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pithelial cancer of the ovary is the most lethal gynecologic malignancy in the United States, with approximately 22,000 new cases and 16,000 deaths occurring annually.1 The relative lack of specific signs and symptoms
of this disease, coupled with the lack of reliable screening
strategies, contributes to a condition that is diagnosed
at advanced stages in most patients, resulting in low overall cure rates.1-3 Patients are primarily managed with surgical resection and subsequent platinum-based chemotherapy. Although many women respond well initially to
this approach, most eventually have recurrence of chemoresistant disease. Overall, the 5-year survival rate is
45%.1
EPIDEMIOLOGY AND ETIOLOGY
CATEGORIES
The 3 categories of ovarian cancer are named for their cell
of origin. Ninety percent of ovarian cancers arise from cells
that make up the epithelial layer that covers the surface of
the ovaries. These are known as epithelial cancers. In general, when the term ovarian cancer is used, it implies
epithelial ovarian cancer, the focus of this review. The
Mayo Clin Proc.
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751
Age
(y)
BRCA1
carriers
(%)
BRCA2
carriers
(%)
Age
(y)
BRCA1
carriers
(%)
BRCA2
carriers
(%)
20
25
30
35
40
45
50
55
60
65
70
0.0
0.1
0.6
4.3
11.6
23.7
38.4
46.0
53.5
59.2
64.7
0.0
0.1
0.7
2.5
6.2
10.4
16.2
23.3
30.6
37.8
44.7
20
25
30
35
40
45
50
55
60
65
70
0.0
0.0
0.0
0.9
2.3
6.5
13.2
17.3
22.1
30.4
38.6
0.0
0.0
0.0
0.0
0.1
0.5
1.2
4.1
7.6
9.4
11.3
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cer who decide not to undergo prophylactic BSO, surveillance with pelvic examinations, measurement of CA-125
levels, and transvaginal pelvic ultrasonography is recommended every 6 months starting at the age of 35 years or 5
to 10 years earlier than the earliest ovarian cancer diagnosed in the family.28 Unfortunately, there is no evidence
that either CA-125 measurement or pelvic ultrasonography, alone or in combination, is able to detect ovarian
cancer at an early stage.32-34 Regarding chemoprevention,
the role of oral contraceptives in reducing the risk of ovarian cancer in mutation carriers is controversial. Although
Narod et al35 showed a possible benefit in BRCA1 or BRCA2
mutation carriers, Modan et al36 found no benefit of chemoprophylaxis with oral contraceptives in reducing the risk of
ovarian cancer.
DIAGNOSIS
CLINICAL PRESENTATION
Symptoms. The symptoms of ovarian cancer are fairly
nonspecific and often occur when the disease is already
spread throughout the abdominal cavity. Abdominal discomfort or vague pain, abdominal fullness, bowel habit
changes, early satiety, dyspepsia, and bloating are frequent
presenting symptoms.37 Occasionally, patients may present
with bowel obstruction due to intra-abdominal masses or
shortness of breath due to pleural effusion. Early-stage
disease is usually asymptomatic, and the diagnosis is often
incidental, although such patients may occasionally present
with dyspareunia or pelvic pain due to ovarian torsion.
Signs. The presence of a pelvic mass at physical examination is the most important sign of ovarian cancer. Irregularity, solid features, and nodularity are the most important
characteristics that suggest ovarian cancer. In advanced
stages, abdominal distension due to ascites and abdominal
masses (the omentum can be palpated when infiltrated by
tumor) can also be felt. In stage IV disease, a pleural effusion
can be detected as well. If nodal metastases are present,
inguinal, supraclavicular, and axillary nodes may be enlarged at palpation. Rarely, paraneoplastic syndromes may
be present, including cerebellar degeneration associated with
antiPurkinje cell antibodies. Superficial thrombophlebitis,
dermatomyositis, and polyarthritis have also been observed.
Ultrasonography or abdominal-pelvic computed tomography is often performed to aid in the evaluation of a pelvic
mass. Features highly suggestive of ovarian cancer include the presence of a complex ovarian mass, with both
solid and cystic components, sometimes with internal echoes and/or septations. The presence of ascites or evidence
of peritoneal metastases, in the presence of an ovarian
mass, is suggestive of advanced ovarian cancer. Other imaging techniques, such as magnetic resonance imaging or
Mayo Clin Proc.
positron emission tomography, may provide additional information but are not routinely necessary in preoperative
evaluation.
MARKERS
After its initial discovery in the early 1980s,38,39 the serum
CA-125 level has been widely used as a marker for a
possible epithelial ovarian cancer in the primary assessment of a pelvic mass. In this setting, false-positive results
may derive from several conditions, especially those associated with peritoneal inflammation, such as endometriosis, adenomyosis, pelvic inflammatory disease, menstruation, uterine fibroids, or benign cysts.40 Malignancies other
than ovarian cancer can also increase CA-125 levels,39 but
the most marked elevations (>1500 U/mL) are generally
seen with ovarian cancer.
The primary use of CA-125 measurement is to monitor
the disease status of patients with ovarian cancer, such as
detecting early recurrence or assessing chemoresponse during chemotherapy. Serum CA-125 levels are also included
in the American College of Obstetricians and Gynecologists and Society of Gynecologic Oncologists guidelines
for referring patients to a gynecologic oncologist. Postmenopausal women with serum levels of CA-125 more
than 35 U/mL or premenopausal women with CA-125
levels higher than 200 U/mL should be referred to a gynecologic oncologist.41 In an attempt to improve CA-125
measurement for the detection of epithelial ovarian cancers, especially at an early stage, recent studies have identified several new candidates for markers. Examples include
lysophosphatidic acid (a lipid found to be elevated in serum
and ascites fluid),42 mesothelin,43 HE4,44 osteopontin,45 vascular endothelial growth factor (VEGF) and interleukin 8,46
macrophage colony-stimulating factor,47 and different kallikreins.48,49 Interestingly, among these potential markers,
HE4 has sensitivity similar to CA-125 in detecting latestage disease but greater specificity than CA-125 in diagnosing early ovarian cancer.50 Validation of HE4 as a diagnostic biomarker in detecting ovarian cancer at early stages
is currently ongoing.
SCREENING PROGRAMS
Early-stage ovarian cancer is associated with an excellent
prognosis after optimal therapy.51 Thus, detection of earlystage disease is a key goal in reducing mortality due to this
disease. Unfortunately, no screening program for ovarian
cancer tested thus far has been shown to achieve this purpose. Several large prospective studies attempted to identify the best strategy for detecting early-stage disease and
therefore reducing mortality by using either CA-12552-54 or
ultrasonography55-59 as the primary test. The positive predictive value for ultrasonography screening alone ranged
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753
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Description
TNM stage
TX
T0
T1
T1a
T1b
T1c
T2
T2a
T2b
T2c
T3 and/or N1
T3a
T3b
T3c and/or N1
M1
*Liver capsule metastasis is T3/stage III; liver parenchymal metastasis MI/stage IV. Pleural effusion must have
positive cytologic test results.
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755
TREATMENT
The first step in the management of patients with epithelial
ovarian cancer is an accurate diagnosis and thorough staging, with optimal surgical cytoreduction of metastatic disease. Postoperative taxane and platinumbased chemotherapy is then administered to patients with a significant
risk of recurrence. In this section we review the role of
surgery and chemotherapy in the management of patients
with ovarian cancer. We highlight surgical approaches to
obtain optimal tumor cytoreduction in those with advanced
disease, showing the benefit of performing such aggressive
procedures. In addition, we describe recent studies that
consider new therapeutic approaches to prolong survival in
patients with advanced disease.
SURGERY
Early-Stage Disease. In patients with disease apparently confined to the pelvis, thorough staging is essential to
define the correct extent of the disease at time of diagnosis.68 Considering the possible routes of spread, other than
the debulking of all visible tumor, peritoneal washing,
peritoneal biopsies representative of the entire abdominal
cavity, and a retroperitoneal assessment that involves both
the pelvic and para-aortic area should be performed. Inadequate surgical staging can lead to understaging and subsequently inadequate postoperative treatment, which can ultimately worsen patients prognosis.
Young et al73 performed a systematic restaging in 100
consecutive patients referred with a diagnosis of early
stage (IA-IIB) ovarian cancer. In 31 (31%) of 100 patients,
the stage was higher, and 23 (77%) of the 31 had stage III
disease. Sites of unsuspected disease were most likely to be
pelvic peritoneum, ascites fluid, other pelvic tissue, paraaortic nodes, and diaphragm. The authors concluded that the
initial staging used in clinical evaluation of patients with
early ovarian cancer is often incomplete and inadequate.73,74
Two large multicenter randomized trials recently showed
that adjuvant therapy for stage I ovarian cancer improves
survival in patients whose disease is not adequately staged
but not in patients with optimally staged disease. Furthermore, in the control arm, the authors observed a survival
benefit that favored patients with optimally staged disease.
These results suggest that a proportion of the patients with
presumed early-stage disease would have had higher-stage
disease if comprehensive staging had been performed. Furthermore, it demonstrates the benefits of adequate staging
and perhaps the best method of treatment of patients with
presumed early-stage disease.75,76 According to these data,
restaging of inadequately staged disease seems to be appropriate, especially for patients who might not require
chemotherapy if confirmed to have no extraovarian disease
756
(low-grade, stage IA disease). Thus, we individualize treatment for these patients based on the extent of surgery
performed, imaging studies, available pathologic findings,
and health of the patient. Depending on these factors, either
adjuvant chemotherapy or restaging is suggested. If chemotherapy alone is to be used, we would typically recommend 6 cycles of therapy rather than the 3 cycles for
patients with thoroughly staged, early-stage disease.
Regarding the need for lymph node assessment during
initial surgery for early-stage disease, we recently described the pattern of lymph node involvement in apparent
early-stage ovarian cancer at the Mayo Clinic, during the
years 1994 to 2002.77 Isolated involvement of the pelvic
nodes was noted in 27.5% of the patients, isolated paraaortic nodes in 33.5%, and both pelvic and para-aortic
nodes in 33.5% (an additional 5.5% of the patients had
inguinal nodes involved). These findings do not support the
practice of omitting either para-aortic or pelvic lymphadenectomy in the management of apparent early-stage
ovarian cancer because nearly equal numbers of patients
had isolated metastases in either location.
Occasionally, patients undergo inadequate initial surgery and are thought likely to harbor residual disease. For
patients in whom a reoperation is not performed to avoid
the morbidity of a second operation (increased rates of
infection, blood loss, wound complications), we have occasionally used reassessment laparotomy. This approach allows immediate treatment with chemotherapy during the
initial recovery and reduces the perioperative complications with immediate reoperation. The reassessment surgery can be performed after 3 cycles of chemotherapy. This
treatment is individualized and certainly different in aim
than interval cytoreduction for a patient who is thought to
have nonresectable disease.
Advanced-Stage Disease. Cytoreductive surgery is the
cornerstone of the initial treatment of patients with advanced
ovarian cancer. After the landmark study78 by Griffiths in
1975, which clearly demonstrated an inverse correlation
between residual tumor diameter and patient survival, the
amount of residual disease after primary surgery is generally
considered the most important modifiable prognostic factor
that influences survival of patients with advanced disease.
Nearly all retrospective and prospective studies have confirmed that the extent of cytoreductive surgery and the
amount of residual disease after primary surgery are the most
important factors that influence the survival of patients with
advanced ovarian cancer,79,80 as reviewed in the meta-analysis by Bristow et al.81 A recent commentary by Eisenkop et
al82 pointed out the clear prognostic benefit of leaving less
residual disease at the end of the primary operation.
Optimal debulking for advanced ovarian cancer is defined as removal of all disease 1 cm or larger in diameter.
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1.0
Surviving patients
0.8
Residual disease
0 cm
>0 to 1 cm
>1 to 2 cm
0.6
0.4
>2 cm
0.2
0.0
0
Follow-up (y)
FIGURE 1. Residual disease affects overall survival in patients with stage IIIC ovarian cancer
(n=194; log-rank test, P<.001). From Obstet Gynecol,91 with permission.
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757
1.0
Surgery
Surviving patients
0.8
Nonradical
Radical
0.6
0.4
0.2
0.0
0
Follow-up (y)
FIGURE 2. Effect of surgical effort on Kaplan-Meier survival for patients with stage IIIC
ovarian cancer with residual disease smaller than 1 cm. Patients were categorized by
surgery required for optimal cytoreduction (n=131; log-rank test, P=.80). From Obstet
Gynecol,91 with permission.
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759
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with platinum-resistant disease.191 Weekly paclitaxel in patients with platinum- and paclitaxel-resistant disease produced an objective response rate of 20.9%.192 Docetaxel, in
a GOG trial of platinum-resistant disease, showed a 22%
objective response, but the median response duration was
only 2.5 months.193
Gemcitabine produced a 16% response rate in patients
with platinum-resistant disease.194 However, gemcitabine
may modify cisplatin resistance and showed an objective
response of 43% with gemcitabine followed by cisplatin on
days 1 and 8 of a 21-day schedule. Four of 6 women in
whom prior single-agent gemcitabine had failed responded
to the combination.195 A trial of gemcitabine (days 1 and 8)
plus liposomal doxorubicin (day 1) showed a 33% response
rate; however, neutropenia grade 3 or 4 occurred in 25% of
patients.196
Intravenous etoposide showed only an 8.3% response rate
in a GOG trial of advanced ovarian cancer197; however, oral
etoposide administered daily for 21 days every 4 weeks
showed a 27% response rate.198 In that study, of 25 patients
with both platinum and taxane resistance, 8 responses were
seen, a 32% response rate. Vinorelbine produced a 21%
response rate in platinum-refractory disease.201
A phase 2 trial of altretamine (hexamethylmelamine)
showed a partial response rate of 9.7%, with 26% of patients experiencing stable disease.199 The conclusion of the
trial was that altretamine should not be chosen as a standard
treatment in patients with platinum-refractory disease but
may be an alternative for patients who prefer oral treatment. Ifosfamide daily for 5 days every 3 weeks produced a
10% response rate in platinum-resistant disease.200
High-dose chemotherapy with autologous stem cell
transplantation has not been shown to produce better disease-free or overall survival than standard therapy.178,202,203
In vitro chemotherapy sensitivity and resistance assays
offer the potential of selecting a chemotherapy regimen
based on response of an individuals tumor in in vitro
assays rather than empiric therapy.204,205 Higher response
rates for assay-guided therapy have been observed in some
studies with little impact on survival.205 The American
Society of Clinical Oncology technology assessment of
chemotherapy sensitivity and resistance assays identified
no assays for which the evidence base was sufficient to
support their use in oncology practice outside a clinical trial
setting.204 At our institution we do not routinely use chemotherapy sensitivity and resistance assays for selecting treatment regimens in ovarian cancer.
Hormonal therapies have been investigated in patients
with recurrent ovarian cancer. In 1977, Malkasian et al,206
from Mayo Clinic, reported no significant benefit with use
of oral medroxyprogesterone acetate, 100, 200, or 400 mg/d.
In 1989, Bruckner and Motwani207 reported use of leuproMayo Clin Proc.
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763
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signal transduction pathways, approaches that harness specific elements of the immune system that ovarian cancers
have successfully suppressed, gene and viral therapy strategies, and antiangiogenesis strategies.
Inhibitors of the erbB family of receptor tyrosine kinases have been studied in ovarian cancer. This receptor
family and their ligands promote tumorigenesis through a
variety of stimulatory and cell survival pathways. Trastuzumab (Herceptin) is a humanized monoclonal antibody
against HER-2/erbB-2. It was studied in a phase 2 trial of
patients with recurrent ovarian and primary peritoneal cancer that overexpressed HER-2. Single-agent trastuzumab
had limited activity in these patients, with an overall response rate of only 7.3%.228 Small molecule inhibitors
of the epidermal growth factor receptor (EGFR, erbB1)
have shown minimal activity in women with recurrent
ovarian or peritoneal cancer.229,230 Humanized monoclonal
antibodies against EGFR are currently being tested either
alone or in combination with chemotherapy in ovarian
cancer. Lapatinib is a potent dual inhibitor of EGFR and
HER-2/erbB2. It is hypothesized that a dual inhibitor of
these important pathways should have significant therapeutic advantages over single receptor inhibitors. Lapatinib is
currently being evaluated in several clinical trials of ovarian cancer.
The driving factor behind angiogenesis in ovarian cancer is VEGF. Several agents have been developed to inhibit
VEGF or its receptors (VEGFR and VEGFR2).231,232 Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody against VEGF, which has shown activity in
ovarian cancer. Specifically, in GOG 170, bevacizumab
was given as a single agent in the salvage setting of women
with recurrent ovarian or primary peritoneal cancer. Thirteen (21%) of 62 women responded, and 40% of patients
had progression-free survival for 6 months or more.233 In
another study, bevacizumab was evaluated in combination
with low-dose metronomic oral cyclophosphamide; a 28%
response rate was seen in patients with recurrent ovarian or
peritoneal cancer.234 A serious adverse effect seen with
bevacizumab is bowel perforation. Wright et al235 performed
a retrospective analysis of patients with ovarian cancer
treated with bevacizumab and summarized the findings of
prospective clinical trials with the agent. Among a total of
158 patients treated, 8 (5%) experienced a perforation. In
an ongoing phase 3 trial in previously untreated patients
with suboptimal stage III and stage IV disease, GOG is
comparing standard carboplatin and paclitaxel with either
placebo or bevacizumab.
Numerous other biologic therapies are being pursued in
ovarian cancer,236,237 including new strategies that target
unique receptors that are overexpressed in ovarian cancer238,239 and a variety of gene- and viral-based approaches.
Mayo Clin Proc.
CONCLUSION
Symptoms of ovarian cancer are fairly nonspecific and
often occur after the disease has spread throughout the
abdominal cavity. The presence of a pelvic mass at physical examination is the most important sign of ovarian cancer. The serum CA-125 level has been widely used as a
marker for a possible epithelial ovarian cancer in the primary assessment of a pelvic mass. The predominant use of
CA-125 measurement is to monitor disease status of patients
with ovarian cancer, such as detecting early recurrence or
assessing response during chemotherapy. The first step in
the management of patients with epithelial ovarian cancer is
an accurate diagnosis and thorough staging, with optimal
surgical cytoreduction of metastatic disease. Platinumtaxane combination chemotherpay yields responses in
most patients with ovarian cancer. Numerous avenues are
being pursued to identify new systemic therapies for this
disease.
We are indebted to Vicki Shea for her help and expertise in the
preparation of the submitted manuscript. We dedicate this review
to our patients with ovarian and primary peritoneal cancer.
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