.
46. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol.
47. Turner N, Tutt A, Ashworth A. Hallmarks of BRCAness in sporadic
cancers. Nat Rev Cancer. 2004;4(10):814-819.
48. Hughes-Davies L, Huntsman D, Ruas M, et al. EMSY links the BRCA2
pathway to sporadic breast and ovarian cancer. Cell. 2003;115(5):523-535.
49. Phase II Randomised, Double Blind, Multicentre Study to Assess the
Efficacy of AZD2281 in the Treatment of Patients With Platinum Sensitive
Serous Ovarian Cancer Following Treatment With Two or More Platinum
Containing Regimens. NCT00753545. http://clinicaltrials.gov/ct2/show/
NCT00753545. Accessed August 18, 2010.
50. Qian X, LaRochelle WJ, Ara G, et al. Activity of PXD101, a histone
deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther.
51. Steele N, Finn P, Brown R, et al. Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo. Br J Cancer. 2009;100(5):758-763.
52. A Phase II Evaluation of Belinostat (NSC #726630, IND #729990)
and Carboplatin (NSC #241240) in the Treatment of Recurrent or Persistent
Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.
NCT00993616. http://clinicaltrials.gov/ct2/show/NCT00993616?term=NCT
00993616&rank=1. Accessed August 18, 2010/
53. Phase II Double Blind Randomized Trial Evaluating the Biologic Effect of Levonorgestrel on the Ovarian Epithelium in Women at High Risk for
Ovarian Cancer (IND# 79,610). NCT00445887. http://clinicaltrials.gov/ct2/
show/NCT00445887?term=NCT00445887&rank=1. Accessed August 18,
54. An Exploratory Evaluation of Fenretinide (4-HPR) as a Chemopreventive Agent for Ovarian Carcinoma. NCT00017134. http://clinicaltrials.
gov/ct2/show/NCT00017134?term=NCT00017134&rank=1. Accessed August 18, 2010.

Cancer Control 51