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Surgical Cytoreduction in Ovarian Cancer

Surgical Cytoreduction in Ovarian Cancer

ABSTRACT: The majority of ovarian cancer patients present with advanced-stage disease, for which the goal of surgery is not only to document the extent of disease but also to perform surgical cytoreduction or tumor debulking. Cytoreductive surgery for ovarian cancer is generally performed at the time of diagnosis, when it is referred to as primary cytoreduction. It is also performed during primary chemotherapy (interval cytoreduction) and after disease recurrence (secondary cytoreduction). Over the past 3 decades, numerous retrospective analyses have established the role of primary cytoreduction in the management of advanced-stage ovarian cancer. However, recent studies have reported that certain patients benefit from a neoadjuvant chemotherapeutic approach, in which chemotherapy is given to those with presumed advanced ovarian cancer prior to cytoreductive surgery. Although several theoretical advantages of this approach over primary cytoreduction have been reported, significant concerns remain. The role of neoadjuvant chemotherapy is being investigated in a randomized study currently being conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada. The benefit of interval cytoreduction was investigated in two randomized prospective trials conducted by the EORTC and the Gynecologic Oncology Group (GOG). Final results were somewhat conflicting, but both studies supported an extensive attempt at surgical cytoreduction during primary therapy. In the management of recurrent disease, the majority of retrospective studies demonstrate a benefit to secondary cytoreduction. The GOG is currently attempting to better define the role of secondary cytoreduction in a prospective, randomized trial.

Ovarian cancer is the third most
common cancer of the female
reproductive tract, yet has the
highest case fatality ratio of all gynecologic
malignancies. Every year, approximately
23,000 American women
are diagnosed with the disease and
about 14,000 die, despite aggressive
management.[1,2] One of the main
reasons for the high fatality ratio
among ovarian cancer patients relates
to the fact that the majority are diagnosed
with advanced disease. Table 1
summarizes the International Federation
of Gynecology and Obstetrics
(FIGO) staging system for ovarian
cancer.[3] The distribution by FIGO
stage of over 4,000 ovarian cancer
patients is presented in Table 2.[3]

Surgery followed by chemotherapy
is the standard approach to the management
of ovarian cancer. Despite
many chemotherapeutic advances over
the past 2 decades, surgery remains the
cornerstone of effective disease management.
For patients who present
with early-stage disease, surgery involves
a comprehensive staging procedure
with the goal of thoroughly
evaluating the peritoneal cavity and
the retroperitoneum to identify clinically
inapparent sites of metastasis.
The rationale and procedures performed
during staging are described elsewhere
and are not the focus of this review.[4]

For patients with advanced-stage
ovarian cancer, the goal of surgery is
cytoreduction or tumor debulking.
"Primary" cytoreduction is performed
at the time of diagnosis, prior to the
initiation of cytotoxic chemotherapy.
In cases of suboptimal primary
cytoreduction, "interval" cytoreduction
has been described as a second
attempt at surgical debulking after
the initiation of primary chemotherapy,
but prior to its completion.
"Secondary" cytoreduction generally
refers to surgical debulking performed
at the time of disease recurrence. The
role of surgical cytoreduction in the
management of advanced and recurrent
ovarian cancer is the subject of
this review.

Primary Cytoreduction

As stated previously, the majority
of ovarian cancer patients present with
advanced disease, for which the goal
of surgery is to document the stage and
extent of the disease, and more importantly,
to resect as much grossly visible
tumor as possible with the knowledge
that microscopic and perhaps
macroscopic tumor will be left behind.
For most solid tumors, such as lung,
pancreatic, and gastric cancer, surgical
"cytoreduction" or "debulking" has
no role in management because no
effective chemotherapy protocol exists
for these malignancies. However, there
are effective chemotherapy protocols
for ovarian cancer. Consequently, both
theoretical and clinical benefits have
been demonstrated after surgical
cytoreduction for the majority of
newly diagnosed cases of ovarian cancer,
as well as in select cases of recurrent
disease.

Theoretical Benefits
The most important theoretical effect
of primary cytoreductive surgery
is its impact on the chemosensitivity
of the residual tumor nodules. Chemotherapeutic
agents exert maximum
cytotoxicity on tumors that are adequately
perfused, well differentiated,
and have a high mitotic index. Smallervolume
residual tumors after cytoreduction
have an adequate blood supply
creating an oxygen- and nutrientrich
environment that promotes cell
division. Bulky noncytoreduced tumors,
however, outgrow their blood
supply, creating a nutrient-deficient
and hypoxic environment that halts
cell division. Cytoreduction, therefore,
maximizes the chemotherapeutic response
because the cell-cycle-specific
and -nonspecific chemotherapeutic
agents act when the cells have a high
mitotic rate and are, therefore, most
susceptible to cytotoxic drugs.

Clinical Benefits
Griffiths[5] was the first investigator
to quantify the diameter of the largest
residual tumor in relation to chemotherapy
response rates and survival.
He demonstrated an inverse relationship
between maximal residual tumor
and patient survival. Since his landmark
study, many authors have confirmed
their observations.[6-9] Today,
the majority of studies use the diameter
of the largest remaining tumor
nodule as the measurement of residual
disease. Patients are divided into optimal
and suboptimal groups, using a
variety of cutoff points-from any visible
disease to 3 cm-to define optimal
cytoreduction. Overall, a clear
clinical benefit is observed when patients
are optimally cytoreduced. These
patients have higher response rates to
chemotherapy and also have higher
median survivals.[10]

In two large Gynecologic Oncology
Group (GOG) studies, Hoskins et
al further clarified the role of primary
cytoreductive surgery in patients with
advanced ovarian cancer.[6] In the first
study, the survival of patients who
were found to have abdominal disease
≥ 1 cm during surgery was compared
to that of patients with abdominal disease
of ≥ 1 cm that had then been surgically
cytoreduced to ≤ 1 cm. If
surgery was the only important prognostic
factor, then survival should have
been the same in the two groups. However,
patients with small-volume disease
survived longer than patients who
were cytoreduced to small-volume disease.
Further analysis showed that the
age of the patient, the grade of the tumor,
and the number of residual tumor
nodules were independent prognostic
factors. Although this study did
not show primary cytoreduction to be
ineffective, it did show that other factors,
including tumor biology, were
also important.

In the second study, cytoreduction
to ≤ 2-cm residual disease resulted in
a significant survival benefit, but all
residual diameters > 2 cm had equivalent
survival. Therefore, unless
cytoreduction resulted in the maximum
residual tumor diameter being
≤ 2 cm, surgical cytoreduction did not
improve survival.[11] Three distinct
groups of patients emerged from these
two studies: (1) those with no grossly
visible residual disease; (2) those with
optimal residual disease (≤ 2 cm); and
(3) those with suboptimal disease
(> 2 cm in diameter). The 4-year survival
rates for these patients were 60%,
35%, and 20%, respectively. Table 3
summarizes the largest studies in the
literature from both cooperative
groups[12,13] and single institutions[
14-16] that have analyzed the
survival of patients with stage III
ovarian cancer by residual disease after
primary cytoreductive surgery and
postoperative platinum-based chemotherapy.

  • Optimal Cytoreduction Parameters-
    Although the benefits of optimal
    cytoreduction for advanced
    ovarian cancer appear to be well established,
    as Table 3 demonstrates,
    the most appropriate cutoff point for
    optimal cytoreduction remains controversial.
    In his seminal paper, Griffith[
    5] used 1.5 cm as the cutoff point
    in defining optimal cytoreduction.
    Other authors have used values between
    any visible disease and 3 cm.
  • In 2001, we reported a 28% survival
    for 73 patients with advanced
    ovarian cancer cytoreduced to between
    1- and 2-cm residual disease, which
    was not significantly different from the
    21% 5-year survival of patients with
    > 2-cm residual disease. These survival
    rates were both significantly
    lower than the 50% 5-year survival for
    patients cytoreduced to ≤ 1 cm. These
    data support the current GOG definition
    of optimal cytoreduction as that
    with residual disease ≤ 1 cm.[16]

    At our institution, the rates of optimal
    cytoreduction for advanced ovarian
    cancer historically have been less
    than 50%.[16-18] In January 2001,
    with strong data supporting the survival
    benefits of optimal cytoreduction,[
    12-16] our service began
    incorporating the use of extensive upper
    abdominal cytoreductive procedures
    including diaphragm-stripping/resection,
    splenectomy, distal pancreatectomy,
    liver resection, resection of tumor
    from the porta hepatis, and cholecystectomy,
    if needed, to achieve optimal
    (≤ 1-cm residual) cytoreduction.

    We studied two separate groups of
    patients. Group 1 consisted of patients
    who had their primary surgery at our
    institution between November 1998
    and May 2000-a time when extensive
    upper-abdominal procedures
    were not utilized during primary
    cytoreductive procedures. Group 2 patients
    underwent their primary surgery
    between January 2001 and May
    2002-a time when a more aggressive
    approach to surgical cytoreduction
    was used. In the first group of patients,
    optimal cytoreduction was attained in
    50% of patients, compared to 76% in
    the second group (P < .01). Although
    operative time and estimated blood
    loss increased, complications did not
    increase significantly.[19]

  • Technologic Advances Allowing
    Maximal Cytoreduction
    -Other advances
    in surgical technology have
    allowed surgeons to maximize cytoreductive
    efforts, enabling them to remove
    virtually all visible disease. The
    main, new technologic advances consist
    of the cavitational ultrasonic surgical
    aspirator and the argon-beam
    coagulator. Bristow and Montz[20]
    have shown the feasibility and success
    of surgical cytoreduction using
    the argon-beam coagulator. They
    reported that the use of this device
    resulted in a 94% successful cytoreduction
    rate, compared to 64% without
    it.

    In a similar study, patients cytoreduced
    with the cavitational ultrasonic
    surgical aspirator had lower
    morbidity, decreased length of hospital
    stay, and a lower serum level of
    CA-125 at 1 and 2 months postsurgery,
    compared to patients not
    cytoreduced with this technology.[21]

Meta-analyses
Despite numerous studies demonstrating
improved survival of advanced
ovarian cancer patients who were optimally
cytoreduced, critics argue that
it is not the surgical cytoreduction that
leads to prolonged survival, but rather,
the inherent biology of the tumor
(which also enables optimal cytoreduction).
The meta-analysis by
Hunter and colleagues[22] is often
cited to support this argument. They
analyzed 58 articles encompassing
6,962 advanced ovarian cancer patients
and found that a 10% increase
in maximal cytoreductive surgery resulted
in a 4.1% increase in median
survival. However, the use of platinum-
based chemotherapy produced
an estimated 53% increase in median
survival. Hunter et al concluded that
surgery had a minor effect on the survival
of women with advanced ovarian
cancer. This meta-analysis has
been criticized because of the low rate
of optimal debulking and the lack of
treatment with optimal platinumcontaining
chemotherapy.[23]

More recently, Bristow et al[24]
performed a meta-analysis on the survival
effect of maximal cytoreduction
for ovarian cancer during the era of
platinum-based chemotherapy. This
analysis evaluated 81 studies involving
6,885 patients with stage III/IV
ovarian cancer and found that during
the platinum era, maximum cytoreduction
was a powerful determinant of
cohort survival. These investigators
showed further that each 10% increase
in maximal cytoreduction resulted in
a 5.5% increase in median survival.
They concluded that expert centers
with optimal cytoreduction rates of
75% or greater offered a 50% increase
in median survival over less experienced
centers with optimal
cytoreduction rates of 25% or less.

Stage IV Disease
The role of primary cytoreduction
in the management of stage III disease
is well defined; however, its benefit in
stage IV disease is not as clear. Most
studies that address survival in ovarian
cancer patients evaluate only stage III
disease or a combination of stage III
and IV disease. In stage IV disease-
which by definition includes extraperitoneal
or intrahepatic metastasis-
the benefit of surgical cytoreduction
has been questioned. An early study
by Wharton et al[25] reported a 4-year
survival of 9% in patients who were
cytoreduced to ≤ 2 cm. This study was
performed before the platinum-based
chemotherapy era, which may explain
the poor outcomes.[25] Additionally,
Goodman et al reported no significant
survival advantage for patients who
underwent optimal cytoreductive surgery
for stage IV epithelial ovarian
cancer compared to patients who were
suboptimally cytoreduced.[26]

Contrary to these reports, most other
studies have shown a survival advantage
for primary cytoreduction in patients
with stage IV ovarian cancer.[
17,27] Curtin and colleagues[17]
reported on 97 patients with stage IV
disease, of which 51% were optimally
cytoreduced (residual disease ≤ 2 cm).
Median survival for the optimally vs
suboptimally cytoreduced group was
40 vs 18 months (P = .0136). Bristow
and investigators[27] have also shown
the value of optimal debulking in
stage IV patients with liver metastases.
In this study, patients with optimal hepatic
and extrahepatic residual disease
had a median survival of 50.1 months,
compared to 27 months for those with
suboptimal hepatic but optimal
extrahepatic residual disease, and
7.6 months for patients with both
suboptimal hepatic and extrahepatic residual
disease. Table 4 summarizes recent
studies of surgical cytoreduction
for stage IV ovarian cancer.[17,26-30]

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy, which
is given to patients with advanced ovarian
cancer prior to cytoreductive surgery,
has several theoretical advantages
over primary cytoreduction.
These include (1) improvement of performance
status, especially in elderly
patients and those with pleural effusions
and ascites, (2) decrease in the
extent and morbidity of surgery by
reducing tumor volume preoperatively,
and (3) increase in the percentage
of patients undergoing optimal
cytoreduction. Several retrospective
studies have evaluated this approach,
but to date, no prospective randomized
data exist.

Vergote et al[31] reported on 285
patients with advanced ovarian cancer
treated between 1980 and 1997. In the
period from 1980 to 1988, all patients
underwent primary debulking surgery.
From 1989 to 1997, patients were
surgically evaluated to determine
whether they should receive primary
chemotherapy (43%) or primary
cytoreductive surgery (57%). The
crude 3-year survival in the later part
of the study was 42%, compared to
26% during the earlier period, when
all patients underwent primary
debulking surgery.

Ansquer et al[32] reported the
French multicenter experience with
neoadjuvant chemotherapy for ovarian
cancer deemed unresectable by either
laparoscopy (61%) or laparotomy
(39%). Patients received a median of
four cycles of chemotherapy preoperatively,
with 80% responding to chemotherapy
and subsequently undergoing
debulking, which was optimal in 91%.
The authors concluded that neoadjuvant
chemotherapy in unresectable
ovarian cancer led to the selection of
chemosensitive patients who, in the
majority of cases, could subsequently
undergo optimal cytoreduction. In addition,
aggressive cytoreduction was
avoided in patients with initial
chemoresistance.

Table 5 summarizes the studies that
have compared the neoadjuvant
approach to standard primary cytoreduction.[
33-36] Many of the patients
managed with neoadjuvant
chemotherapy had significant medical
comorbidities, and except for the
series reported by Kuhn and colleagues,[
35] none of the median survivals
using the neoadjuvant chemotherapy
approach those attained with
optimal primary cytoreduction.
Therefore, many authorities are
hesitant to uniformly use this strategy,
because it may result in a significant
number of patients being deprived
of the opportunity for optimal
cytoreduction and 5-year survival
rates of up to 50%.

However, if preoperative evaluation
could predict which patients had
disease so extensive that optimal
cytoreduction could not be performed,
these patients would be ideal candidates
for neoadjuvant chemotherapy.
Retrospective studies have evaluated
the accuracy of computed tomography
(CT) scanning and serum CA-125
level in selecting candidates for
optimal cytoreduction. These studies
report sensitivities, specificities,
positive predictive values, and negative
predictive values ranging from
50% to 100%, 63% to 100%, 61% to
100%, and 75% to 100%, respectively.[
37-40] We are currently evaluating
the ability of preoperative CT
scan and serum CA-125 to predict
optimal primary cytoreduction for
patients with advanced ovarian
cancer in a multicenter prospective
trial.

The role and indications for
neoadjuvant chemotherapy may be
further elucidated after the completion
of a randomized prospective trial
being performed jointly by the European
Organization for the Research
and Treatment of Cancer (EORTC)
and the National Cancer Institute of
Canada (NCI-C). In this trial, patients
with biopsy-proven stage IIIC/IV
ovarian cancer will be randomized to
primary cytoreduction vs neoadjuvant
chemotherapy. Both arms will receive
six cycles of paclitaxel and platinum
chemotherapy. The trial is expected
to close to accrual in 2005.[23]

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