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SYMPOSIUM ON SOLID TUMORS

CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

Current Management Strategies for Ovarian Cancer


GIOVANNI D. ALETTI, MD; MARY M. GALLENBERG, MD; WILLIAM A. CLIBY, MD; AMINAH JATOI, MD;
AND LYNN C. HARTMANN, MD
Epithelial ovarian cancer originates in the layer of cells that
covers the surface of the ovaries. The disease spreads readily
throughout the peritoneal cavity and to the lymphatics, often
before causing symptoms. Of the cancers unique to women,
ovarian cancer has the highest mortality rate. Most women are
diagnosed as having advanced stage disease, and efforts to
develop new screening approaches for ovarian cancer are a high
priority. Optimal treatment of ovarian cancer begins with optimal
cytoreductive surgery followed by combination chemotherapy.
Ovarian cancer, even in advanced stages, is sensitive to a variety
of chemotherapeutics. Although improved chemotherapy has increased 5-year survival rates, overall survival gains have been
limited because of our inability to eradicate all disease. Technologic advances that allow us to examine the molecular machinery
that drives ovarian cancer cells have helped to identify numerous
therapeutic targets within these cells. In this review, we provide
an overview of ovarian cancer with particular emphasis on recent
advances in operative management and systemic therapies.

Mayo Clin Proc. 2007;82(6):751-770


AUC = area under the curve; BSO = bilateral salpingo-oophorectomy;
EGFR = epidermal growth factor receptor; FIGO = International
Federation of Gynecology and Obstetrics; GOG = Gynecologic Oncology
Group; HNPCC = hereditary nonpolyposis colon cancer; ICON =
International Collaborative Ovarian Neoplasm; VEGF = vascular endothelial growth factor

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.

other 2 types are germ cell tumors and stromal tumors.


Stromal tumors arise in the hormonally active elements
within the connective tissue stroma of the ovary. Germ cell
tumors and stromal tumors each account for approximately
5% of ovarian cancers.4
RISK FACTORS
Environmental and Hormonal Factors. The median
age at which a woman is diagnosed as having epithelial
ovarian cancer is 63 years.5 Although it is generally accepted that ovarian cancer arises from the coelomic epithelium that covers the ovarian surface, the processes of initiation and progression of carcinogenesis are still debated and
under intense study. Epidemiological research has shown
that multiple pregnancies, lactation, and oral contraceptive
use are associated with a reduced risk of developing ovarian cancer.6 Conversely, nulliparity, early menarche, and
late menopause are associated with an increased risk. One
theory regarding causation is that more frequent ovulations, with repeated cycles of wounding, inflammation,
proliferation, and healing on the surface of the ovarian
epithelium, may predispose to malignant transformation.3,6
Tubal ligation procedures appear to be a protective factor,
although the mechanism is unclear.7 Some studies have
suggested that fertility drugs might increase the risk of
ovarian cancer.8 However, a subsequent meta-analysis did
not confirm those previous findings.9 Epidemiological
studies that analyzed dietary factors (diet high in meat and
animal fat, proteins, fiber, vitamin A and C) have been
inconsistent. Regarding environmental factors, reports
have been conflicting about exposure to carcinogens, including radiation (diagnostic or therapeutic), use of talcum
powder, and exposure to asbestos.

From the Division of Gynecologic Surgery (G.D.A., W.A.C.), Department of


Obstetrics and Gynecology (M.M.G.), and Division of Medical Oncology (A.J.,
L.C.H.), College of Medicine, Mayo Clinic, Rochester, Minn.
This study was supported by a grant (R01 CA86888) from the National
Institutes of Health and grants from the Andersen Foundation and the
Minnesota Ovarian Cancer Alliance.
Address correspondence to Lynn C. Hartmann, MD, Division of Medical
Oncology, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN
55905 (e-mail: hartmann.lynn@mayo.edu). Individual reprints of this article
and a bound reprint of the entire Symposium on Solid Tumors will be available
for purchase from our Web site www.mayoclinicproceedings.com.
2007 Mayo Foundation for Medical Education and Research

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751

CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

TABLE 1. Risk of Breast and Ovarian Cancer by Increasing Age


in BRCA1 and BRCA2 Carriers
Breast cancer incidence

Ovarian cancer incidence

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

Data from Am J Hum Genet.25

Hereditary Predisposition. A strong family history of


either breast or ovarian cancer is the most important risk
factor for the development of epithelial ovarian cancer;
approximately 10% to 15% of all epithelial ovarian cancers
have a hereditary predisposition.10-12 Hereditary ovarian
cancer is seen most commonly within the breast-ovarian
cancer family syndrome because of mutations in BRCA1 or
BRCA2.2,13,14 Features that point toward a hereditary breastovarian cancer syndrome include early-onset breast cancer
(age <50 years), the presence of ovarian cancer, male
breast cancer, and Ashkenazi Jewish ancestry. Ovarian
cancer can also be seen in families with hereditary nonpolyposis colon cancer (HNPCC), along with an excess of
colorectal and endometrial cancers.15 A small number of
families have been reported to have an excess of ovarian
cancer but no breast cancer, called site-specific ovarian
cancer families.16 These cancers have been linked to mutations in BRCA1 and are thought to represent a unique
phenotype of the hereditary breast-ovarian syndrome. For
a woman who has 1 first-degree relative with ovarian cancer but no other features to suggest a hereditary predisposition, her chance of developing epithelial ovarian cancer by
the age of 70 years is approximately 5%.17
BRCA1 and BRCA2. The BRCA1 and BRCA2 genes are
located on chromosomes 17q and 13q, respectively, their
products functioning as DNA repair proteins.18 In most
populations, germline BRCA mutations are reported uncommonly, with less than 1 carrier in 500 individuals.
Notably, in certain ethnic groups, including Ashkenazi
Jews, the probability of harboring germline BRCA1 or
BRCA2 mutations is 1 in 40 individuals.14,19 The 3 most
common mutations that occur in healthy Ashkenazi Jewish
women are the 185delAG mutation in BRCA1, the
5382insC mutation in BRCA1, and the 6174delT mutation
in BRCA2. The frequency of such mutations in Ashkenazi
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Mayo Clin Proc.

Jewish women diagnosed as having ovarian cancer has


been reported to be as high as 26% to 41% in different
studies.20-23
The lifetime risk of ovarian cancer in women with a
germline mutation in BRCA1 approaches 40%, whereas in
women with germline mutations in BRCA2, the lifetime
risk ranges from 10% to 20%.14,20,24,25 The cumulative incidence of ovarian cancer in BRCA1 and BRCA2 carriers,
from ages 20 to 70 years, is given in Table 1.
HNPCC. A second inherited disorder with an increased
risk of ovarian cancer is the HNPCC syndrome, also called
Lynch syndrome II, but this accounts for only approximately 1% of all ovarian cancers. Family members with
HNPCC are at increased risk of ovarian cancer, with a
cumulative incidence of 12%.26 The HNPCC syndrome
results from inherited mutations in DNA mismatch repair
genes.15 At-risk family members also have an increased
lifetime risk of colon cancer (70%), endometrial cancer
(40%-60%), and gastric cancer.15
RISK REDUCTION
The identification of women at high risk of ovarian cancer
is essential for individualized tailoring of risk-reducing
strategies. We recently reviewed the impact of bilateral
salpingo-oophorectomy (BSO) on surgical risk reduction.27
Surgery. Bilateral salpingo-oophorectomy is generally
recommended for women with a known germline mutation
in BRCA1 or BRCA2 at approximately 35 to 40 years of
age, depending on which gene is affected and the age at
onset of ovarian cancer in the family.28 Currently, it is
considered the preventive measure of choice for these highrisk patients.29,30 Although prophylactic BSO reduces the
risk of ovarian cancer by more than 90%, high-risk patients
with germline mutations in BRCA1 or BRCA2 can still
develop primary peritoneal cancer, which develops in 4%
to 5% of women at 20 years after prophylactic BSO.31
Appropriate timing of risk-reducing BSO is a major issue.
The cumulative incidence of ovarian cancer by given age
for BRCA carriers is given in Table 1.27 In general, for
BRCA1 carriers, BSO is recommended at the age of 35 to
40 years.28 Because BRCA2-related ovarian cancers are
diagnosed in women at a similar age as those with sporadic
cancers, BSO can be delayed safely until the patient is
closer to menopause.27 The decision to undergo prophylactic BSO is highly personal. Risks and benefits must be
discussed with the patient, including the impact of premature menopause, the possible use of hormone replacement
therapy after BSO, and the emotional and psychological
impact of the procedure.
Other Approaches. Alternative options for women at
risk of ovarian cancer include increased surveillance or
chemoprevention. For patients at high risk of ovarian can-

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CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

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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from 1.5% when abdominal ultrasonography was used55 up


to close to the screening-recommended 10% when transvaginal ultrasonography was used in a cohort of roughly
15,500 women. This low positive predictive value is due to
the commonality of benign pelvic lesions, even in postmenopausal women. High specificity is vital in screening
strategies for ovarian cancer because a positive test result
generally requires definitive surgical assessment. Given
the relatively low prevalence of ovarian cancer, a test with
95% specificity would result in 50 surgical procedures for
every ovarian cancer detected.34
In one prospective trial, Einhorn et al60 screened 5550
women with CA-125 alone. This approach resulted in an
unacceptable 29 operations for every cancer detected. Another major limitation of CA-125 screening is that serum
levels are elevated in only approximately 50% of patients
with stage I disease.52-54
Because a wide range of both gynecological and nongynecological conditions may also elevate CA-125 levels,
combination test strategies have been studied to improve the
predictive value of CA-125. The most encouraging results
with this strategy were published by Jacobs et al61 in 1999.
They randomized 22,000 postmenopausal women to be
screened with 3 annual CA-125 measurements or to no
screening. If patients had CA-125 levels higher than 30 U/mL,
they underwent transvaginal ultrasonography. Twenty-nine
women were referred for surgical exploration, and 6 were
diagnosed as having ovarian cancer (3 of whom had stage I).
The positive predictive value was 20.7%. Ten additional
women in the screening arm developed ovarian cancer during follow-up. Twenty women in the control arm developed
ovarian cancer. The investigators were able to show a survival benefit (median survival time, 73 months in the
screened arm vs 42 months in the control group; P=.01).
Even though the study did not have sufficient power to show
a mortality reduction, these results have encouraged further
studies.
Two large randomized studies are currently ongoing.
The National Institutes of Health Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial enrolled 75,000
women between 55 and 74 years of age from 1992 to
2001.62 The study randomly assigned women to either
screening (ie, annual pelvic examination, transvaginal ultrasonography, and CA-125 assay) or no screening. The
recently published prevalence data from this study revealed
familiar findings: 31 women operated on for every invasive
cancer detected and a high proportion of advanced-stage
cancers.63 However, these initial results are affected greatly
by the benign and malignant conditions prevalent at a
womans first screening evaluation. The true effectiveness
of the screening strategy will now be tested by its ability to
detect new cancers during the next several years.34 The
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second study, started in 2001, called the United Kingdom


Collaborative Trial of Ovarian Cancer Screening,64 has completed randomization of 200,000 postmenopausal women to
transvaginal ultrasonography, multimodality screening, or a
control group. It is hoped that these large studies will answer
the debated issue of whether ultrasonography with or without CA-125based screening in women with ovarian cancer
can reduce mortality due to this disease.
Finding an effective strategy to screen for ovarian cancer is a high priority in the cancer research community.
Current approaches being studied include high-throughput
techniques using microarray technology and proteomic
screening to identify panels of novel markers that may be
altered early in the disease.65,66 A research group at the
Mayo Clinic recently reported the feasibility of using this
approach in detecting potential markers and their possible
clinical application.67
PATHOLOGIC FINDINGS
According to the International Federation of Gynecology
and Obstetrics (FIGO), it is recommended that all ovarian
epithelial tumors be classified histologically as follows68:
serous tumors, mucinous tumors, endometrioid tumors, clear
cell tumors, Brenner tumors, undifferentiated tumors (too
poorly differentiated to be placed in any other group), mixed
epithelial tumors (composed of 2 of the 5 major cell types
of common epithelial tumors, which are usually specified),
and intraperitoneal cancer (the ovaries appear to be incidentally involved and not the primary origin, which should be
classified as extraovarian peritoneal cancer).
Serous tumors are the most common type, accounting
for almost half of all epithelial ovarian cancers. These cells
histologically resemble cells that line the fallopian tube.
They tend to be high grade and are the cancers most often
seen in BRCA mutation carriers. Endometrioid cancers resemble the cells that line the uterus (endometrium). These
cancers are sometimes associated with endometriosis.
Clear cell tumors are relatively uncommon, occurring most
often in women in their 40s. Approximately 50% of women
with clear cell tumors have associated endometriosis. Although most clear cell cancers are diagnosed at an early
stage, these tumors tend to behave aggressively. The cells
of mucinous tumors resemble those of the cervix or intestine. Mucinous tumors are more likely to be found in
younger women, and 75% to 80% are benign and develop
in only 1 ovary. Cancerous mucinous tumors are more
common in older women. These cancers do not tend to
secrete CA-125.
Epithelial tumors of the ovary are also further subclassified by grading68: Gx, grade cannot be assessed; G1, well
differentiated; G2, moderately differentiated; and G3,
poorly differentiated. Grade is related to prognosis in ovar-

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TABLE 2. International Federation of Gynecology and Obstetrics (FIGO)


and TNM Stages of Cancer of the Ovary*
FIGO
stage
0
I
IA
IB
IC
II
IIA
IIB
IIC
III
IIIA
IIIB
IIIC
IV

Description

TNM stage

Primary tumor cannot be assessed


No evidence of primary tumor
Tumor confined to ovaries
Tumor limited to 1 ovary, capsule intact
No tumor on ovarian surface
No malignant cells in the ascites or peritoneal washings
Tumor limited to both ovaries, capsules intact
No tumor on ovarian surface
No malignant cells in the ascites or peritoneal washings
Tumor limited to 1 or both ovaries, with any of the following: capsule ruptured,
tumor on ovarian surface, positive malignant cells in the ascites or
positive peritoneal washings
Tumor involves 1 or both ovaries with pelvic extension
Extension and/or implants in uterus and/or tubes
No malignant cells in the ascites or peritoneal washings
Extension to other pelvic organ
No malignant cells in the ascites or peritoneal washings
IIA/B with positive malignant cells in the ascites or positive peritoneal washings
Tumor involves 1 or both ovaries with microscopically confirmed peritoneal
metastasis outside the pelvis and/or regional lymph nodes metastasis
Microscopic peritoneal metastasis beyond the pelvis
Macroscopic peritoneal metastasis beyond the pelvis 2 cm in greatest dimension
Peritoneal metastasis beyond the pelvis >2 cm in greatest dimension and/or
regional lymph nodes metastasis
Distant metastasis beyond the peritoneal cavity

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.

ian cancer, with patients with low-grade cancers doing


better. Grade information is factored into treatment decisions for women with stage I disease.
STAGING
According to FIGO, the following procedures should be
performed to adequately stage ovarian cancer when malignancy is suspected preoperatively68: midline incision for
adequate exposure; careful evaluation of all peritoneal surfaces; 4 washings of the peritoneal cavity (diaphragm, right
and left sides of the abdomen, and pelvis); omentectomy;
complete or selected lymphadenectomy of the pelvic and
para-aortic lymph nodes; biopsy and/or resection of any
suspicious lesions, masses, and adhesions; random blind
biopsies of normal peritoneal surfaces, including that from
the undersurface of the right hemidiaphragm, bladder reflection, cul-de-sac, right and left paracolic recesses, and
both pelvic sidewalls; total abdominal hysterectomy and
BSO; and appendectomy for mucinous tumors. The most
commonly used staging system is the FIGO system modified in 1988. It is based on findings made mainly through
surgical exploration, as outlined in Table 2.
SPECIAL CASES: BORDERLINE TUMORS
Borderline ovarian tumors, or tumors of low malignant
potential, also develop in the epithelial cells that cover the
Mayo Clin Proc.

surface of the ovaries. Although borderline tumors have


some malignant features, such as malignant-appearing histologic features and excess proliferation, they generally
behave in an indolent manner.69-72 One hallmark of borderline tumors is that they do not invade the underlying supportive tissue or stroma of the ovary. Borderline tumors make up
10% to 15% of all epithelial ovarian tumors.69 Approximately 3000 women in the United States are diagnosed as
having borderline tumors each year. Although these tumors
can occur in women of all ages, they are more typically seen
in younger woman than are epithelial ovarian cancers. They
tend to have the same risk factors as epithelial ovarian cancer. At diagnosis, approximately 20% of borderline tumors
have spread beyond the ovary via peritoneal implants, but
unlike epithelial ovarian cancer implants, these borderline
peritoneal implants are noninvasive, meaning that the cells
do not invade the underlying tissue. However, in less than
5% of borderline tumors, so-called invasive implants can be
found that invade below the peritoneal surface layer. A
borderline tumor with invasive implants behaves more aggressively than does a borderline tumor with noninvasive
implants. Surgery is the mainstay of treatment for women
with borderline tumors of the ovary. Chemotherapy can be
considered for women with borderline tumors that have
more aggressive features, such as invasive implants or
rapid recurrence after surgery.

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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
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(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.

Unfortunately, numerous studies have shown that many


women with ovarian cancer do not undergo optimal surgery.83-85 The quoted sites of disease most frequently precluding optimal cytoreduction are the diaphragm, bowel,
and portal triad.86 Studies have consistently shown that
specialized surgeons, gynecologic oncologists, are more
likely than general surgeons to perform optimal surgery for
ovarian cancer.32,85,87,88 As a result, the National Institutes of
Health, American College of Obstetricians and Gynecologists, and Society of Gynecologic Oncologists all recommend that women with ovarian cancer be referred to a
gynecologic oncologist for their initial surgery.83
A recent survey of surgical care for 3067 patients with
ovarian cancer who were 65 years or older revealed that
1377 (45%) were operated on by a general gynecologist,
1017 (33%) by a gynecologic oncologist, and 673 (22%) by
a general surgeon. Staging lymph node dissections in patients with apparent early-stage disease were performed in
60% of cases by gynecologic oncologists vs 16% by general surgeons and 36% by general gynecologists. Similarly,
debulking procedures were more likely to be performed by
specialty surgeons.83
An often-stated justification against aggressive surgical
resection arises from the hypothesis that the initial extent of
advanced disease correlates with the aggressiveness of the
underlying tumor biology and that this will ultimately dictate outcome, independent of the amount of residual disease at the end of the surgical procedure.89,90
In an attempt to address this critical issue of whether
aggressive surgical procedures can improve survival in
patients with advanced ovarian tumors, we performed a
retrospective study of 194 consecutive patients with adMayo Clin Proc.

vanced ovarian cancer who had undergone their primary


surgery at Mayo Clinic from January 1994 to December
1998.91 The main findings include the following: (1) residual
disease at the conclusion of the surgery was the only independent predictor of outcome in patients with stage IIIC
ovarian cancer (Figure 1); (2) radical surgical resection and
residual disease independently affected survival of patients
with the most clinically aggressive disease at the beginning
of the surgical procedure; and (3) considering patients with
optimal cytoreduction (residual disease <1 cm), survival was
the same whether they underwent radical or nonradical surgical procedures (Figure 2). Thus, minimizing residual disease through aggressive surgical resection appeared to be
beneficial, especially in patients with carcinomatosis.
Radical Procedures. Several radical surgical procedures, including intestinal resection,92,93 splenectomy,94 diaphragmatic resection,95 and hepatic resection,96 have been
described as treatments of advanced ovarian cancer with
acceptable morbidity. At our institution, rectosigmoidectomy with stripping of pelvic peritoneum was associated
with a survival advantage for patients with disease in the
cul-de-sac area.97 We also described the technique for
eradicating tumor nodules from the diaphragm.98 Furthermore, we showed the survival benefit attributable to these
procedures performed in patients with disease in the upper
abdomen.99 Finally, we demonstrated the role of hepatic
resection(s)96 and splenectomy100 in the context of either a
primary or a secondary debulking.
Interval Debulking: A Different Approach? Interval
debulking surgery is defined as an operation performed
after a course of induction (or neoadjuvant) chemotherapy,
usually 2 or 3 cycles of chemotherapy. The primary aim of

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CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

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.

this procedure, which is the same as for up front surgery, is


to reduce the volume of residual disease and hence improve
the likelihood of complete response to chemotherapy. The
main proposed use of neoadjuvant chemotherapy and subsequent interval debulking is for the patient with a high risk
of major perioperative morbidity at initial diagnosis. Many
clinicians and medical centers have already started this
alternative treatment strategy, even though the precise role
of neoadjuvant chemotherapy in the management of advanced-stage epithelial ovarian cancer has not yet been
established. This type of operation can be performed after a
suboptimal primary attempt of debulking, followed by 2 to
3 courses of platinum-based chemotherapy. The role of
interval debulking in this setting has been investigated in 2
large prospective randomized trials: a European Organization for Research and Treatment of Cancer study101 and a
Gynecologic Oncology Group (GOG)102 study. Both trials
showed that interval debulking surgery by a trained gynecologic oncologist improves survival in patients who had
undergone initial suboptimal primary debulking surgery.
Interestingly, interval debulking surgery does not seem to
benefit patients who were primarily operated on by a gynecologic oncologist attempting maximal surgical effort at
initial surgery. In general, we have found that the most
appropriate candidates for a neoadjuvant approach are patients whose performance status would make them unsuitable for a prolonged surgical effort or those having just
undergone major but suboptimal surgery. In these patients,
cytoreduction with chemotherapy may improve the performance status to allow a full surgical effort later.
758

Mayo Clin Proc.

Surgical Resectability: Can It Be Predicted? As a


corollary to the previous section, a critical, decisive, and
challenging point in defining patients who might benefit
either from an upfront radical surgical or an interval
debulking approach is the development of models that
allow physicians to have clear and reliable selection criteria
for identifying patients who are not candidates for primary
cytoreduction. Numerous studies have tried to develop a
model to predict which patients are more likely to be able to
undergo optimal debulking using features that can predict
surgical outcome, such as disease extent on imaging,
amount of ascites, serum marker CA-125, or gene expression.103-108 The prediction rate in these studies ranged
widely, from 67% to 94%, indicating that it is unclear
whether these results are patient or center dependent. In a
recent study in which we examined the surgical practice at
our institution and reasons for suboptimal debulking,109 we
reported that the range of expected rates of optimal
cytoreduction for advanced-stage ovarian cancer varies
widely and is surgeon dependent, even within an overall
aggressive surgical practice. We also showed that patients
with substantial dissemination of disease and poor performance status are less likely to undergo optimal debulking
in aggregate.
Secondary Debulking. Although primary cytoreduction is universally considered the cornerstone of initial
management for patients with advanced disease, the role of
such aggressive surgery in patients with recurrent disease is
debated. Several studies110-126 have emphasized the value of
complete surgical resection at the time of secondary de-

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CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

bulking for recurrent disease in highly selected patients.


Because of the retrospective, nonrandomized nature of these
studies, selection bias doubtless plays a significant role in the
findings. Several factors correlate with good prognosis after
secondary cytoreductive surgery: longer disease-free interval, number of tumor nodules at time of recurrence, smaller
residual tumor at primary surgery, good response to first-line
platinum chemotherapy, and smaller size of maximum tumor at recurrence. Recent studies124-126 have tried to identify
ideal candidates for secondary surgery. Onda et al124 suggested that patients with recurrent ovarian cancer be considered ideal candidates for secondary surgery when they have
3 or all of the following 4 factors at recurrence: (1) diseasefree interval longer than 12 months, (2) no liver metastasis,
(3) a solitary tumor, and (4) tumor size smaller than 6 cm.
Exclusion criteria included (1) age of 75 years or older at
recurrence, (2) performance score of 3 or 4, and (3) progressive disease during presurgical chemotherapy, if undertaken.
Salani et al126 identified the best candidates for secondary
cytoreduction as patients with 1 or 2 radiographic recurrence
sites and a diagnosis-to-recurrence interval of 18 months or
longer. A complete secondary surgical cytoreduction was
achievable in most of these selected patients and was associated with a significant survival benefit.
Fertility-Sparing Procedures. Two groups of young
patients with epithelial cancer may be considered for a
conservative surgical approach. Borderline ovarian tumors
are often diagnosed incidentally after oophorectomy or
cystectomy in young women. The rate of recurrence after a
conservative treatment is very low (3%-6%),127 suggesting
that eventual restaging after an incomplete primary staging
is not required. However, 2 recent larger series72,128 reported that patients who underwent conservative surgery
experienced more recurrences than patients who had a
hysterectomy and BSO performed. However, no overall
survival difference was noted. Therefore, since the outcome of patients with both staged and unstaged disease is
similar, thorough surgical staging after the final pathologic
report of ovarian borderline tumor is unnecessary.129,130 If
there is a question about a possible borderline tumor and
because the final pathologic diagnosis may differ from the
frozen section pathologic diagnosis,131,132 it is prudent to
wait for the final pathologic report before proceeding with
additional surgery.
A conservative approach might also be offered to young
patients with invasive ovarian cancer macroscopically confined to 1 ovary. These patients should be offered a unilateral salpingo-oophorectomy with comprehensive staging,
including peritoneal biopsies and bilateral pelvic and paraaortic lymph node sampling up to the renal vessels.
Again, the recurrence rate and the overall survival rate have
been reported to be similar among patients with ovarian
Mayo Clin Proc.

cancer who were treated conservatively and those who


underwent more aggressive surgical procedures.133 Pregnancies after fertility-sparing procedures have also been
reported.133
CHEMOTHERAPY
Early-Stage Disease. The role of chemotherapy for
patients with stage I and II ovarian cancer was studied by
GOG in 1980; 12 cycles of oral melphalan were compared
to observation.134 The 5-year disease-free and overall survival rates were 91% and 94% for untreated patients,
and 98% for those receiving melphalan. This study identified a group of patients, those with early-stage (stage IA
and IB) ovarian cancer with well-differentiated or moderately differentiated tumors, who do not require adjuvant
therapy.
Several studies have compared intraperitoneal chromic
phosphate P 32 (32P) with chemotherapy.74,135-138 A GOG
study compared 32P and melphalan in patients with earlystage disease and unfavorable prognostic factors (stage IA
and IB with poorly differentiated tumor, stage IC with
tumor on the ovarian surface, ruptured capsule, ascites or
positive peritoneal washings, and all patients with stage II
disease).74 The 5-year disease-free survival rate was 80%
for both arms, and the 5-year survival rates were 78% for
32
P and 81% for melphalan. Two studies compared 6 cycles
of adjuvant cisplatin with intraperitoneal 32P and found no
difference in 5-year survival.137,138 GOG compared 32P with
3 cycles of cisplatin plus cyclophosphamide in patients
with early-stage disease with unfavorable prognostic factors.135 The 10-year recurrence-free survival rate was 65%
for the 32P arm and 72% for the chemotherapy arm. This
study concluded that, with better progression-free survival
with chemotherapy and with the bowel toxicity noted with
32
P, chemotherapy was the standard treatment of earlystage, high-risk ovarian cancer.
The GOG 157 study examined high-risk patients with
stage I and stage II disease and compared 3 vs 6 cycles of
paclitaxel at 175 mg/m2 for 3 hours plus carboplatin with an
area under the curve (AUC) of 7.5.139 The estimated probability of surviving 5 years was 81% vs 83%. The conclusion was that after complete surgical staging 3 cycles of
paclitaxel plus carboplatin was reasonable treatment, with
an additional 3 cycles of therapy providing only a modest
reduction in risk of recurrence with a significant increase in
toxicity. The results of the most recent GOG trial in earlystage ovarian cancer (trial 175), which compared 3 cycles
of paclitaxel plus carboplatin with 3 cycles of the same
combination followed by weekly paclitaxel for 26 weeks,
are pending.
Two large randomized trials compared chemotherapy
with no immediate therapy for early-stage ovarian cancer:

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CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

the International Collaborative Ovarian Neoplasm (ICON)


trial 175 and the Adjuvant ChemoTherapy In Ovarian Neoplasm Trial.76 Analysis of the combined result showed
survival rates of 82% vs 74%, an 8% increase in favor of
chemotherapy. The survival rate of patients with stage I
disease who experienced disease relapse after observation
only was similar to that of patients with stage III disease
with salvage of only 20%.140
Current recommendations are for no postoperative treatment of patients with early-stage (stage IA and IB) ovarian
cancer with well- or moderately well-differentiated tumors.
Postoperative treatment with either paclitaxel plus carboplatin or participation in clinical trials is recommended
for patients with early-stage disease with poor prognostic
features.
Advanced-Stage Disease. Evolution of Chemotherapy
for Advanced-Stage Ovarian Cancer. From the 1960s to
the present, chemotherapy for ovarian cancer has evolved
from single-agent alkylating agent therapy to combination
chemotherapy, intraperitoneal therapy, biologic agents,
and immunotherapy for patients with advanced disease.
Despite these advances, most patients with stage III and IV
ovarian cancer are not cured of their disease.
Melphalan, chlorambucil, or cyclophosphamide as
single agents in advanced ovarian cancer produced response rates of 35% to 65%, with median survival times of
10 to 14 months.141 In the 1970s, combination chemotherapy resulted in improved response rates and survival times
compared with single-agent therapy. The first study to
show improved survival with combination chemotherapy
was published in 1978. The combination of altretamine
(hexamethylmelamine), cyclophosphamide, methotrexate,
and fluorouracil was compared with melphalan, with overall
response rates of 75% vs 54% and a longer median survival
(29 vs 17 months; P<.02) for the combination.142 Additional
combination chemotherapy trials, such as melphalan vs cyclophosphamide, altretamine (hexamethylmelamine), and
fluorouracil143; cyclophosphamide vs cyclophosphamide
and doxorubicin144; cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin (Adriamycin), and cisplatin
vs melphalan145; and melphalan plus doxorubicin (Adriamycin) vs melphalan146; showed improved response rates
and in some studies improved median survival with combination therapy.147
In 1982, a study by Decker et al148 at Mayo Clinic
reported 2-year survival rates of 52% and 19% with cyclophosphamide plus cisplatinum vs cyclophosphamide alone.
In 1986, GOG reported a study of doxorubicin plus cyclophosphamide vs cyclophosphamide, doxorubicin (Adriamycin), and cisplatin with median survival times of 7.7 vs 13.1
months and an overall survival time of 9.7 vs 15.7 months.149
These studies and a Netherlands Cancer Institute study es760

Mayo Clin Proc.

tablished the routine addition of cisplatin to combination


chemotherapy for advanced ovarian cancer.150
Randomized clinical trials failed to show a long-term
survival advantage for the inclusion of doxorubicin in
cisplatin-containing regimens.151,152 A Mayo Clinic study
of cyclophosphamide, cisplatin, plus leuprolide acetate
showed no benefit of the addition of a gonadotropin-releasing hormone to cyclophosphamide and cisplatin in stage III
or IV ovarian cancer.153
With the widespread adoption of adjuvant platinumbased combination chemotherapy for advanced-stage disease, the relapse-free interval after completion of that
therapy (or the platinum-free interval) has been recognized
as a predictor of the likelihood of subsequent response to
chemotherapy. Patients with a relapse-free interval of more
than 6 months (platinum sensitive) have a higher probability
of responding to platinum again and to other chemotherapeutics. Platinum-resistant disease includes disease that relapses within 6 months of adjuvant therapy or disease that
progresses while the patient is taking platinum in the salvage
setting.
In 1989, paclitaxel was reported as an active agent in
ovarian cancer with a response rate of 24% in platinumresistant disease.154 A phase 1 trial of paclitaxel and cisplatin
showed that the drugs could be given safely in combination,
with paclitaxel administered first as a 24-hour infusion followed immediately by cisplatin.155 In 1996, McGuire et al156
reported the results of GOG 111, which studied cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stages III and IV ovarian cancer. The
study found response rates of 60% vs 73%, progression-free
survival times of 13 vs 18 months, and median survival times
of 24 vs 38 months, all favoring the paclitaxel and cisplatin
combination. A European-Canadian trial, OV-10, published
in 2000, confirmed the superiority of paclitaxel plus cisplatin
over cyclophosphamide and cisplatin.157
Early studies with paclitaxel used a 24-hour schedule,
selected to reduce the risk of hypersensitivity reactions to the
vehicle of the water-insoluble paclitaxel molecule.158 A European-Canadian trial showed equivalent efficacy of a 3hour vs 24-hour infusion schedule for paclitaxel for recurrent
ovarian cancer with a decrease in bone marrow toxicity and
an increased incidence of neuropathy with the shorter infusion.159 The sequence of administration of paclitaxel and
cisplatin was shown to be greatly important; administration
of cisplatin before 24-hour paclitaxel delays clearance of the
paclitaxel.155 Other studies have shown enhanced cytotoxicity when paclitaxel was administered before cisplatin and
antagonism when the sequence was reversed.158,160,161 This
effect is not seen with carboplatin. Carboplatin administration before paclitaxel has not been shown to interfere with
clearance of paclitaxel.158

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Several studies, including GOG 158, have shown that


cisplatin and carboplatin have equivalent benefit when used
with paclitaxel.162-164 In GOG 158, in patients with optimally
debulked stage III disease, 6 cycles of paclitaxel at 135 mg/m2
for 24 hours plus cisplatin at 75 mg/m2 vs paclitaxel at 175
mg/m2 for 3 hours plus carboplatin (AUC of 7.5) showed no
significant difference in median progression-free or overall
survival.164 Fewer gastrointestinal and metabolic toxic effects occurred with carboplatin, and no difference in neurotoxicity was found in the 2 arms of the study. Thus, 3-hour
paclitaxel with carboplatin became the standard first-line
chemotherapy for epithelial ovarian cancer.
A study by Neijt et al162 published in 2000 that compared
paclitaxel at 175 mg/m2 for 3 hours with cisplatin at 75 mg/m2
or carboplatin (AUC of 5) and a study by du Bois et al163 that
compared paclitaxel at 185 mg/m2 with either cisplatin at 75
mg/m2 or carboplatin (AUC of 6) showed similar response,
progression-free survival, and overall survival in the cisplatin and carboplatin groups. More gastrointestinal and neurologic toxicity was found in patients receiving cisplatin and
more myelosuppression in patients randomized to carboplatin.
The ICON group reported a randomized study (ICON-3)
of women with stages I to IV ovarian cancer who received
paclitaxel plus carboplatin vs either single-agent carboplatin
or cyclophosphamide, doxorubicin (Adriamycin), and cisplatin.165 No difference was found in overall survival between paclitaxel plus carboplatin and controls (36.1 vs 35.4
months at follow-up of 51 months). The investigators concluded that single-agent carboplatin and cyclophosphamide,
doxorubicin (Adriamycin), and cisplatin were as effective as
paclitaxel plus carboplatin as first-line treatment, and the
more favorable toxicity profile of single-agent carboplatin
suggested it as first-line chemotherapy for ovarian cancer.
These results contradict the findings of GOG 111156 and OV10.157 However, ICON-3 included early and advanced stages
of disease and had other trial design limitations. In the
United States, paclitaxel with carboplatin remained the firstline treatment for advanced ovarian cancer.
GOG 182ICON-5 was a 5-arm phase 3 trial of intravenous paclitaxel and carboplatin vs that same doublet plus a
third agent, gemcitabine, pegylated liposomal doxorubicin
(Doxil), or topotecan, in patients with advanced stage ovarian or primary peritoneal cancer.166 No evidence was available to indicate that adding a third cytotoxic agent prolonged progression-free survival. Analysis of overall survival
is in progress. A recent international consensus conference
recommended intravenous carboplatin and paclitaxel as the
standard chemotherapy for ovarian and peritoneal cancer.167
Intraperitoneal Chemotherapy. Because advanced
ovarian cancer is often limited to the peritoneal cavity,
intraperitoneal as opposed to systemic administration of
chemotherapy was proposed as a strategy to increase drug
Mayo Clin Proc.

concentrations in the abdominal cavity. In 1996, Alberts et


al168 reported a trial of intravenous cisplatin at 100 mg/m2
plus cyclophosphamide at 600 mg/m2 intravenously vs cisplatin at 100 mg/m2 intraperitoneally plus cyclophosphamide at 600 mg/m2 intravenously, with survival of 41 vs 49
months. This trial was followed in 2001 by Markman et
al169 who reported a trial of standard dose intravenous
cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2) intravenously every 21 days for 6 cycles vs moderately high-dose
carboplatin (AUC of 9 two times intravenously) followed by
intravenous paclitaxel (135 mg/m2) and intraperitoneal
cisplatin (100 mg/m2) every 21 days for 6 cycles.169 Overall
survival was 52.5 vs 63.2 months for the intraperitoneal arm.
In January 2006, Armstrong et al170 published the results
of GOG 172, which compared paclitaxel at 135 mg/m2 for
24 hours followed by cisplatin at 75 mg/m2 intravenously
every 21 days for 6 cycles vs paclitaxel at 135 mg/m2
intravenously for 24 hours with intraperitoneal cisplatin at
100 mg/m2 on day 2 with paclitaxel at 60 mg/m2 intraperitoneally on day 8 every 21 days for 6 cycles in optimally
debulked stage III ovarian or primary peritoneal cancer.
Only 42% of the patients in the intraperitoneal group completed 6 cycles of the assigned therapy, but the median
progression-free survival times were 18.3 and 23.8 months,
with median overall survival times of 49.7 and 65.6 months,
favoring the intraperitoneal regimen. Neutropenia, gastrointestinal toxicity, fatigue, pain, and metabolic events
were increased in the intraperitoneal group. Quality of life
was assessed and was significantly worse in the intraperitoneal therapy group before cycle 4 and at 3 to 6 weeks after
treatment, but by 1 year after treatment, quality of life was
similar in both arms. On the basis of these findings of
increased survival with intraperitoneal therapy in these 3
studies, the National Cancer Institute issued a clinical advisory that recommended a regimen containing intraperitoneal
cisplatin and a taxane given intravenously or intravenously
and intraperitoneally for women with optimally debulked
stage III ovarian cancer.171 The optimal dose and schedule
of intraperitoneal chemotherapy are under investigation.
Of note, these 3 clinical trials have been the subject of
considerable controversy and criticism. The trial by Alberts
et al in 1996 did not include paclitaxel in either arm and
thus was believed not to reflect contemporary therapy.
Moreover, in that trial, the subset of patients with the
lowest volume disease did not demonstrate benefit from the
intraperitoneal approach. In the trial by Markman et al,
patients in the intraperitoneal arm received intravenous
carboplatin (AUC of 9) for 2 cycles before the intraperitoneal therapy, raising the question if more chemotherapy,
rather than the intraperitoneal route, conferred the benefit. In
GOG 172, the experimental arm used 24-hour intravenous
paclitaxel on day 1 and then both cisplatin (day 2) and

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CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

paclitaxel given intraperitoneally (day 8). The added day 8


paclitaxel regimen introduces another variable beyond the
intraperitoneal mode of delivery. Moreover, on the basis of a
cross-trial analysis, some argue that the results seen with the
latest intraperitoneal trial are not significantly better than
what can be achieved with intravenous carboplatin and 3hour paclitaxel.172,173 Unfortunately, no intraperitoneal regimen has been compared with what many consider the current
standard, intravenous carboplatin and paclitaxel.174
Consolidation Therapy. Although the majority of patients with ovarian cancer achieve a clinical complete remission with first-line chemotherapy, disease will recur in
most. Overall, the 5-year survival rate for patients with
advanced ovarian cancer is approximately 30%.175 To improve survival, consolidation therapy, maintenance therapy, neoadjuvant therapy, novel cytotoxic agents, and
novel biologic agents are being studied.
For consolidation therapy, in a GOG trial of intraperitoneal radioactive 32P vs observation in patients with stage III
disease after negative second-look laparotomy, 32P did not
decrease the risk of relapse or improve survival.176 A prospective randomized trial of whole abdominal radiation
therapy after induction therapy did not improve survival.177
Cure et al178 found no improvement in overall survival with
high-dose chemotherapy and stem cell support compared
with 3 cycles of conventional dose carboplatin and cyclophosphamide after response to primary therapy for advanced disease.
Maintenance Therapy. Maintenance therapy with topotecan,179 interferon alfa,180 and vaccines targeting CA-125181
did not improve survival after chemotherapy. A randomized
trial of 12 vs 3 months of maintenance paclitaxel after complete response to initial therapy improved progression-free
survival but not overall survival.182 The GOG 212 trial is in
progress comparing 12 cycles of paclitaxel vs 12 cycles of
paclitaxel poliglumex vs observation after a complete response to front-line therapy is achieved to further address
the benefit of maintenance therapy.
Neoadjuvant Therapy. Neoadjuvant therapy is a strong
consideration for those individuals who are deemed to be poor
surgical candidates at the time of initial diagnosis. In addition,
for patients diagnosed with stage IV disease, especially those
with a high burden of metastatic disease, treatment can begin
with chemotherapy and response to chemotherapy can dictate subsequent decisions about aggressive surgical debulking. No published randomized trials have evaluated neoadjuvant chemotherapy, but one trial is in progress.183
CHEMOTHERAPY FOR RECURRENT DISEASE
Unfortunately, most women with advanced-stage ovarian
cancer will experience disease relapse after primary chemotherapy and will develop symptomatic recurrent dis762

Mayo Clin Proc.

ease. Median survival after recurrence is 2 years.184 Cure is


not likely, and the primary goal of therapy is management
of symptoms. Women with an asymptomatic recurrence do
not require immediate therapy because no evidence is
available to indicate that survival is improved by earlier administration of chemotherapy.184 However, many women
choose to initiate second-line therapy when CA-125 levels
increase or recurrent disease is confirmed. As described
previously, the platinum-free interval after adjuvant therapy is a strong predictor of response to chemotherapy for
recurrent disease. For example, patients with a treatmentfree interval of greater than 24 months had a response rate of
approximately 60% to re-treatment with a platinum agent.185
Two randomized trials have compared single-agent
treatment with a platinum compound vs combination therapy with either paclitaxel plus carboplatin or gemcitabine
plus carboplatin in patients with platinum-sensitive recurrent ovarian cancer.184 The ICON-4Arbeitsgemeinschaft
Gynaekologische Onkologie ovarian cancer trial (paclitaxel plus platinum vs single-agent platinum) showed a
2-year survival rate of 57% vs 50%, favoring the combination. In the second study, the Arbeitsgemeinschaft Gynaekologische Onkologie group compared gemcitabine plus
carboplatin with single-agent carboplatin.186 The overall
response rate was 47.2% vs 30.9%, favoring the combination. The median time to progression was 8.6 vs 5.8
months. The trial was not powered to detect a difference in
overall survival. In both studies the combination regimens
had greater hematologic toxicity than single-agent therapy.
For patients with platinum-resistant disease, several
agents have shown some activity, including topotecan,187,188
liposomal doxorubicin,189,190 taxanes,191-193 gemcitabine,194-196
oral etoposide,197,198 altretamine (hexamethylmelamine),199
and ifosfamide.200 Topotecan produced response rates of
12.4% in patients with platinum-resistant disease and of
19.2% in those with platinum-sensitive disease.187
In a phase 2 trial, liposomal doxorubicin showed a response rate of 26% in platinum- and taxane-resistant disease.189 A large randomized trial compared liposomal
doxorubicin and topotecan in platinum-sensitive and platinum-resistant disease.190 The overall response rates (19.7%
vs 17%) and overall survival times (60 vs 56.7 weeks) were
not statistically different. However, a retrospective analysis
in patients with platinum-sensitive disease showed a statistically significant benefit in overall survival with liposomal
doxorubicin (108 vs 71 weeks). Response rates with both
drugs were lower in patients with platinum-resistant than in
platinum-sensitive disease. The major toxicity of topotecan
was hematologic; the major toxicity of liposomal doxorubicin was palmar plantar erythrodysthesia.
With paclitaxel doses of 135 to 175 mg/m2 every 3
weeks, response rates of 24% to 30% were seen in patients

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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.

lide acetate in a small group of patients with advanced


disease. High-dose oral megestrol acetate showed a 10%
response in patients with advanced disease.208 A study of
sequentially administered ethinyl estradiol and medroxyprogesterone acetate in patients with refractory ovarian
cancer with positive estrogen receptors showed a 17%
response rate.209 A tamoxifen trial in patients with recurrent
disease had a 3.2% complete response and a 6.4% partial
response.210 No correlation was found between response
rate and estrogen receptor status.
The issue of how many treatment regimens to use in
patients with advanced ovarian cancer is an area of controversy. With low response rates with subsequent chemotherapies, patients need to decide whether to continue
chemotherapy or receive supportive care only.184 Because
chemotherapy and hormonal therapy for recurrent ovarian
cancer have relatively low response rates, patients with
recurrent ovarian cancer should be encouraged to participate in clinical trials.
PALLIATIVE STRATEGIES FOR BOWEL OBSTRUCTION
As mentioned previously, the overall 5-year survival for
ovarian cancer is 45%.1 Many of these women have experienced or will experience recurrences of their cancer. What is
the outcome for the majority of patients diagnosed with this
malignancy? Most women ultimately die of cancer and contend with pronounced morbidity during their lifetimes.
Bowel obstruction is a major end-of-life complication in
patients with ovarian cancer.211, 212 von Gruenigen et al213
catalogued end-of-life events among 62 women with ovarian cancer. Within the last 3 months of life, bowel obstruction was the most common cause of morbidity, giving rise
to a total of 13 hospital admissions. The extensive spread of
ovarian tumors within the abdominal-pelvic cavity places
these patients at high risk for this complication.
Important first steps in evaluating and treating patients
with ovarian cancer who are suspected of having a bowel
obstruction consist of ordering the appropriate diagnostic
testing (often computed tomography to determine a site of
obstruction) and attempting conservative management, such
as withholding oral intake, nasogastric tube suctioning, and
seeking surgical consultation. When conservative measures
alone do not lead to resumption of bowel function, surgery is
often considered, but the decision to operate can be challenging and is best approached in a multidisciplinary fashion.
Thus, the patients overall health, the aggressiveness of the
cancer, the extent of disease within the peritoneal cavity, and
the availability of future chemotherapy options for a specific
patient must all be carefully considered before making the
decision to operate. The most common reason to forgo surgery is the extent of involvement of the intestinal tract;
generally, there is not a single site that causes the obstruc-

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763

CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

tion. Of note, informal comparisons between surgical and


nonsurgical series suggest that survival rates are comparable
among patients with chemotherapy-refractory disease.213
If the decision is made to forgo surgery, the value of
palliative therapy for patients with malignant bowel obstruction must be well understood. Palliative therapy can
be subdivided into nonmedical interventions, such as stent
placement and gastric venting, and medical interventions,
such as octreotide and other antisecretory agents, corticosteroids, pain medications, and antiemetics. With regard to
the former, stent placement can be used to open or expand
the bowel lumen in a patient who might not be healthy
enough to withstand surgery but who nonetheless has a
single focus of obstruction accessible to an endoscope.214
Moreover, gastric venting, which can be accomplished
with radiographic guidance or with the help of a gastroenterologist, can allow a patient to remain free of a nasogastric tube and, at the same time, allow proximal decompression of the gastrointestinal tract to decrease distension
and enhance comfort.215
Similarly, medical management has been shown to provide notable palliation. First, octreotide is a somatostatin
analogue that blocks certain gut hormones, such as vasoactive intestinal peptide, that increase intestinal secretions
and result in pressure and discomfort proximal to the obstruction. Comparative trials have shown that within 24
hours octreotide can decrease bowel secretory output and
improve nausea and vomiting in patients with bowel obstruction.216-218 Thus, octreotide doses of 600 to 800 g/d
provide a well-documented palliative effect. Second, although findings have not been borne out in a recent metaanalysis,219 Philip et al220 observed that dexamethasone, 8
mg/d, intravenously or subcutaneously, improved pain,
nausea, and vomiting among 9 of 13 patients with bowel
obstruction. The well-described antiemetic and anti-inflammatory effects of corticosteroids add to the plausibility
of these observations and suggest that corticosteroids can
be helpful for patients with bowel obstruction who have
nausea, vomiting, and marked abdominal distension. Third,
previous studies have shown that oral pain medications can
be used in these patients, but transdermal and buccal medications are also available for patients who might not tolerate oral medications. Fourth, although few studies have
tested antiemetics specifically in patients with inoperable
bowel obstruction, the success of various agents with diverse mechanisms of action suggests that these agents
might also be effective in relieving nausea and vomiting in
the setting of bowel obstruction. However, an important
point to underscore is the poorly defined role of metoclopramide. Because this agent enhances motility, it often
worsens pain in patients with bowel obstruction and therefore is not recommended in these patients.213
764

Mayo Clin Proc.

One of the most distressing issues faced by patients,


family members, and health care professionals is the inability of patients with inoperable bowel obstruction to maintain oral intake. Because of the patients inability to maintain adequate oral nutrition, the issue of parenteral nutrition
often arises. Multiple randomized studies of nutritional
support in patients with advanced cancer have failed to
show benefit in survival or quality of life.221-225 Hoda et al226
recently described Mayo Clinics 20-year experience
with home parenteral nutrition in patients with cancer.
Among the 52 patients who had been carefully selected as
candidates for home parenteral nutrition, 6 had ovarian
cancer. Although 2 of these 6 patients with ovarian cancer
appeared to derive some benefit from parenteral nutrition,
living for 35 and 19 months, the other 4 died within weeks
to months and did not appear to benefit. Of the 2 patients
with ovarian cancer who survived beyond 1 year, 1 had a
fistula that necessitated the use of total parenteral nutrition; the other had short bowel syndrome and malabsorption in addition to problems with obstruction. Other than
such exceptional cases, we know of no data that provide
clear-cut justification for the use of parenteral nutrition in
patients with ovarian cancer who have inoperable bowel
obstruction.
NEW THERAPEUTIC STRATEGIES
Ovarian cancer presents unique challenges and opportunities to the medical and scientific communities. Because
ovarian cancer can be debulked surgically and because of
its sensitivity to chemotherapeutic agents, we have the
ability to perform surgery to reduce disease extent to a low
level initially. Unfortunately, as has been discussed, in
women with advanced disease, cells initially resistant to
chemotherapy can later regrow. Thus, the development of
new therapeutic approaches is a high priority. Numerous
strategies are being pursued. One is to use current highthroughput genomic studies to analyze thousands of genes
in the tumors of women with chemosensitive vs chemoresistant disease.227 The goal of this approach is to be able
to predict, at the outset, which women will benefit significantly from standard chemotherapy approaches vs those
who should be treated with alternative approaches. Such
genomic studies can serve not only for clinical prediction
but also to identify the genes and their resultant proteins
that mediate resistance to chemotherapy, ideal targets for
silencing or modifying agents.
Technologic advances that allow us to examine the molecular machinery driving cancer cells have helped to
identify numerous mediators within ovarian cancer cells
that can be targeted with new molecular strategies. Examples include agents that block stimulatory growth factor
receptors at the cell surface, small molecule inhibitors of

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CURRENT MANAGEMENT STRATEGIES FOR OVARIAN CANCER

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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