2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Intraperitoneal Treatment in Ovarian Cancer:
The Gynecologic Oncology Group Perspective
in 2012
By Deborah K. Armstrong, MD, Keiichi Fujiwara, MD, PhD, and Danijela Jelovac, MD
Overview: The peritoneal cavity is the major site of disease in
ovarian cancer. The peritoneal predominance of disease provides
a rationale for administration of chemotherapy within
the peritoneal cavity. Intraperitoneal (IP) chemotherapy for
ovarian cancer has been studied rigorously for more than 30
years and has been reproducibly shown to improve the survival
of patients with ovarian cancer. Three large randomized
trials of IP compared with intravenous (IV) therapy have
THE PERITONEAL cavity is the major site of disease in
ovarian cancer. 1 Whereas ovarian cancer can spread
hematogenously or via the lymphatic system, the bulk of the
tumor will be found on peritoneal surfaces. This peritoneal
disease results from shedding of ovarian tumor cells into the
peritoneal cavity, circulation of these cells throughout the
abdomen and pelvis, and eventual implantation onto peritoneal
surfaces. Viability of these cells and successful tumor
growth is further dependent on the development of sufficient
neovasculature to support cell survival and tumor growth.
This unique pattern of spread within the relatively accessible
peritoneal cavity has led to attempts at surgical cytoreduction
before administration of chemotherapy. Dating
back more than 30 years, nearly every study has demonstrated
an inverse correlation between volume of tumor
remaining at the completion of initial surgery and overall
survival for patients with ovarian cancer. 2 The peritoneal
predominance of ovarian cancer also provides a rationale
for administration of chemotherapy within the peritoneal
cavity.
When drugs are administered intravenously they are
immediately diluted in the blood. When the same drugs are
administered via the intraperitoneal (IP) route, the peritoneum
can have sustained exposure to higher concentrations
of drugs for a more prolonged period of time, whereas normal
tissues such as the bone marrow may be relatively spared.
The pharmacologic advantage of administering a drug by
the peritoneal route can be quantified by the ratio of the
drug concentration (usually measured in area under the
curve [AUC]) in the peritoneal cavity to that in the plasma
after IP compared with IV injection. Table 1 shows this
pharmacologic advantage for some drugs commonly used in
ovarian cancer. 3-5
The rate at which the peritoneal drug concentration decreases
is a function of the volume of the fluid in the
peritoneal cavity, the surface area through which the drug
diffuses out of the cavity, the permeability of this surface,
and the difference in free drug concentration between the
cavity and the plasma. The clinical effectiveness of a drug
administered IP is affected not only by this pharmacologic
advantage but also by tumor penetration and distribution of
the drug within the peritoneal cavity. It is thus predicted
that tumor volume and the presence of substantial adhesive
disease will influence the efficacy of IP therapy. 5
IP chemotherapy was first used in the 1950s for palliation
of ascites, primarily from colorectal carcinoma. In the 1970s
IP treatment became more feasible with the development of
demonstrated statistically significant improvement in clinical
outcome measures. Despite this, the IP approach has not
gained widespread acceptance in the treatment of ovarian
cancer. Here, we review reported, recently completed, and
ongoing trials of IP therapy in ovarian cancer including attempts
to improve the tolerability and acceptance of this
proven approach.
permanent indwelling peritoneal catheters that allowed for
repetitive IP administration without requiring repeated
placement of temporary peritoneal catheters. Shortly after
this breakthrough, IP therapy began to be studied in ovarian
cancer. Following is a review of data from completed trials of
IP therapy in ovarian cancer, and a summary of ongoing and
recently completed trials and of novel and innovative approaches
to IP therapy, with a particular focus on randomized
phase III trials and studies from the Gynecologic
Oncology Group (GOG).
Randomized Trials of IP Versus IV Therapy in
Ovarian Cancer
Eight published comparative studies of IP compared with
IV administration for initial therapy of ovarian cancer were
the subject of a Cochrane meta-analysis in 2007. 6 This
analysis of 1,819 women showed that they were less likely to
die if they received an IP component to the chemotherapy
(hazard ratio [HR] � 0.79) and that the disease-free interval
was also significantly prolonged (HR � 0.79). They did also
note that there may be greater serious toxicity with IP
therapy and that there is a potential for catheter-related
complications in patients receiving IP therapy.
In January 2006, the U.S. National Cancer Institute (NCI)
released a clinical announcement of IP therapy for ovarian
cancer. 7 They evaluated data from eight trials and concluded
that IP chemotherapy is beneficial for optimally
debulked stage III ovarian cancer. On average, for the eight
trials, IP therapy was associated with a 21.6% decrease in
the risk of death (HR � 0.79) which is estimated to translate
into a 12-month increase in overall median survival. The
three largest trials, responsible for more than 75% of the
patients in this analysis, were conducted as U.S. cooperative
group trials and will be further discussed in this section.
The first of these trials, led by Southwest Oncology Group
(SWOG #8501) with the GOG (GOG #104), used IV cyclophosphamide
(600 mg/m 2 ) with either IP or IV cisplatin (100
mg/m 2 ) administered every 3 weeks for six cycles. 8 This
study showed a survival advantage for the group receiving
From the Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Deborah K. Armstrong, MD, Associate Professor of Oncology,
Associate Professor of Gynecology & Obstetrics, Johns Hopkins Sidney Kimmel Cancer
Center, 1650 Orleans Street, Room 190, Baltimore, MD 21231; email: darmstro@jhmi.edu.
© 2012 by American Society of Clinical Oncology.
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