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Update on Ovarian Cancer: Waiting for New Therapeutic Concepts
Introduction
Of considerable interest, the gynecologic sessions at the
American Society of Clinical Oncology (ASCO) 40th Annual
Meeting, held June 5-8, 2004, in New Orleans, Louisiana,
included descriptions of a number of highly innovative
approaches, including additions of drugs and alterations in
dosing schedules and an examination of targeted therapy and
treatment with novel monoclonal antibodies and other new
compounds. Although the results were not always encouraging,
it is reasonable to believe that one or more of these
approaches will prove beneficial when used to treat the
malignancy in the future.
Adding a Third Drug to Platinum-Taxane Primary Chemotherapy in Advanced Ovarian Cancer
Based on the results of a series of well-designed and
well-conducted phase 3 randomized trials reported during
the past decade, standard therapy for advanced ovarian
cancer includes the administration of a platinum agent and
a taxane (paclitaxel or docetaxel). Although cisplatin- and
carboplatin-based regimens result in comparable survival
outcomes, carboplatin is generally the platinum agent of
choice due to its more favorable toxic effect profile
(less emesis, both acute and delayed, as well as less
neurotoxicity, nephrotoxicity, and requirement for
hydration).
A logical approach to improving the activity of
antineoplastic therapy in ovarian cancer would be to add a
third class of drugs with a differing mechanism of
cytotoxicity compared with the platinum and taxane agent.
Previous investigative efforts suggested that doxorubicin,
when added to platinum-based (non-taxane-containing)
combination chemotherapy had the potential to improve
long-term survival in ovarian cancer (between 5% and 7% at
5-year follow-up). However, such data were controversial,
since individual randomized phase 3 trials that examined
the question of a survival advantage associated with the
addition of an anthracycline failed to reveal a
statistically significant improvement in outcome. It was
only through the use of meta-analysis (combining the
results of multiple studies) that this theorized advantage
could be observed. Further, a more recent randomized trial,
the International Collaborative Ovarian Neoplasm Study
(ICON-2), which could not be criticized for having an
inadequate sample size to compare survival outcomes, failed
to reveal any advantage of using the multiagent combination
chemotherapy regimen of CAP (cisplatin, doxorubicin,
cyclophosphamide) compared with the administration of
carboplatin alone.
However, many investigators have maintained that the
provocative question of whether a survival advantage is
associated with anthracycline administration was not
resolved by the results of ICON-2 and have desired that
this issue be further investigated. At the 2004 ASCO
meeting, results were reported from 2 randomized phase 3
trials that specifically examined the benefits of adding
epirubicin to a carboplatin-paclitaxel combination
chemotherapy regimen.[1,2]
In the European and Canadian combined cooperative group
effort, 887 patients were randomized to receive either 6 to
9 cycles of carboplatin (area under the curve 5) plus
paclitaxel (175 mg/m2 over 3 hours), with or without the
addition of epirubicin, 75 mg/m2. Treatment was repeated on
an every-21-day schedule.[1] With a median follow-up of 30
months for the surviving patients, there was no
statistically significant difference in progression-free
survival between the regimens. Further, there was no
benefit for the 3-drug combination in patient populations
with either smaller volume or larger volume disease. The
median overall survival had not been reached at the time of
presentation of the abstract.
In a randomized phase 3 trial reported from Germany, 1282
women with advanced ovarian cancer were treated with
carboplatin and paclitaxel either with or without
epirubicin (60 mg/m2).[2] With a median follow-up of 46
months, there was also no statistically significant
difference in survival between the regimens, but patients
receiving the epirubicin-containing program experienced a
considerably greater risk for serious adverse effects of
treatment.
These data, along with results from the 2003 ASCO meeting
where the addition of several cycles of topotecan
"consolidation" following carboplatin- and paclitaxel-based
chemotherapy failed to improve progression-free survival
compared with the use of carboplatin-paclitaxel alone,
argue that the current standard of care for primary
treatment of advanced ovarian cancer remains 2-drug
treatment with a platinum agent and a taxane.
A major international cooperative initiative, headed by the
Gynecologic Oncology Group (GOG) in the United States, is
nearing completion of a 4000-patient phase 3 randomized
trial specifically comparing the impact of 4 experimental
approaches to adding a third cytotoxic agent to carboplatin
and paclitaxel in advanced ovarian cancer. Agents being
explored in this multination effort include topotecan,
pegylated liposomal doxorubicin, and gemcitabine. There are
2 gemcitabine-containing regimens being evaluated, one of
which looks at sequencing doublets of carboplatin-
gemcitabine followed by carboplatin-paclitaxel; the second
uses the triplet program of carboplatin-paclitaxel-
gemcitabine given together. The results of this trial are
awaited with considerable interest.
High-Dose Chemotherapy in Chemoresponsive Advanced Ovarian Cancer
Ovarian cancer is perhaps the ideal solid tumor in which to
explore the potential clinical utility of dose-intensive
chemotherapy. The malignancy is highly chemosensitive
(60% to 80% objective response rate to primary platinum-
and taxane-based chemotherapy), with a substantial subgroup
of women presenting with advanced disease achieving a
surgically defined complete response. Unfortunately,
despite these data, most women with stage 3 to 4 ovarian
cancer ultimately experience recurrence of the disease
process and die of complications of advanced malignancy.
It might be argued that if it were possible to safely
escalate the intensity of cytotoxic therapy in ovarian
cancer, outcome might be improved. Although previously
reported retrospective data supported this hypothesis,
definitive randomized phase 3 trial data of "dose intensity"
in advanced ovarian cancer has, in general, failed to
support this theory.
However, it is reasonable to argue that such trials really
only doubled the dose-intensity of systemically delivered
treatment, since they did not use existing technology
(bone marrow or peripheral progenitor cell reinfusion),
which would permit a far more aggressive dose-intensive
approach. Additional support for the potential clinical
relevance of this strategy are data from 3 randomized phase
3 trials that have revealed a survival benefit associated
with intraperitoneal chemotherapy, an alternative method of
producing dose-intensive drug delivery in ovarian cancer.
To directly explore the clinical relevance of this management strategy, investigators in France randomized women with stage III ovarian cancer who had undergone a second-look surgical procedure and who had been documented to have achieved an objective response to primary chemotherapy to either 3 additional cycles of conventional dose maintenance therapy (carboplatin and cyclophosphamide) or a course of high-dose carboplatin and cyclophosphamide plus peripheral blood cell support.[3] A total of 110 patients were entered into this critically important investigative effort. As reported at the 2004 ASCO, with a median follow-up of 60 months, there was no statistically significant difference in either progression-free or overall survival between the 2 study arms.
Although the results of this trial certainly do not support
the routine use of high-dose chemotherapy in advanced
ovarian cancer, it would be inappropriate to simply discard
this therapeutic strategy. First, as previously noted,
the results of 3 randomized phase 3 trials of primary
intraperitoneal chemotherapy in ovarian cancer have
revealed a favorable impact of this "dose-intensive"
approach on survival in the malignancy. Second, it is
possible that an alternative systemically delivered
high-dose chemotherapy strategy (eg, different agents,
"tandem transplantation") might be more successful in
improving outcome. Finally, although use of high-dose
chemotherapy alone may not substantially alter outcome in
ovarian cancer, it is possible that combining this approach
with another management strategy (eg, maintenance
chemotherapy) may produce superior survival than possible
with either approach alone. Such questions are the
appropriate domain of future well-conceived and well-
conducted phase 3 randomized trials.
Other Randomized Studies of Primary Therapy of Ovarian Cancer
The results of several additional phase 3 trials, which are
examining innovative approaches as primary antineoplastic
therapy of advanced ovarian cancer, were reported at the
2004 ASCO. Unfortunately, like those noted above, the
outcomes were also negative.
The GOG explored the potential clinical utility of
delivering paclitaxel as a longer infusion than the
standard 3-hour (when used with carboplatin) or 24-hour
(when given with cisplatin) schedules used in routine
clinical practice.[4] The rationale for this strategy was
the hypothesis that paclitaxel, a known cycle-specific
cytotoxic agent, might produce greater tumor cell kill if
infused over a longer period. Thus, in this trial, patients
with suboptimal residual stage III or stage IV ovarian
cancer were randomized to receive either the GOG standard
program of cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2
infused over 24 hours) or the experimental regimen of
cisplatin (same dose) plus paclitaxel (120 mg/m2 infused
over 96 hours). The study revealed no difference in
progression-free or overall survival between the treatment
programs. These results strongly argue against any benefits
associated with the very modest increase in drug exposure
to slowly dividing tumor cells associated with this
paclitaxel-infusion schedule, in contrast to that
occurring with interactions between neutrophil precursors
and the cytotoxic agent.
It is interesting to note the substantial difference
between the results of this trial and the previously
reported data regarding the clinical outcome observed with
12 additional cycles (maintenance therapy) of single-agent
monthly paclitaxel in women who achieved a clinical
complete response to platinum-paclitaxel primary
chemotherapy, where a highly statistically significant
reduction in the risk of disease recurrence (50% compared
with the control population) was observed. In this case, it
is reasonable to argue that a larger population of the
slowly cycling tumor cells was exposed to the agent,
enhancing its cytotoxic potential.
Finally, in the multi-institutional Study of Monoclonal
Antibody Radioimmunotherapy (SMART) trial, patients with
ovarian cancer who achieved a laparoscopy-defined complete
response to primary chemotherapy were randomized to receive
either standard therapy (for that institution) or a single
intraperitoneal administration of 90yttrium-labeled
monoclonal antibody, HMFGI.[5] A previously reported small
phase 2 trial had suggested that this approach could result
in prolonged disease-free survival in this clinical setting.
A total of 447 patients were treated in this trial.
Although it used a highly novel approach, designed to
harness a patient's immune response in increasing tumor
cell kill, this study again failed to demonstrate any
improvement in either progression-free or overall survival
associated with intraperitoneal administration of the
monoclonal antibody.
Second-Line Therapy of Platinum-Sensitive Ovarian Cancer
A recent report of a randomized phase 3 trial revealed that
the combination of carboplatin plus paclitaxel results in a
superior survival outcome, compared with single-agent
carboplatin alone, when used as second-line treatment of
recurrent, potentially platinum-sensitive ovarian cancer.
This study, the first to clearly demonstrate both a
progression-free and an overall survival advantage
associated with a combination platinum-based program used
as second-line treatment in this clinical setting, also
revealed that the combination paclitaxel-containing regimen
was associated with a far greater risk for the development
of clinically relevant peripheral neuropathy (20% incidence
of grade 2 to 3 compared with 1% for single-agent treatment).
Thus, the results of a randomized phase 3 trial reported at
the 2004 ASCO meeting comparing single-agent carboplatin
with a combination of carboplatin plus gemcitabine (total
patients entered, 356), were of particular interest. The
trial revealed a favorable impact of the combination
regimen on objective response rate and progression-free
survival, with no difference in the risk of serious
neuropathy between the regimens.[6] As anticipated,
there was greater bone marrow suppression in the
combination program, although the risk of serious morbidity
(eg, febrile neutropenia) was similar between the study arms.
At the time of the report of this trial, data on overall
survival in the treated populations were not available,
although this study was not specifically powered to observe
a survival difference between the regimens.
References
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Kristensen GB, Vergote I, Eisenhauer E, et al. First
line treatment of ovarian/tubal/peritoneal cancer
FIGO stage IIb-IV with paclitaxel/carboplatin with or
without epirubicin: a Gynecologic Cancer Intergroup
study of the NSGO, EORTC GCG, and NCIC CTG: results on
progression free survival. Proc Am Soc Clin Oncol.
2004;23:448a. Abstract 5003.
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Du Bois A, Combe M, Rochon J, et al. Epirubicin/
paclitaxel/carboplatin vs paclitaxel/carboplatin in
first-line treatment of ovarian cancer FIGO stages
IIB-IV: an AGO-GINECO Intergroup phase III trial.
Proc Am Soc Clin Oncol. 2004;23(suppl):16a. Abstract
5007.
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Cure H, Battista C, Guastalla JP, et al. Phase III
randomized trial of high-dose chemotherapy and
peripheral blood stem cell support as consolidation
in patients with advanced ovarian cancer: 5-year
follow-up of a GINECOP/FNCLCC/SFGM-TC study. Proc Am
Soc Clin Oncol. 2004;23:449a. Abstract 5006.
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Spriggs DR, Brady M, Rubin S, et al. A phase III
randomized trial of cisplatin and paclitaxel
administered by either 24 hour or 96 hour infusion in
patients with selected stage III or stage IV
epithelial ovarian cancer. Proc Am Soc Clin Oncol.
2004;23:449a. Abstract 5004.
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Seiden MV, Benigno BB; the SMART study investigator
group. A pivotal phase III trial to evaluate the
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90yttrium-labeled monoclonal antibody, HMFGI, in
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(suppl):16a. Abstract 5008.
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Pfisterer J, Plante M, Vergote I, et al. Gemcitabine/
carboplatin vs. carboplatin in platinum sensitive
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Clin Oncol. 2004;23:449a. Abstract 5005.
Source
http://www.medscape.com
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