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Introduction
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:
gardnerg@mskcc.org
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
44 Cancer Control
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
Rx Group
IV
IP
0.1
Alive
93
117
Dead
117
88
Total
210
205
0.0
0
12
24
36
48
60
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
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*
Paclitaxel
80 mg/m2 IV over 1 hour days 1, 8 and 15
Carboplatin
AUC 6 IV on day 1
Bevacizumab
15 mg/kg IV on day 1 beginning on cycle 2
Newly
diagnosed
ovarian,
primary
peritoneal
or
fallopian
tube
cancer
R
A
N
D
O
M
I
Z
E
Paclitaxel
80 mg/m2 IV over 1 hour days 1, 8 and 15
Carboplatin
AUC 6 IP on day 1
Bevacizumab
15 mg/kg IV on day 1 beginning on cycle 2
Paclitaxel
135 mg/m2 IV over 3 hours day 1
Cisplatin
75 mg/m2 IP on day 1
Paclitaxel
60 mg/m2 IP on day 8
Bevacizumab
15 mg/kg IV on day 1 beginning on cycle 2
Weekly IV
Bevacizumab
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
Chemoprevention
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
Conclusions
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.
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Cancer Control 51