2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Dose-Dense Chemotherapy and Neoadjuvant
Chemotherapy for Ovarian Cancer
By Keiichi Fujiwara, MD, PhD, Noriyuki Katsumata, MD, PhD, and
Takashi Onda, MD, PhD
Overview: Two of the innovative chemotherapeutic approaches
to ovarian cancer treatment, dose-dense chemotherapy
and neoadjuvant chemotherapy, will be discussed
herein. The primary concept of dose-dense chemotherapy is to
administer the same cumulative dose of chemotherapy over a
shorter period. Increased dose density is achieved by reducing
the interval between each dose of chemotherapy. The
Japanese Gynecologic Oncology Group (JGOG) first demonstrated
the survival advantage of dose-dense weekly administration
of paclitaxel in 2009. However, there are unanswered
questions, such as the question of dose-dense carboplatin
versus less dose-intensive regimens. Clear cell or mucinous
carcinomas seem to need other strategies, such as targeted
agents. The aim of neoadjuvant chemotherapy is to reduce
OVARIAN CANCER is the most lethal disease among
gynecologic malignancies because this disease remains
most commonly diagnosed in advanced stages. 1
Treatment of ovarian cancer has been investigated for
more than 30 years, since cisplatin was introduced in the
1970s. The clinical outcome of ovarian cancer was improved
because of the development of new anticancer agents and
advancements in surgical technique, equipment, and anesthesia.
Consequently, current standard therapy for advanced
ovarian cancer became a combination of maximum
surgical effort to remove bulky abdominal disease followed
by chemotherapy with paclitaxel plus carboplatin. However,
this has not changed since 1999, despite great efforts to find
new therapeutic strategy.
The first approach to improve survival was by finding
other effective drugs or treatment modalities. The most
thrilling area at this time is the development of new anticancer
drugs, especially targeted agents. It is unfortunate,
however, that most pharmaceutical companies have not paid
great attention to gynecologic cancer. Therefore, we had to
wait until 2010 before the first targeted agent, bevacizumab,
showed positive results in ovarian cancer chemotherapy. 2,3
In the meantime, investigators have conducted academic
trials to find a way to improve the prognosis of patients with
ovarian cancer. Those trials include intraperitoneal (IP)
chemotherapy, maintenance chemotherapy, and dose-dense
weekly chemotherapy.
On the basis of the results of these large-scale randomized
trials, the 4 th Ovarian Cancer Consensus Conference in
2010 4 yielded the following statement: “It was agreed unanimously
that the basic minimum comparator in a phase III
trial of advanced ovarian carcinoma must contain a taxane
and a platinum agent given for 6 cycles. Acceptable alternatives
must be supported by at least 1 clinical trial demonstrating
noninferiority or superiority to a standard taxane/
platinum regimen. Acceptable alternatives at present
include IP delivery to patients with small-volume residual
disease, weekly paclitaxel in combination with carboplatin
every 3 weeks, bevacizumab given concurrently with paclitaxel/carboplatin
followed by bevacizumab maintenance,
and 12 months of monthly paclitaxel maintenance given to
tumor volume or spread before main treatment. This could
then make the main procedures easier or less invasive, just
like breast-conserving surgery after neoadjuvant chemotherapy.
In advanced ovarian cancer, standard procedure is maximum
primary debulking surgery followed by chemotherapy.
Recently, a prospective randomized trial demonstrated that
neoadjuvant chemotherapy followed by interval debulking
surgery was not inferior to the standard procedure. However,
there are several questions that remain unanswered, such as
the suitable number of chemotherapy cycles before interval
debulking surgery. Some of those questions regarding dosedense
chemotherapy or neoadjuvant chemotherapy may be
resolved by ongoing or future prospective trials.
patients who achieve a clinical complete response with 6
cycles of standard paclitaxel/carboplatin.” Dose-dense paclitaxel
was the one regimen that dramatically improved the
survival of patients with ovarian cancer.
A second approach is to attempt to reduce the patient’s
tumor burden, if the clinical outcome is the same regardless
of the intensity or aggressiveness of the treatment. These
less-invasive treatments will improve the patients’ quality of
life compared with more intensive therapies. Neoadjuvant
chemotherapy is one of these approaches, although it is
controversial. In the 4 th Ovarian Consensus Conference
statement, 4 it was concluded that “Delayed primary surgery
following neoadjuvant chemotherapy is an option for selected
patients with stage IIIC and IV ovarian cancer as
included in EORTC 55971, 5 ” although this was the only
issue among the consensus conference in which the total
consensus was not reached.
Dose-Dense Chemotherapy
The basic concept of dose-dense therapy is to administer
the same cumulative dose of chemotherapy over a shorter
period. Increased dose density is achieved by reducing the
interval between each dose of chemotherapy. The theoretical
basis for this dose-dense chemotherapy strategy is derived
from the Gompertzian model, which is based on Norton-
Simon’s hypothesis. 6 In the Gompertzian model, smaller
tumors grow faster and so tumor regrowth between treatment
cycles is more rapid when cell kill is greatest. The
Norton-Simon model suggests that increasing the dose density
of chemotherapy will increase efficacy by minimizing
From the Department of Gynecologic Oncology, Saitama Medical School International
Medical Center, Saitama, Japan; Department of Medical Oncology, Nippon Medical
School, Musashikosugi Hospital, Kawasaki-City, Japan; Department of Gynecology, Kitasato
University School of Medicine, Sagamihara-City, Kanagawa, Japan.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Keiichi Fujiwara, MD, PhD, Department of Gynecologic
Oncology, Saitama Medical School, International Medical Center,1397-1 Yamane, Hidaka-
City, Saitama, 350-1298, Japan; email: fujiwara@saitama-med.ac.jp.
© 2012 by American Society of Clinical Oncology.
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