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Management of Early Ovarian Cancer

Management of Early Ovarian Cancer

ABSTRACT: Epithelial ovarian cancer is the leading cause of death from gynecologic malignancies in the United States due, in large part, to the advanced stage at which it is commonly diagnosed. However, approximately one-third of cases are discovered at an early stage, when tumor is limited to the pelvis. Certain prognostic factors have been identified, which place patients with early disease at risk for recurrence and warrant the use of adjuvant therapy. Systemic chemotherapy remains the most commonly used adjuvant therapy in this setting, and several randomized European trials have recently suggested a benefit to its use. These studies, however, suffered from the lack of comprehensive staging, which must be considered when interpreting the literature on earlystage disease. Ideally, these patients should have access to a gynecologic oncologist prior to their initial surgical procedure.

Ovarian cancer consistently ranks
as the number 1 cause of death
from gynecologic malignancies
in the United States. In 2003, an
estimated 25,400 new cases of ovarian
cancer were diagnosed and approximately
14,300 women died from the
disease.[1] The death total exceeds
that of all other gynecologic cancers
combined, due in large part to the
advanced stage at which the majority
of ovarian cancers are diagnosed.

For purposes of this review, earlystage
ovarian cancer can be classified
as disease that has not spread beyond
the true pelvis; ie, International Federation
of Gynecology and Obstetrics
(FIGO) stage I or II (Table 1). Earlystage
ovarian cancer comprises approximately
one-third of all cases of
the disease and is associated with a
5-year survival rate ranging from 66%
to 90%.[2]

Early-stage ovarian cancer can be
further subclassified based on the need
for adjuvant therapy. The risk of recurrence
is defined by certain prognostic
factors, and although several
clinicopathologic factors have consistently
proven to place a patient at risk
of relapse, there is disagreement about some factors. Controversy also continues
as to what constitutes optimal
treatment.

This article focuses on epithelial
ovarian cancers, which comprise the
majority of ovarian cancers. Unfortunately,
many studies of early-stage ovarian
cancer are limited by inadequate
staging and may overestimate the incidence
of early disease while underestimating
prognosis. In addition, the
unrecognized inclusion of borderline
tumors could potentially skew results.

Development of Ovarian Cancer

Epithelial ovarian cancer is believed
to originate from the single
layer of surface epithelium that covers
the ovary. Disruption of this layer
during ovulation may lead to invagination
and result in cystic ovarian
growths. Molecular genetic and morphologic
techniques have provided
evidence in support of this hypothesis.
Examination of stage I ovarian
carcinomas has demonstrated that they
contain inclusion cysts with a morphologic
continuum of normal epithelium,
dysplastic epithelium, and
invasive carcinoma.[3]

Further evidence that epithelial inclusions
may be the origin of ovarian
carcinoma has also been demonstrated
on the genetic level. Using laser
capture microdissection and microarray
technology, Leitao et al[4] showed
that the gene expression profiles of
ovarian cystic epithelium were significantly
different from those of surface epithelial cells. They identified
126 genes that were differentially
expressed in cysts compared to surface
epithelium, with upregulation of
cancer-specific antigens and putative
oncogenic factors, downregulation of
putative tumor suppressors, and altered
expression of numerous genes
associated with invasive disease.
These data support the theory that epithelial
inclusions represent a likely
site of origin of ovarian cancer.

Disease Spread
At a certain point, ovarian cancer
cells will spread beyond the confines
of the ovary. This is believed to occur
by either direct extension, exfoliation
of cells into the peritoneal cavity, lymphatic
spread, or hematogenous dissemination.
Ovarian cancer will
eventually violate the ovarian capsule
and spread directly to adjacent organs.
In addition, once the capsule
has been disrupted, exfoliated viable
cells can be transported throughout
the peritoneal cavity by normal peritoneal
fluid and can implant on the parietal and visceral peritoneal surfaces,
resulting in carcinomatosis.

Lymphatic spread of ovarian cancer
is believed to follow the vascular
drainage of the ovary. In particular,
the right ovarian vein drains directly
into the inferior vena cava, and the
left drains into the left renal vein. Lymphatic
drainage from the ovary also
occurs via the broad ligament and can
lead to nodal disease in the pelvis. On
occasion, spread via the round ligament
can lead to involvement of the
inguinal lymph nodes. Finally, hematogenous
spread can result in liver,
lung, central nervous system, or bone
metastases. An understanding of the
potential routes of spread is essential
prior to undertaking a search for
extraovarian spread of disease.

Staging of Ovarian Cancer

The importance of properly staging
ovarian cancer cannot be overemphasized,
given that adjuvant
chemotherapy is recommended to treat
all but the earliest stages of disease.
The current FIGO staging system for
ovarian cancer is based on a comprehensive
surgical evaluation of the abdomen
and pelvis and the spread
pattern of the disease. Any surgeon
who is confronted with an ovarian
mass must be prepared to perform a
staging procedure. The critical elements
of the staging procedure are
listed in Table 2.

Inadequate Staging
Despite the importance of the primary
surgical exploration, the procedure
is performed in many women by
a general obstetrician/gynecologist or
general surgeon. McGowan et al demonstrated
that nearly half of 291
patients who underwent surgical exploration
for ovarian cancer had incomplete
documentation of stage at
initial laparotomy.[5] When the data
were analyzed by specialty, only 35%
of general surgeons and 52% of general
obstetricians/gynecologists documented
a complete staging procedure,
compared to 97% of gynecologic oncologists.
However, only 12% of patients
had their initial surgery performed
by a gynecologic oncologist.

Trimbos et al also illustrated the problem of improper staging of early-
stage ovarian cancer.[6] In this series
from the Netherlands, 59 patients
underwent their initial surgical procedure
at a peripheral hospital, and
only 9 (15%) had a comprehensive
staging procedure. The majority of
patients were operated on by a general
gynecologist/obstetrician, and 2
(5%) of 43 were deemed as having
undergone a complete staging procedure.
When a general gynecologist
performed the procedure with a vascular
surgeon, 38% (5/13) had a complete
procedure. Difficult, potentially
morbid components of the staging
procedure that were most commonly
not performed were the diaphragmatic
biopsies and sampling of the retroperitoneal
lymph nodes. Surprisingly,
simple, nonmorbid portions of the
staging procedure, such as peritoneal
biopsies, were also omitted. The authors
concluded that a lack of surgical
skill and a lack of knowledge
about potential sites of spread were
equally responsible for the incomplete
staging in this series.

Recent reports from the National
Institutes of Health (NIH) indicate that
only 9% of patients with early-stage
ovarian cancer are treated appropriately.[
7] The NIH has recommended
that women with ovarian masses who
have been identified preoperatively
as having a significant risk of ovarian
cancer be given the option of having
their surgery performed by a gynecologic
oncologist. In addition, the Society
of Gynecologic Oncologists
recently issued their guidelines for referral
to or consultation with a gynecologic
oncologist (Table 3).[8]

Thorough surgical staging will reveal
that a significant portion of patients
with suspected early-stage
disease actually have more advanced
disease. Young et al demonstrated that
as many as 31% of women with suspected
early-stage disease will be upstaged
after undergoing additional
procedures.[9] The majority (77%) of
patients in this series who were upstaged
were found to have stage III
disease. Of these, 66% had their disease
detected by procedures other than
second laparotomy. The use of alternative
approaches to staging will be
reviewed.

Surgical ApproachesMinimally Invasive Surgery
Despite the fact that laparotomy
remains the standard approach to the
management of most major gynecologic
malignancies, over the past decade
there has been a dramatic move
toward incorporating minimally invasive
surgery into the practice of gynecologic
oncology. Better technology
and improved operator skills have
made many of the procedures that
once required large abdominal incisions
feasible with a minimally invasive
approach. Decreased morbidity
and hospital stay are some of the attractive
features of minimally invasive
surgery.

  • Feasibility of Laparoscopy-The
    use of laparoscopy in the management
    of early ovarian cancer was first
    cited in a case report.[10] Unfortunately,
    a comprehensive staging procedure
    was not performed. Querleu
    and Leblanc first described the complete
    laparoscopic staging of ovarian
    cancer patients.[11] They described
    the procedure in nine patients who
    had initially undergone incomplete
    staging. Of these nine patients, seven
    were presumed to have stage IA
    disease and underwent surgery for
    staging purposes; two patients, who
    obviously had stage III disease at the
    time of initial surgery, were comprehensively
    staged during their secondlook
    procedure.

    In this report, laparoscopic staging
    comprised infrarenal para-aortic lymphadenectomy,
    peritoneal cytology,
    and multiple peritoneal biopsies.[11]
    Omentectomy, appendectomy, pelvic
    lymphadenectomy, contralateral salpingo-
    oophorectomy, salpingectomy,
    and/or laparoscopically assisted vaginal
    hysterectomy were performed, if
    they had not been done previously.
    The mean total operative time was
    227 minutes (range: 130-360 minutes),
    and the mean time for the paraaortic
    node dissection was 111
    minutes (range: 65-240 minutes).
    Mean para-aortic node count was 8.6
    (range: 5-17), and only one patient
    was found to have microscopic disease
    on the right diaphragm. No major
    intraoperative complications occurred,
    and the mean hospital stay was 2.8
    days (range: 1-5 days). These authors
    suggested that laparoscopy may be an
    acceptable alternative to a restaging
    laparotomy; however, they cautioned that this approach should only be undertaken
    by an accomplished surgeon
    trained in gynecologic oncology and
    laparoscopy.

    Childers et al reported on the laparoscopic
    staging of 14 patients with
    presumed stage I disease.[12] The
    staging consisted of pelvic and paraaortic
    lymphadenectomy, omentectomy,
    and washings. A hysterectomy
    was performed in five patients, and
    eight patients (57%) were upstaged
    based on operative findings-two to
    stage IC, three to stage II, and three to
    stage IIIC. Childers and his colleagues
    reported two perioperative complications,
    neither of which required conversion.
    The mean hospital stay was
    1.6 days. The authors concluded that
    laparoscopic staging appeared to be
    an accurate technique that required
    further validation.

    Other groups have also demonstrated
    the feasibility of this staging
    procedure in patients with suspected
    early disease.[13] Recently, Leblanc
    et al updated their series in 28 patients
    with apparent stage I invasive
    ovarian cancer who underwent laparoscopic
    staging after an inadequate
    initial procedure (n = 25) or full laparoscopic
    management at initial surgery
    (n = 3).[14] The mean operative
    time was 230 minutes, and the mean
    hospital stay was 3.3 days. The median
    pelvic and para-aortic node counts
    were 13.7 and 19.7, respectively. One
    patient required conversion to laparotomy
    laparotomy
    secondary to adhesions, and
    one pelvic abscess developed after
    appendectomy. Of 28 patients, 6 were
    upstaged, and of the 22 pathologic
    stage IA patients, 1 (4.5%) recurred
    at 4 years.

  • Laparoscopy vs Laparotomy-
    Although many of the technical aspects
    of the staging procedure have
    been shown to be feasible, the question
    remains as to whether laparoscopy
    can produce results similar to those
    of laparotomy. Critics of laparoscopic
    staging cite loss of the ability to
    palpate and inspect the entire abdominal
    cavity.[15] The Gynecologic Oncology
    Group (GOG) has completed
    a phase II study (protocol 9302) of
    the feasibility and adverse effects of
    laparoscopic staging of early-stage
    ovarian, tubal, or peritoneal cancer.
    Results are pending, but hopefully
    this will begin to clarify the role of
    laparoscopy in the management of
    early-stage ovarian cancers. Currently,
    laparotomy is considered the standard
    staging approach to early-stage
    disease, and patients should be so
    informed during their presurgical
    consultation.
  • Hand-Assisted Laparoscopy-A
    new technique that has recently become
    available is called hand-assisted
    laparoscopic surgery (HALS). This
    technique employs a port that allows
    the surgeon to insert one hand into
    the abdominal cavity while maintaining
    the pneumoperitoneum. Although
    this requires a larger incision than traditional
    laparotomy, tactile sensation
    is restored.

    Krivak et al have reported on the
    use of this technique in ovarian cancer.[
    16] The authors studied 25 patients
    who were either staged or
    cytoreduced using HALS. Three patients
    with advanced-stage disease required
    conversion to traditional
    laparotomy to optimize cytoreduction.
    The procedure was also used to stage
    seven patients referred with unstaged
    disease. Procedures reported included
    hysterectomy, modified radical
    hysterectomy, bilateral salpingooophorectomy,
    omentectomy, pelvic
    and para-aortic node dissection, appendectomy,
    small bowel resection,partial colectomy, and low anterior
    resection. With a mean hospitalization
    of 1.8 days (range: 1-8 days), the
    authors concluded that this was a feasible
    alternative to laparotomy in carefully
    selected patients. The use of this
    technique warrants further investigation
    in the management of ovarian
    cancer.

Conservative Surgery
Although epithelial ovarian cancer
is a disease of the postmenopausal
population, it can occur in younger
patients for whom the preservation of
fertility is an issue. In fact, 7% to 8%
of all malignant stage I epithelial cancers
of the ovary occur in women less
than 35 years old.[17] The standard
surgical therapy for ovarian cancer
would render these women infertile;
thus, several studies have examined
the role of conservative surgery in the
management of early-stage ovarian
cancer.

Schilder et al reported the multiinstitutional
experience in patients
with stage IA and IC epithelial ovarian
cancer who were treated with
fertility-sparing surgery.[18] They
identified 52 patients (42 stage IA, 10
stage IC) who had undergone unilateral
oophorectomy and surgical staging;
20 patients also received adjuvant
chemotherapy. With a median followup
of 68 months, five recurrences were
recorded, of which three developed
in the remaining ovary. Two patients
died of disease, and the 5-year survival
rate was estimated to be 98%.
Of the 24 patients who attempted conception,
17 were successful, with 26
full-term deliveries and 5 spontaneous
abortions. The authors concluded
that fertility-sparing surgery should
be considered a treatment option for
patients with stage I disease who wish
to bear children.

The survival of patients with early-
stage epithelial ovarian cancer who
have undergone fertility-sparing surgery
has been compared to that of
patients who have undergone hysterectomy
and bilateral salpingooophorectomy
in addition to staging.
In a retrospective review, Brown et al
identified 16 patients under age 40
with stage I epithelial ovarian cancer,
who had undergone preservation of the contralateral ovary and hysterectomy
at the time of surgical staging.[
19] Of these women, 37%
received adjuvant platinum-based chemotherapy
due to high-risk features.
At a median follow-up of 66 months
(range: 1-174 months), 14 patients
(88%) were alive and disease-free.
Two of the 16 patients developed a
recurrence in the retained ovary and
died of their disease.

Over the same time period, 92 patients
with stage I disease underwent
hysterectomy and bilateral salpingooophorectomy
in addition to staging.[
19] Of these 92 patients, 80 (87%)
were alive without disease. There were
eight successful pregnancies among
five patients treated with fertility-sparing
surgery. The authors concluded
that fertility preservation in stage I
patients is possible after comprehensive
staging and does not appear to
decrease survival.

The subject of fertility preservation,
however, remains controversial
for this group of patients. These women
should be counseled on the importance
of comprehensive staging and
the possibility of fertility preservation,
and this conservative approach
should be limited to patients who
meet certain criteria (Table 4). Furthermore,controversy exists as to
whether patients with grade 2 tumors
should be managed with conservative
therapy.[15,20]

Second-Look Surgery
Second-look surgery is a systematic
surgical exploration in an asymptomatic
patient who has completed a
planned course of chemotherapy for
ovarian cancer. Its use has been evaluated
in patients with early-stage disease.
Walton et al reported on 112
patients with FIGO stage I/II ovarian
carcinoma who underwent secondlook
surgery after completion of adjuvant
therapy in an Ovarian Cancer
Study Group/GOG trial.[21] Of the
95 patients who were asymptomatic
at 18 months, only 5% had positive
findings compared to 53% of the 17
patients who were symptomatic (eg,
bowel obstruction, abdominal or pelvic
complaints, weight loss, or other
symptoms suspicious for recurrent
disease).

In a smaller series, Rubin et al reported
on 54 stage I patients who
underwent second-look surgery following
complete surgical staging and
adjuvant chemotherapy.[22] They,
like Walton et al, found that only 5.5%
had disease.[22] None of the patients with grade 1 tumors had disease. Tumor
grade was a significant predictor
of recurrence following a negative
second-look procedure, with grade 1/2
tumors associated with a 0% risk of
recurrence compared to a 52% risk
for grade 3 tumors. Substage, histologic
type, and chemotherapy type or
duration did not predict recurrence.

Given the small positive yield of
second-look surgery in early-stage
patients who have been comprehensively
staged initially, this strategy is
not routinely recommended.

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