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Gynecologic Oncology
New, Expanded, and Modified Use of Approved Antineoplastic
Agents in Ovarian Cancer
MAURIE MARKMAN
Key Words. Ovarian cancer • Cancer chemotherapy • Combination chemotherapy • Second-line chemotherapy
ABSTRACT
Over the past several years, clinical research efforts in
ovarian cancer employing a number of U.S. Food and
Drug Administration (FDA)-approved antineoplastic
agents have permitted the development of approaches
that both improve the effectiveness and decrease the
toxicities of systemic therapy of ovarian cancer. These
initiatives, including prospective trials and retrospective examinations of large clinical experience, have involved agents previously approved by the FDA for use
in ovarian cancer (e.g., cisplatin, paclitaxel, topotecan, and liposomal doxorubicin) and the development
of new strategies for drugs approved for other malignant conditions (e.g., gemcitabine, docetaxel, etoposide, irinotecan, vinorelbine, and bevacizumab). It
can be anticipated that future studies involving novel
approved agents will further expand the oncologist’s
weapons against ovarian cancer. The Oncologist 2007;
12:186 –190
INTRODUCTION
ported ovarian cancer studies involving FDA-approved
antineoplastic agents and their impact on routine management of the malignancy.
Over the past several decades, trials in ovarian cancer have resulted in initial approval of a number of novel antineoplastic
agents by the U.S. Food and Drug Administration (FDA), with
subsequent studies in other tumor types substantially expanding the indications for their routine clinical use. For example,
both carboplatin and paclitaxel, two of the most frequently employed agents in oncologic practice, were first examined for
their clinical utility in women with ovarian cancer [1–3].
Recently, however, this drug development paradigm
has reversed course. Chemotherapy agents active in other
tumor types have subsequently been explored in patients
with ovarian cancer, with positive results. Furthermore,
during the last few years, considerable clinical research efforts in this area have focused on optimizing the benefits
associated with drugs already known be active in the malignancy. This review highlights important recently re-
PACLITAXEL
Despite the long-established role of paclitaxel in ovarian
cancer [3, 4] and extensive trial experience with the drug in
the disease, recently reported data have clearly demonstrated that there is much more to learn regarding this important antineoplastic drug to further optimize its use in the
treatment of this female pelvic cancer [5– 8].
Several multicenter phase II trials have revealed that
weekly administration of paclitaxel results in a 20% objective response rate in ovarian cancer patients with clinically
defined platinum- and paclitaxel-resistant (“standard”
3-week schedule) disease [5, 6]. (Note that the definition of
both platinum- and paclitaxel-resistant ovarian cancer is
Correspondence: Maurie Markman, M.D., University of Texas M.D. Anderson Cancer Center (Mail Box 121), 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-745-7140; Fax: 713-563-9586; e-mail: [email protected] Received August 2, 2006; accepted for publication November 22, 2006. ©AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncologist.122-186
The Oncologist 2007;12:186 –190 www.TheOncologist.com
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Department of Gynecologic Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston,
Texas, USA
Markman
DOCETAXEL
A phase III randomized trial has demonstrated the therapeutic
equivalence of carboplatin plus docetaxel, compared with carboplatin plus paclitaxel, when employed as primary treatment
of advanced ovarian cancer [10]. The regimens differ in their
toxicity profiles, with the paclitaxel-containing program being
associated with a higher incidence of peripheral neuropathy
and the docetaxel program having a greater risk of clinically
relevant neutropenia. The data clearly demonstrate that either
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carboplatin-based combination may be employed as primary
therapy of advanced ovarian cancer.
It should also be noted that previously reported phase II
trial data had revealed that the use of single-agent docetaxel
resulted in an objective response rate of approximately 20%
in patients with platinum- and paclitaxel-resistant (3-week
schedule) ovarian cancer [11, 12]. Thus, this drug is another
rational management option in the setting of resistant disease.
CISPLATIN
Although cisplatin is a very well-established agent in the
treatment of ovarian cancer, the results of three randomized
phase III trials revealing that the intraperitoneal delivery of
the drug results in a 20%–25% improvement in the risk of
death compared with intravenous administration led the
National Cancer Institute to issue a “Clinical Announcement” informing oncologists, patients, and the public of this
outcome in early 2006 [8, 13, 14]. Future studies in this
arena will hopefully seek to optimize use of this drugdelivery technique, employing both cisplatin and other antineoplastic agents (e.g., carboplatin and paclitaxel).
GEMCITABINE
Phase II trial data have shown that gemcitabine produces
objective responses in approximately 10%–15% of patients
with platinum-resistant ovarian cancer, making this a reasonable therapeutic option in this clinical setting [15, 16].
A recently reported phase III trial examined the clinical
utility associated with a combination carboplatin-plusgemcitabine regimen compared with single-agent carboplatin in women with recurrent ovarian cancer [17]. The
treated population was similar to that evaluated in the previously noted ICON-4 study. The trial results revealed that
the combination program produced a higher objective response rate and longer progression-free survival compared
with the single-agent regimen. However, there was no difference in overall survival found between the study arms.
Of note, in contrast to the ICON-4 results, the incidence
of peripheral neuropathy was the same for single-agent carboplatin and the combination strategy. Thus, despite the
lack of impact on overall survival associated with the carboplatin-plus-gemcitabine regimen, this combination chemotherapy approach is a highly reasonable option for
patients with recurrent ovarian cancer where there is concern for the potential toxicity (risk of neuropathy) of a carboplatin-plus-paclitaxel program.
TOPOTECAN
Topotecan is well established as an active agent in ovarian
cancer [18]. As many as one third of treated patients with
recurrent ovarian cancer may achieve an objective response
[19, 20]. However, the standard 5-day treatment strategy is
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failure to respond to prior platinum and paclitaxel treatment
or documented disease recurrence within 6 months of the
completion of such therapy.)
The biological explanation of this provocative observation is uncertain but may relate to the recognized cell-cycle
specificity of paclitaxel cytotoxicity. Alternatively, the
documented tumor shrinkage could be related to an entirely
different mechanism of action (e.g., antiangiogenesis).
A phase III trial underway in Japan compares carboplatin plus standard paclitaxel (3-week schedule) to a program
of carboplatin plus weekly paclitaxel employed as primary
treatment of advanced ovarian cancer and has recently competed accrual. The results of this study, which should be
available within the next 2 years, hold considerable interest.
For the present, based on existing data, it is appropriate
to conclude that the weekly delivery of paclitaxel is an acceptable treatment option for patients with resistant (both
platinum and every 3-weeks paclitaxel) ovarian cancer [5, 6].
In the setting of recurrent disease, where patients had a
treatment-free interval of at least 6 months, paclitaxel plus a
platinum agent were directly compared to a platinum agent
without paclitaxel in a randomized phase III trial [9]. This
somewhat complex study (International Collaborators in
Ovarian Neoplasm [ICON]-4) revealed that the two-drug
combination containing paclitaxel was associated with both
longer progression-free and overall survival (2-year survival, 57% vs. 50%; p ⫽ .02) compared with the nonpaclitaxel-containing program [9]. Because most patients
treated with paclitaxel received carboplatin as the platinum
agent, and the control arm was most commonly singleagent carboplatin, most oncologists have interpreted this
study to demonstrate the superiority of second-line carboplatin plus paclitaxel compared with carboplatin alone in
the setting of recurrent ovarian cancer.
Unfortunately, the combination regimen was also associated with a far greater risk of clinically relevant neuropathy
(grade 2–3, 20% vs. 1%) [9]. However, for a patient who has
not experienced significant neurotoxic effects from her prior
primary platinum/taxane regimen, this two-drug combination
is a rational approach in the setting of recurrent disease.
187
Antineoplastic Agents in Ovarian Cancer
188
LIPOSOMAL DOXORUBICIN
Similar to the experience with topotecan, the substantial toxicity (mucositis, stomatitis, and “hand-foot syndrome”) associated with the delivery of liposomal doxorubicin at the FDAapproved dose of 50 mg/m2 on an every-4-weeks schedule
[29, 30] has prompted investigators to examine alternative approaches for drug administration. Several reports have shown
that at a liposomal doxorubicin dose of 40 mg/m2 (delivered
on an every-4-weeks schedule) [31–34], the objective response rate is similar to that achieved with the FDA-approved
regimen (10%–15%), but with a substantially improved adverse-effect profile. These data provide strong support for the
conclusion that, in the palliative setting, the lower-dose treatment program should be employed to optimize the chances for
clinical benefit without excessive toxicity.
BEVACIZUMAB
Of considerable interest, several reports of single-agent bevacizumab employed as second-line therapy of ovarian
cancer have revealed considerable activity for the agent
(approximately a 15% objective response rate), including in
individuals with well-characterized platinum-resistant disease [35–38]. Although a number of studies have also explored the use of bevacizumab in combination with
chemotherapy in this clinical setting, there is currently no
evidence that such regimens are superior to administration
of the antiangiogenic agent alone [36].
REFERENCES
1
2
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In addition to the toxicities of bevacizumab noted in other
clinical settings (e.g., severe hypertension), bowel perforation
has been observed in 5%–10% of patients treated with this
agent in ovarian cancer [38]. It has been suggested this serious
adverse effect may be particularly relevant when bevacizumab
is administered to patients with extensive intra-abdominal cancer present [38]. Further careful examination of this issue will
be required to define the populations at risk and determine how
this hazard may be minimized.
OTHER FDA-APPROVED ANTINEOPLASTIC AGENTS
Several additional cytotoxic drugs approved for indications
other than ovarian cancer may be reasonably employed by
oncologists as a second-line strategy in this malignancy
based on phase II clinical trial results where objective response rates of at least 10% have been reported in the peerreviewed literature. These agents include irinotecan [39],
vinorelbine [40 – 42], and oral etoposide [43, 44].
Three additional agents that have not as yet been approved by the FDA for administration outside the investigative setting are noteworthy for their possible future
routine use in ovarian cancer. Trabectedin has shown particular promise in several trials in patients with sarcomas
[45], and objective activity has also been documented in
previously treated patients with ovarian cancer [46]. In clinical trials, TLK286, delivered as a single agent or as a component of a combination regimen, has demonstrated
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previously treated patients should be reported in the near future. Finally, the results of a randomized trial examining the
effectiveness of a novel bispecific monoclonal anti-CD-3anti-EpCAm antibody in the therapy of malignant ascites is
anticipated with considerable interest. It is hoped that one
or more of these agents will soon be available to oncologists
to employ in the management of ovarian cancer.
DISCLOSURE OF POTENTIAL CONFLICTS
OF INTEREST
M.M. has acted as a consultant for Eli Lilly, Genentech, Tibutec, GlaxoSmithKline, Cell Gene, Tebex, Merck, and Wyeth.
3
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New, Expanded, and Modified Use of Approved Antineoplastic Agents in
Ovarian Cancer
Maurie Markman
The Oncologist 2007;12;186-190;
DOI: 10.1634/theoncologist.12-2-186
This information is current as of September 22, 2011
Updated Information
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including high-resolution figures, can be found at:
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