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Is There a Role for Intraperitoneal Chemotherapy in the Management of Ovarian

Is There a Role for Intraperitoneal Chemotherapy in the Management of Ovarian

ABSTRACT: Phase I and II clinical trial data have demonstrated the safety, pharmacokinetic advantage, and potential for enhanced cytotoxicity associated with the intraperitoneal administration of antineoplastic agents in the management of ovarian cancer. In two randomized phase III studies comparing the intraperitoneal and intravenous administration of cisplatin (Platinol) as initial therapy for small-volume residual advanced ovarian cancer, intraperitoneal delivery of the agent produced superior progression-free and overall survival. Reluctance to employ intraperitoneal cisplatin in the standard management of ovarian cancer appears to be related to the added time, effort, and potential morbidity associated with the approach, as well as a general preference for the less toxic, less complicated carboplatin (Paraplatin)-based regimen. However, existing data support the use of this unique method of drug delivery in carefully selected patients outside of the clinical trial setting. [ONCOLOGY 15(1):93-105, 2001]

Introduction

What role, if any, should intraperitoneal chemotherapy play
in the management of ovarian cancer? It is rather remarkable that this question
must be asked after more than 2 decades of clinical investigation.[1,2] Perhaps
we should first inquire as to why it has taken so long to answer this question.

History of Intraperitoneal Therapy for Ovarian Cancer

In the earliest days of the modern chemotherapeutic era (1950s),
it was recognized that the direct delivery of cytotoxic agents into the
peritoneal cavity had the potential to be a clinically useful approach in the
treatment of malignancies principally confined to this body compartment.[3,4]
However, it was only with the publication of a pharmacokinetic modeling study by
Dedrick et al in the late 1970s that a sound theoretical rationale for this
approach in the management of ovarian cancer was presented.[1]

Simply stated, this model predicted that for certain cytotoxic
agents, higher concentrations and longer durations of tumor exposure could be
achieved with the intraperitoneal, rather than systemic, delivery of the same
drug. This article stimulated considerable interest in the concept of regional
therapy
with antineoplastic drugs in the treatment of ovarian cancer, and subsequently,
numerous phase I and II trials of single-agent and combination intraperitoneal
chemotherapies were conducted.[2,5-7]

These studies, conducted during the 1980s and early 1990s,
revealed a major pharmacokinetic advantage associated with the regional delivery
of selected antineoplastic agents (Table 1),[2,5-7] and established the
feasibility and safety of this approach. These studies also demonstrated that
surgically defined complete responses and long-term survival could be observed
following cisplatin (Platinol)-based intraperitoneal therapy delivered in the
second-line setting in patients with ovarian cancer (Table
2
).[8-16]

Unfortunately, these studies failed to provide a definitive
answer to the question asked in the title of this article: Is there a role for
intraperitoneal chemotherapy in the management of ovarian cancer? In fact, this
question could only be answered directly through well-designed randomized phase
III studies, the results of which were not available until relatively recently.

Phase III Trials of Intraperitoneal Therapy as Initial
Management
of Ovarian Cancer

Table 3 lists the regimens studied in the few phase III trials
of intraperitoneal therapy in the initial management of ovarian cancer.

Cisplatin Plus Cyclophosphamide

In 1996, investigators from the Southwest Oncology Group (SWOG)
and the Gynecologic Oncology Group (GOG) published the results of the first
large randomized phase III trial comparing intraperitoneal chemotherapy to
standard intravenous (IV) chemotherapy in the treatment of advanced ovarian
cancer.[17] In this landmark study, more than 600 patients, whose largest
residual intraperitoneal tumor mass was < 2 cm in maximum diameter, were
randomized to receive either IV or intraperitoneal cisplatin (100 mg/m2). All
patients were also treated with IV cyclophosphamide (Cytoxan, Neosar) 600 mg/m2.

Toxicity: As anticipated, there was more abdominal
discomfort in the patient population receiving the intraperitoneal program than
the IV approach. However, in the majority of treated individuals, this
discomfort was temporary and patients were able to continue with the planned
treatment program.

Of some surprise, the study revealed a statistically significant
reduction in both neutropenia and ototoxicity associated with the regional
treatment regimen. Overall, however, there were no major differences between the
two treatment arms in terms of severe toxicity, including treatment-related
deaths or removal from the study due to side effects. The toxicity data
generated in this study were of interest, particularly considering the
"learning curve" required by both surgeons and medical oncologists
participating in this trial (many of whom had never previously administered
intraperitoneal chemotherapy).

 Survival: The study was most notable for the overall
survival results of the two treatment arms. There was a statistically
significant improvement in overall survival associated with the intraperitoneal
cisplatin arm—49 months for the intraperitoneal arm vs 41 months for the IV
arm (P = .02). This outcome translated into approximately a 22% reduction of
relative risk of death. To place these results into perspective with other
currently accepted standard-of-care interventions, the relative risk reduction
observed in this important intraperitoneal trial is comparable to that observed
with the use
of adjuvant tamoxifen (Nolvadex)
for women with node-positive breast cancer.[18]

Thus, it is now appropriate to ask: If the results of this
randomized trial were so favorable, why did the oncology community not embrace
them and begin using intraperitoneal therapy as a standard treatment approach in
small-volume residual advanced ovarian cancer? While several possible answers
might be provided, perhaps the most likely is the fact that this study did not
include the use of paclitaxel (Taxol)
in either the control or experimental treatment arm.

Cisplatin, Paclitaxel, and Carboplatin

The role of paclitaxel in the standard initial management of
ovarian cancer had not been demonstrated at the time the aforementioned
randomized intraperitoneal study was initiated.[19] Thus, investigators
questioned whether the favorable results associated with the use of
intraperitoneal cisplatin would still be achievable in a regimen that included
paclitaxel (rather than cyclophosphamide). Therefore, researchers from SWOG,
GOG, and the Eastern Cooperative Oncology Group (ECOG) conducted a second
randomized, controlled trial examining the clinical utility of intraperitoneal
vs intravenous cisplatin in patients with small-volume residual advanced ovarian
cancer, but this time also administered IV paclitaxel to all patients as a
component of the treatment program.[20]

Before discussing the results of this trial, several additional
features of this study should be noted. First, the maximum tumor diameter
permitted for entry into this trial was only 1 cm, compared to 2 cm for the
previously discussed study.[15] Presumably, this clinical feature would improve
the survival outcome for both treatment arms. Second, the investigators
attempted to optimize the chances that the high local concentrations of
cisplatin present within the peritoneal cavity following regional delivery could
be translated into a favorable outcome by administering two courses of
moderately high-dose IV carboplatin (Paraplatin) prior to the initiation of the
regional program. It was hypothesized that this IV therapy could
"chemically debulk" the tumor, thereby decreasing the size of any
residual tumor masses before the administration of intraperitoneal
cisplatin.[21]

Results: To date, the outcomes associated with this
randomized trial have been presented only in abstract form.[20] However, the
preliminary results provide additional data regarding a potential role of
intraperitoneal drug delivery in the management of small-volume residual
advanced ovarian cancer.

Unfortunately, the two courses of moderately high-dose
carboplatin were associated with severe bone marrow suppression, particularly
thrombocytopenia, which resulted in 19% of patients in the experimental arm
receiving two or fewer courses of intraperitoneal therapy. In addition,
gastrointestinal toxicity was significantly greater in the experimental
treatment arm. Consequently, the experimental regimen could not be delivered as
initially planned in a substantial percentage of individuals, thereby
potentially reducing the impact of regional drug delivery on the ultimate
outcome.

Nevertheless, use of the intraperitoneal program was found to be
associated with a statistically significant improvement in progression-free
survival (28 vs 22 months, P = .01) and a borderline improvement in overall
survival (63 vs 52 months, P = .05).[20] The relative risk reduction for death
(19%) was remarkably similar to that seen in the previously discussed randomized
intraperitoneal chemotherapy study—a finding that provides strong support for
the general conclusions regarding the effectiveness of regional therapy observed
in the individual
trials.

Investigators of this second randomized intraperitoneal study
appropriately concluded that the survival advantage associated with this regimen
could not justify the level of toxicity. Consequently, they recommended that
this specific program not be employed in standard clinical practice or
considered for further clinical development. However, despite the observed
toxicity, the results of this study continued to stimulate interest with regard
to defining a role for intraperitoneal drug delivery in ovarian cancer.

Cisplatin Plus
Intraperitoneal Paclitaxel

To further explore this potential, GOG investigators
subsequently initiated a third randomized intraperitoneal trial, this time
examining an experimental regimen containing intraperitoneal cisplatin and both
intravenous and intraperitoneal paclitaxel. The study arm of this trial was
again compared to a control arm of IV cisplatin and IV paclitaxel.

The use of intraperitoneal paclitaxel in this trial was based on the impressive pharmacokinetic advantage (>
1,000-fold increased exposure of the peritoneal cavity vs the systemic
compartment) noted with the regional delivery of the agent.[22,23] In addition,
previously reported phase II data had revealed that the intraperitoneal
administration of paclitaxel, employed as second-line therapy for ovarian
cancer, was associated with a high surgically documented complete response rate
in patients with microscopic disease only at the initiation of the regional
treatment program.[24]

Results: Preliminary results of this ongoing randomized
intraperitoneal chemotherapy trial are anticipated within the next 2 years.
These results should help define a role for regional treatment in the front-line
management of small-volume residual advanced ovarian cancer. This study is
particularly relevant because it utilizes the intraperitoneal route to
administer both the most active drug in ovarian cancer (a platinum agent) and
the drug with the most profound pharmacokinetic advantage for cavity exposure
(paclitaxel) following regional delivery.

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