As Drs. Sabbatini and Spriggs point out in their review, the majority
of ovarian cancer patients continue to present with advanced-stage
disease, and only a minority are cured after primary surgery and
chemotherapy. At present, recurrent disease is best viewed as a
chronic illness that requires ongoing management. A number of
therapeutic options are available, but opportunities for cure remain
limited. My comments will focus on post-remission therapy,
small-volume residual disease, intraperitoneal therapy, secondary
cytoreductive surgery, choice of second-line chemotherapy, and
participation in phase II studies.
The framework employed by the authors for classifying refractory,
persistent, and recurrent disease is useful. The schema could be
broadened to include patients in clinical and pathologic complete
remission, as we know that the majority of these individuals harbor
residual microscopic disease and will eventually relapse. Clinical
trials have not yet documented the efficacy of additional
intraperitoneal or systemic chemotherapy in this setting.
In an example from Memorial Sloan-Kettering Cancer Center (MSKCC)
cited by the authors, the use of intraperitoneal cisplatin (Platinol)
and etoposide following negative second-look laparotomy reportedly
improved disease-free survival, as compared with concurrent
historical controls. Confounding variables in this analysis
include selection bias and a reduced frequency of paclitaxel
(Taxol)-containing therapy in the controls. In addition, variations
in the monitoring for recurrent disease, including serum CA-125,
could have led to differences in the estimation of disease-free
survival. Overall survival would be a more objective end point but
probably would not be convincing in the absence of a randomized
trial. Without more compelling data, this remains an interesting
pilot study that has not changed routine clinical practice.
Results from a randomized trial of intraperitoneal phosphorus-32 (32P)
in patients with negative second-look laparotomy are pending, and
the current randomized trial sponsored by the Gynecologic Oncology
Group (GOG) and Southwest Oncology Group (SWOG) is evaluating the
role of intraperitoneal interferon-alfa (Intron A, Roferon-A), based
on encouraging results in patients with small-volume residual
disease. This is an important study, but it will be difficult to
complete due to the declining rate of second-look laparotomy.
Small-Volume Residual Disease
Although microscopic or small-volume residual disease would appear to
be a good target for intraperitoneal chemotherapy, the role of
primary or secondary intraperitoneal therapy has not been
established. The authors quote the inverse relationship between tumor
size and survival observed in the intergroup randomized trial of
primary intraperitoneal vs intravenous therapy (GOG-104). However,
this size-related survival advantage was seen in both arms of
the trial. No additional impact of intraperitoneal therapy on
survival was detected in patients with microscopic or small-volume
disease, who would have been predicted to show maximal benefit due to
restricted drug penetration, although the study did not have
sufficient statistical power to reveal small differences uncoverd by
The value of primary therapy with intraperitoneal cisplatin remains
unclear, and the use of intravenous therapy with carboplatin
(Paraplatin) and paclitaxel remains prevalent in the community. Data
from a recently completed randomized trial that includes
intraperitoneal cisplatin and intravenous paclitaxel (GOG-114) are
awaited, and this question will be addressed further in a new GOG
trial comparing intravenous and intraperitoneal paclitaxel.
Unfortunately, there are no randomized trials planned that will
evaluate secondary intraperitoneal chemotherapy in patients with
recurrent or persistent disease.
Assessment of residual disease by laparotomy can be imprecise. In
particular, it is not always clear which patients are in the midst of
an ongoing tumor response and, thus, may benefit from further
therapy, and which have already developed drug-resistant disease.
Also, a small number of patients with microscopic residual disease
have achieved pathologic remission at third-look laparotomy without
intervening chemotherapy, suggesting that not all residual disease
may be clonogenic.
Finally, from a purely technical perspective, the increased incidence
of adhesions and loculations can restrict peritoneal access in
patients with recurrent disease and/or multiple prior surgical
procedures. Ultimately, intraperi- toneal therapy may be more
successful with immunologic approaches, such as regulatory cytokines
or vaccines, that do not depend on direct tumor contact to mediate
indirect antitumor effects.
Investigators at MSKCC have conducted several nonrandomized phase II
studies to evaluate second-line therapy in ovarian cancer. Although
these studies show encouraging results in comparison to historical
controls, it is important to remember that randomized phase III
trials are needed to answer many of the questions that have been
raised by these pilot data. For example, the authors report that a
small number of patients have remained disease-free after achieving
pathologic complete remission following intraperitoneal cisplatin.
However, long-term disease-free survival has also been observed in
patients with small-volume disease who received intraperitoneal
interleukin-2 (Proleukin) and interferon-alfa. Other phase II
studies have failed to show an advantage for consolidation with
intraperitoneal cisplatin after primary systemic therapy, suggesting
that only a highly selected minority may benefit from this approach.
The optimal management of small-volume persistent disease following
initial therapy with platinum and paclitaxel remains unclear. As
previously mentioned, reassessment laparotomy is generally unable to
accurately distinguish drug-resistant residual disease from sensitive
disease or nonclonogenic tumor remnants. However, there is a
hypothesis that some patients with responsive disease may benefit
from high-dose consolidation--a question that cannot be resolved with
additional phase II studies.
Although hampered by poor initial accrual, GOG-164 is a phase III
randomized trial that aims to evaluate high-dose therapy with
stem-cell support following response to initial chemotherapy. Recent
amendments to broaden eligibility criteria should improve physician
acceptance and patient accrual to this important study, but it
remains to be determined whether there will be adequate accrual to
satisfy the study objectives in a timely fashion. I agree with the
authors that there is no role for dose-intensive therapy in patients
with persistent disease outside of a clinical trial.
Secondary Cytoreductive Therapy
The authors refer to secondary cytoreductive surgery in the context
of recurrent platinum-sensitive disease. Certainly, some patients
with a platinum-sensitive recurrence may derive palliative benefit
from surgery. However, this group of patients can also benefit from
chemotherapy, and usually harbor additional sites of disease. Once
again, recommendations suffer from a lack of data, particularly from
phase III randomized trials.
As we learn more about tumor invasion, angiogenesis, and
adhesion molecules, it may become possible to predict outcome on
the basis of tumor biology, rather than the technical ability to
perform debulking surgery. It would be appealing to design a phase
III study of initial vs delayed cytoreductive surgery with assessment
of biological markers and clinical end points. Thus far, physician
bias has prevented the development of such a trial for the management
of either initial or recurrent disease. In the minority of patients
who present with solitary or regional recurrence, secondary
cytoreductive surgery or radiation may provide palliative benefit but
would be unlikely to substantially improve overall survival.
Choice of Second-Line Chemotherapy
Many options exist for systemic management of recurrent disease
following initial response to chemotherapy. The use of platinum,
paclitaxel, topotecan (Hycamtin), gemcitabine (Gemzar), liposomal
doxorubicin (Doxil), prolonged oral etoposide, vinorelbine
(Navelbine), and other agents are discussed in detail by the authors.
Choices among these different therapies are guided largely by
physician and patient preference and issues of convenience or cost.
Regardless of the therapy chosen, it is important to monitor tumor
response so that alternative therapies can be considered prior to
excessive deterioration in vital organ function or performance
status. In the absence of dose-limiting toxicity or tumor
progression, patients should remain on their current therapy. Stable
disease is a common and acceptable outcome in this palliative
setting. Some agents, such as topotecan and paclitaxel, offer little
cumulative toxicity and can be safely administered over multiple
cycles to patients with stable disease.
Participation in Phase II Studies
Careful consideration should be given to current phase II studies,
which aim to define new agents and optimize the use of established
agents. Although patients with a prolonged disease-free interval have
an increased likelihood of responding to platinum-based therapy,
platinum will not be curative in this population, and other standard
or investigational therapy can be safely used prior to retreatment
with platinum. Of note, prolongation of the platinum-free interval
with non-platinum-based therapy can restore platinum sensitivity in
some patients with previously documented platinum-resistant
disease. Thus, it is appropriate to defer platinum therapy and
consider participation in clinical trials even for patients with
There is no role for dose-intensive therapy in the setting of
recurrent disease. Randomized trials evaluating more aggressive
regimens, such as higher doses of paclitaxel, have reported a modest
increase in response rates but no improvement in progression-free
interval or survival. Single agents should be used at standard
doses and schedules, with adjustments based on patient tolerance. The
primary goal in this setting is control of disease and maintenance of
quality of life, not maximal tumor shrinkage. Hematopoietic growth
factors should not be routinely used or required for maintenance of
dose intensity, although erythropoietin (Epogen, Procrit) might be
considered to reduce the frequency of blood transfusions in heavily
pretreated patients receiving multiple cycles of marrow-suppressive
therapy, such as topotecan.
In the palliative setting, where platinum resistance is common, it is
unclear whether combinations offer any advantage over single agents.
One randomized phase II study favored the use of a platinum-based
combination over single-agent paclitaxel, but this study has been
presented only in abstract form.
There is certainly an increased risk of toxicity from combinations,
and it is not always possible to determine which drug is responsible
for clinical response or toxicity. However, preclinical models have
suggested that some combinations may offer synergy, such as the use
of either gemcitabine or topotecan with cisplatin, or topotecan
followed in sequence by etoposide. These and other combinations are
under evaluation in phase I/II trials. Outside of a clinical trial, I
would favor the use of single agents, unless the patient has had a
prolonged disease-free interval of more than 2 years.
The authors have written a thoughtful review of second-line therapy,
drawing on their extensive experience with phase I/II trials at
MSKCC. This provides a useful framework for clinical decision-making
in patients with ovarian cancer. Again, emphasis should be placed on
greater patient participation in clinical trials to define more
active regimens for primary therapy. This is of particular importance
in view of the diverse chemotherapeutic agents that have been found
to be active in this setting.