Since the 1970s, dose intensity has
been the siren song of the medical
oncologist. Simply stated, the words of the song keep repeating: "More is
better." The tendency of ovarian cancer is to spread via intraperitoneal
dissemination and to remain grossly confined to the peritoneal cavity throughout
much of its natural history. Fortunately or unfortunately, this tendency enables
an alternative to stem cell-supported high-dose therapy, by which we can
achieve even greater dose intensity.
Proof of Efficacy of
Gynecologic and medical oncologists have studied intraperitoneal
chemotherapy for 22 years. Several observations over that time form the basis of
intraperitoneal therapy. First, it is feasible to administer the most active
agents for ovarian carcinoma directly into the peritoneal cavity. Second, in
terms of peak drug levels, as well as area under the concentration-time curve
(AUC), the intraperitoneal route offers significant pharmacokinetic advantages
over intravenous (IV) administration. Third, significant systemic exposure to
cisplatin (Platinol) is still achieved because the drug is taken up into the
vascular compartment to a great extent. Fourth, phase I and II studies have
reported numerous responses.
While these rationales were being drawn, however, several
potential problems were largely downplayed: Extraperitoneal spread was not
infrequent; drugwas unevenly distributed in the peritoneal cavity because of
adhesions; intraperitoneal drug had poor depth of penetration into larger (>
0.5 cm) nodules; and there was a lack of evidence of the value of doubling dose
intensity instead of using the usual dose ranges of agents. These problems,
along with the adverse effects that are unique to intraperitoneal therapy, as
well as the more complex logistics of intraperitoneal drug administration,
mandate that there be a clinically documented advantage to the intraperitoneal
route in terms of efficacy before this approach is adopted as part of standard
As Dr. Markman correctly points out, the introduction of a more
complex and potentially more toxic approach requires a positive randomized phase
III trial. He cites three different clinical settings in which he believes
intraperitoneal therapy would be a rational option for ovarian carcinoma (Table
4 of the Markman article). Many of the reports on which this is based, however,
do not distinguish between patients who responded to front-line therapy (and
hence can be expected to be chemosensitive) and those who failed to respond to
Intraperitoneal Regimens as Second-Line Therapy
In a 1991 report, Dr. Markman and colleagues detailed studies of
72 patients treated with intraperitoneal platinum-based regimens after
front-line therapy. In those who responded to front-line therapy, a high
response rate was observed (59%), whereas those who failed to respond to
front-line platinum exhibited only a 9% response rate. Even in patients who were
chemosensitive, IV platinum-based second-line therapy produced similar results.
This raises serious questions about any defined role for intraperitoneal
chemotherapy in the second-line setting. Most telling, there are no randomized
phase III trials to establish any advantage for intraperitoneal therapy.
Intraperitoneal Therapy in the Front-Line Setting
In contrast to the second-line setting, three randomized phase
III trials have compared IV and intraperitoneal regimens for front-line
therapy.[2-3; D. Armstrong, personal communication, 2000.] In his article, Dr.
Markman discusses these extensively. The first of these, a Southwest Oncology
Group (SWOG)/ Gynecologic Oncology Group (GOG) trial compared IV
cyclophosphamide (Cytoxan, Neosar) plus either IV or intraperitoneal cisplatin
in patients with disease up to 2 cm in diameter. Results showed a statistically
significant survival advantage for the intraperitoneal regimen. Unfortunately,
however, this study suffers from several problems.
The initial goal of the study was to accrue 400 patients to seek
a hazard ratio of 0.67. At the midpoint of accrual, the investigators decided to
extend accrual to 650 patients to accrue sufficient patients with < 0.5-cm
disease to allow a subset analysis on the basis that only these patients could
be expected to benefit. The final analysis included all 650 patients and
detected a significant hazard ratio of 0.77. The original goal of the studya
hazard ratio of 0.67 was never achieved. Furthermore, the subset of patients
with < 0.5-cm residual disease did not significantly benefit from
intraperitoneal therapy (median survival: 51 vs 46 months). These problems raise
serious questions about any conclusion that the intraperitoneal regimen was
The second study, a GOG-SWOG study compared IV paclitaxel
(Taxol)/cisplatin to a dose-intense regimen of two cycles of carboplatin
(Paraplatin), AUC 9, followed by IV paclitaxel plus intraperitoneal cisplatin.
This trial was never intended as a study of intraperitoneal vs IV therapy.
Instead, the study compared a standard regimen to a dose-intense regimen
patterned after an approach developed at Memorial Sloan-Kettering Cancer Center.
This study showed a significant improvement in progression-free survival; but
the difference in survival is only of borderline significance. The
dose-intensive regimen was significantly more toxic.
Thus, while it is true that two randomized phase III trials have
shown a possible advantage for an intraperitoneal regimen, both studies have
sufficient problems in that neither can serve as the basis for using
intraperitoneal therapy as part of standard care. Dr. Markman perhaps stated it
best: "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." In short, even Dr. Markman feels there is no
defined role for intraperitoneal therapy at this point.
The third trial, a GOG study compared IV paclitaxel/cisplatin
to IV paclitaxel followed by intraperitoneal cisplatin and paclitaxel. This
studywhich has completed accrual and is now maturingshould answer once and
for all whether intraperitoneal therapy plays any front-line role in ovarian
cancer. In the absence of results from this third effort, however,
intraperitoneal regimens should not be used for ovarian carcinoma outside of
If, after all of this, there remain skeptics who insist that
intraperitoneal therapy has a proven advantage, such individuals should ask
themselves these questions: If the issue were settled, why was a third trial
necessary? If the advantages are clear, why do so few physicians dealing with
ovarian carcinoma recommend intraperitoneal therapy? More is better, more is
better, more is better. . . . It is, isn’t it?
1. Markman M, Reichman B, Hakes T, et al: Responses to
second-line cisplatin-based intra- peritoneal therapy in ovarian cancer:
Influence of a prior response to intravenous cisplatin. J Clin Oncol
2. Alberts D, Lui P, Hannigan E, et al: Intra-peritoneal
cisplain plus intravenous cyclophosphamide versus intravenous cisplatin plus
intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med
3. Markman M, Bundy B, Benda J, et al: Randomized phase 3 study
of intravenous cisplatin/paclitaxel versus moderately high-dose intravenous
carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in
optimal residual ovarian cancer: An intergroup trial (GOG, SWOG, ECOG)
(abstract). Proc Am Soc Clin Oncol 17:361a, 1998.