Ovid: Cancer: Principles & Practice of Oncology

Ovid: Cancer: Principles & Practice of Oncology http://ovidsp.tx.ovid.com/sp-3.27.2b/ovidweb.
cgi
Editors: DeVita, Vincent T.; Hellman, Samuel; Rosenberg, Steven A.

Title: Cancer: Principles & Practice of Oncology, 7th Edition
Copyright ©2005 Lippincott Williams & Wilkins
> Table of Contents > Volume One > Part 3 - Practice of Oncology > Chapter 32 - Gynecologic Cancers > SECTION 4: Ovarian Cancer, Peritoneal
Carcinoma, and Fallopian Tube Carcinoma > OVARIAN CANCER
OVARIAN CANCER
On the basis of distinct pathologic and clinical features, ovarian cancer can be separated into three distinct histologic
subtypes: epithelial tumors, germ cell tumors, and sex cord–stromal tumors. The vast majority of ovarian cancers are
epithelial in origin, with these tumors accounting for more than 90% of the estimated 25,400 new cases of ovarian cancer
diagnosed in the United States in 2003.1 Fallopian tube carcinomas and extraovarian primary peritoneal carcinomas are
much less common, but because their biology and clinical characteristics are markedly similar to those of epithelial
ovarian carcinomas, these tumors are also discussed in this chapter. Approximately 14,300 U.S. women died of ovarian
cancer in 2003, which makes this tumor the leading cause of gynecologic cancer death.1 Overall, ovarian cancer accounts
for 4% of all cancer diagnoses and 5% of all cancer deaths. The lifetime risk of developing ovarian cancer is approximately
1.7%, and approximately 1 in 60 women will die of the disease.
The vast majority of epithelial ovarian carcinomas are diagnosed in postmenopausal women, and the median age at
diagnosis is 63 years. The age-specific incidence increases from 15 to 16 per 100,000 in the 40- to 44-year-old age group to
a peak rate of 57 per 100,000 in the 70- to 74-year-old age group.2 There has been a statistically significant improvement
in the 5-year survival rates over the last decades, with a rate of 37% in 1976, 41% in 1985, and 53% in 1998.1 This
improvement in survival is likely the result of more effective chemotherapies and improvements in surgery and supportive
care. African American women in the United States have a lower incidence of ovarian cancer (10.3 per 100,000 women)
compared to white women; however, the overall survival rate of 53% is identical. The stage distribution and stage-specific
5-year survival rates for white and African American women are also very similar.1
PATHOGENESIS
The common epithelial tumors account for 60% of all ovarian neoplasms and for 80% to 90% of ovarian malignancies. The
remaining tumors arise from ovarian germ cells or stromal cells. The epithelial tumors arise from the surface epithelium or
serosa of the ovary. During embryogenesis, the lining of the coelomic cavity consists of mesothelial cells of mesodermal
origin, and the gonadal ridge is covered by serosal epithelium. Müllerian ducts, which give rise to the fallopian tubes,
uterus, and vagina, are the result of invagination of the mesothelial lining. When the epithelium becomes malignant, it
can express a variety of müllerian-type histologic morphologies. Serous carcinomas can resemble the fallopian tube,
mucinous tumors the endocervix, and endometrioid carcinomas the endometrium. It is thought that germ cell tumors
originate in cells derived from the primitive streak that ultimately migrated to the gonads. The mesenchyma gives rise to
the ovarian stroma, and stromal tumors arise from this original cell type.
In the majority of cases, malignant epithelial ovarian tumors disseminate throughout the peritoneal cavity after
exfoliation of malignant cells from the surface of the ovary. The typical circulation of the peritoneal fluid along the
undersurface of the right hemidiaphragm facilitates the frequently observed pattern of widespread dissemination of
malignant tumor cells within the peritoneal cavity. In addition, the omentum frequently attracts these malignant cells and
is thus a common site of metastasis. Tumor spread also occurs via the lymphatics from the ovary. A primary source of
drainage follows the ovarian blood supply in the infundibulopelvic ligament to lymph nodes around the aorta and vena
cava to the level of the renal vessels. There is also lymphatic drainage through the broad ligament and parametrial
channels; consequently, pelvic sidewall lymphatics, including the external iliac, obturator, and hypogastric chains, are
also frequently involved. More rarely, spread may occur along the course of the round ligament, resulting in involvement
of inguinal lymph nodes. Spread to lymph nodes is common. Approximately 10% of patients with ovarian cancer that
appears to be localized to the ovaries have metastases to paraaortic lymph nodes, and retroperitoneal lymph node
involvement is found in the majority of cases of advanced ovarian cancer. Hematogenous metastases to extraabdominal
sites can occur but are relatively uncommon. There can also be direct extension of the tumor from the ovary to involve
the adjacent peritoneal surfaces of the bladder, rectosigmoid, and pelvic peritoneum.
HISTOLOGIC CLASSIFICATION OF EPITHELIAL TUMORS

Table 32.4-1 details the classification of common epithelial tumors that has been developed by the World Health
Organization and the International Federation of Gynecology and Obstetrics.3 The nomenclature for these tumors reflects
the cell type, location of the tumor, and degree of malignancy, ranging from benign lesions to tumors of low malignant
potential (LMP) to invasive carcinomas. Tumors of LMP (“borderline malignancy”) have an excellent prognosis compared
with invasive carcinomas, and their clinical behavior and management are outlined later in this chapter. Tumors of LMP
are characterized by epithelial papillae with atypical cell clusters, cellular stratification, nuclear atypia, and increased
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mitotic activity. The differentiation between these tumors and carcinomas is primarily made on the basis of pathologic
architecture and the presence of stromal invasion. Overtly malignant tumors are characterized by an infiltrative
destructive growth pattern, with cytologically bizarre cells growing in a disorganized pattern with dissection into stromal
planes.
TABLE 32.4-1. World Health Organization Classification of Malignant Ovarian Tumors
COMMON EPITHELIAL TUMORS
Malignant serous tumor
Adenocarcinoma, papillary adenocarcinoma, papillary cystadenocarcinoma
Surface papillary carcinoma
Malignant adenofibroma, cystadenofibroma
Malignant mucinous tumor
Adenocarcinoma, cystadenocarcinoma
Malignant endometrioid tumor
Carcinoma
Adenocarcinoma
Adenoacanthoma
Endometrioid stromal sarcoma
Mesodermal (müllerian) mixed tumor: homologous and heterologous
Clear cell (mesonephroid) tumor, malignant
Carcinoma and adenocarcinoma
Brenner tumor, malignant
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Mixed epithelial tumor, malignant
Undifferentiated carcinoma
Unclassified
SEX CORD–STROMAL TUMORS
Granulosa–stromal cell tumor
Granulosa cell tumor
Tumor in the thecoma-fibroma group
Fibroma
Unclassified
Androblastoma: Sertoli-Leydig Cell Tumor
Well differentiated
Tubular androblastoma, Sertoli cell tumor (tubular adenoma of Pick)
Tubular androblastoma with lipid storage, Sertoli cell tumor with lipid storage
Sertoli-Leydig cell tumor (tubular adenoma with Leydig cells)
Leydig cell tumor, hilus cell tumor
Of intermediate differentiation
Poorly differentiated (sarcomatoid)
With heterologous elements
Gynandroblastoma
Unclassified
Germ cell tumor
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Dysgerminoma
Endodermal sinus tumor
Embryonal carcinoma
Polyembryoma
LIPID (LIPOID) CELL TUMORS
Choriocarcinoma
Teratoma
Immature
Mature dermoid cyst with malignant transformation
Monodermal and highly specialized
Struma ovarii
Carcinoid
Struma ovarii and carcinoid
Others
Mixed forms
GONADOBLASTOMA
Pure
Mixed with dysgerminoma or other form of germ cell tumor
The invasive epithelial carcinomas are characterized by histologic cell type and the degree of differentiation (tumor
grade). The histologic cell type has limited prognostic significance independent of clinical stage; however, tumor grade is
an important independent prognostic factor, especially in patients with early-stage epithelial tumors. Grading systems
have been based on cytologic detail or a pattern grading classification
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based on the degree to which a tumor forms papillary structures or glands versus solid tumor.
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DIAGNOSIS AND SYMPTOMS

Epithelial cancers of the ovary have been described as silent killers because the overwhelming majority of patients do not
present with symptoms until the disease has spread outside of the ovary and indeed outside of the pelvis. However,
studies surveying ovarian cancer patients have demonstrated that 95% of these women have nonspecific abdominal
symptoms many months before diagnosis.4 Approximately 70% of patients with epithelial cancers of the ovary present with
stage III or IV disease, whereas 70% of patients with germ cell ovarian malignancies present with stage I disease. Unlike
epithelial cancers, ovarian germ cell malignancies tend to stretch and twist the infundibulopelvic ligament, causing severe
pain while the disease is still confined to the ovary. Functioning ovarian tumors of the sex cord–stromal type may present
with symptoms suggestive of excessive endogenous estrogen or androgen production. Granulosa cell tumors occurring in
premenarchal girls may present with precocious puberty. Women in the reproductive years with granulosa cell tumors may
present with amenorrhea or abnormal menses, and postmenopausal women may present with postmenopausal bleeding.
Sertoli-Leydig cell tumors may present with symptoms of virilization, but none of these hormonal manifestations is a
reliable diagnostic criterion.
Abdominal discomfort and bloating are the most common symptoms experienced by women with epithelial ovarian
cancers, followed by vaginal bleeding, gastrointestinal symptoms, and urinary tract symptoms. Patients presenting with
nonspecific lower abdominal discomfort and bloating require at least a prompt and careful pelvic and rectovaginal
examination. The most common physical signs are ascites and a pelvic mass. The mass is frequently firm, hard, and fixed
with multiple nodularities palpable in the cul-de-sac.
Level of the cancer antigen 125 (CA 125) tumor biomarker is elevated in more than 80% of serous epithelial ovarian
cancers, but it can also be elevated in a variety of benign conditions and other nongynecologic malignancies. Furthermore,
in early-stage ovarian cancers, CA 125 level is elevated in less than half of cases. Other tumor markers, such as CA 19-9,
which is elevated in many mucinous ovarian carcinomas, and carcinoembryonic antigen, which may be elevated in 7% to
37% of patients with ovarian cancer, are less frequently used. Preoperatively, tumor marker levels are useful in predicting
the potential for malignancy. During treatment for ovarian cancer, CA 125 level is a very useful barometer of disease
activity and can be used to follow response to therapy and to detect an early recurrence.
Chest radiographs are routinely performed to look for malignant pleural effusions, which occur in 10% of patients, and
metastatic pulmonary disease, which is very rare. Barium enema examination is not routinely performed but may be
helpful in patients with blood in the stool, obstipation, or anemia to rule out a primary gastrointestinal malignancy.
Results of barium enema examinations are not very useful in predicting the need for colon resection. Mammography may
also be indicated preoperatively to rule out a possible metastatic or synchronous breast carcinoma.
Transvaginal ultrasonography (TVS) and abdominal ultrasonography are the most useful diagnostic examinations in the
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evaluation of a pelvic mass because of their ability to accurately discern the ovarian morphology and other pelvic
pathology. Some of the sonographic characteristics associated with ovarian cancer include irregular ovarian cyst borders,
solid elements within the cysts, papillary projections, bilateral ovarian involvement, and the presence of ascites. Color
Doppler imaging evaluates blood flow to an ovarian mass and can potentially identify a malignant process based on the
presence of abnormal neovascularization. Several studies suggest that color Doppler imaging may improve the specificity
for detecting ovarian cancer when a mass is seen; however, Doppler imaging cannot definitively identify malignancy.5
Three-dimensional ultrasonography has the potential benefit of improved definition of the ovarian surface and internal
cyst morphology; however, its usefulness in the diagnosis of ovarian cancer is still under study.
Cross-sectional imaging, such as computed tomography (CT) and magnetic resonance imaging, may be helpful in
characterizing the liver, identifying lymph node involvement, peritoneal studding, and omentum caking, and
characterizing the mesentery of the bowel. CT scans may be helpful in distinguishing a gynecologic malignancy from a
metastatic pancreatic neoplasm for which surgery may not be warranted. Magnetic resonance imaging in patients with an
ovarian mass has not been shown to have a clear advantage over CT, except for the evaluation of adnexal masses in
pregnant patients when ultrasonography is inconclusive and the desire is to avoid CT due to the radiation exposure.
Other studies such as bone and liver scintigraphy do not add any useful information. Intravenous pyelograms or renal scans
may be helpful in patients with abnormal renal function or abnormal findings on ultrasonography, but they are rarely
used. Positron emission tomography (PET) is a form of functional imaging that most frequently uses the positron-emitting
glucose analogue, [18F]fluorodeoxyglucose. Tumor masses are imaged based on their relatively increased glucose
metabolism compared to normal tissues. The role of PET in preoperative evaluation for suspected recurrent ovarian
carcinoma is being studied at a number of centers, and the more recent development of fusion PET-CT technologies,
combining cross-sectional and functional images, has shown very promising early results.6
The most common complaints associated with ovarian malignancies in the pediatric population are pain, abdominal
swelling, and pelvic mass. Ovarian masses in premenarchal girls require prompt evaluation and frequently an exploratory
laparotomy, because functional cysts should not occur. Most premenarchal adnexal masses, however, ultimately prove to
be benign.
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Small ovarian cysts are often identified on ultrasonographic examinations of postmenopausal ovaries. Five percent to 10%
of asymptomatic postmenopausal women may be found to have small ovarian cysts, especially in the first decade after
menopause. These cysts do not need to be removed if they appear to be sonolucent and unilocular on ultrasonography and
are associated with normal CA 125 levels.8 Postmenopausal women with complex pelvic masses, simple cysts in
association with elevated serum CA 125 levels, or simple cysts in association with abnormal color Doppler flow studies
should undergo surgical evaluation.
Enlarged ovaries in reproductive-age women are relatively common and are frequently due to either functioning ovarian
cysts, such as endometriomas and corpus luteum cysts, or to benign ovarian cysts. Women found to have such cysts may
be evaluated by measurement of serum CA 125 levels. However, caution is warranted in interpreting these data because
CA 125 levels can be elevated due to other benign processes in these young women. Benign conditions such as
leiomyomas, adenomyosis, endometriosis, and salpingitis, to name just a few, can be associated with elevated CA 125
levels, and no absolute cutoff exists to distinguish benign from malignant pathologies.7
Cysts that appear by ultrasonographic criteria to be functional or simple in nature may be followed through several
menstrual cycles. Often they disappear over this short observation interval. Functional cysts may also disappear when oral
contraceptives are used. Neoplastic cysts do not disappear under the influence of oral contraceptives. Even in
postmenopausal women, persistent unilocular ovarian cysts are very rarely associated with malignancy.8 Rising values in
serial CA 125 assays obtained during the observation period are an indication that a malignancy may be present. In turn,
CA 125 values that are stable or declining generally reflect the presence of a functional cyst or other benign condition.
Diagnostic laparoscopy may be extremely useful to evaluate unexplained pelvic pain or adnexal masses of uncertain
pathology. Extreme caution and sound surgical judgment are required when choosing this minimally invasive approach,
however, because rupturing a malignant tumor and up-staging a stage IA ovarian cancer to a stage IC cancer may result in
the need to administer chemotherapy or may even alter patient survival. Although there is no definitive evidence that
rupture of an early-stage ovarian malignancy decreases survival, avoidance of rupture should be the routine when
approaching ovarian masses suspicious for malignancy.
Serum CA 125 level is the gold standard for tumor markers in the evaluation of pelvic masses, particularly epithelial
ovarian cancers. In younger women, serum levels of α-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are
helpful in recognizing the presence of an endodermal sinus tumor, embryonal carcinoma, choriocarcinoma, or mixed germ
cell tumors. However, these patients often are not suspected preoperatively to have a malignancy. Measurement of AFP
and HCG levels is best applied in serial monitoring of the effectiveness of therapy. Failure to identify elevations of these
markers preoperatively does not preclude one from using them postoperatively in determining efficacy and duration of
treatment for these diseases. Inhibin is a transforming growth factor-β–like peptide normally secreted by the ovarian
stroma and functions in the feedback loop in the hypothalamic-pituitary-ovarian axis. Serum inhibin levels are useful
markers for granulosa cell tumors and can aid in this diagnosis when an ovarian stromal tumor is suspected preoperatively.
Patients with a preoperative evaluation consistent with the diagnosis of ovarian cancer do best if referred to a gynecologic
oncologist. Survival data suggest that those patients operated on by gynecologic oncologists for early-stage and late-stage
disease have better outcomes in terms of progression-free and overall survival. This observation is at least in part due to
the more complete surgical cytoreduction frequently accomplished by gynecologic oncologists, who have a better
understanding of ovarian cancer biology and the nearly linear relationship between residual tumor and survival.9,10
SCREENING AND EARLY DETECTION

Successful early detection of ovarian cancer should decrease mortality and morbidity from the disease. However, there
are
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no currently available tests that achieve this goal, and thus routine screening for asymptomatic ovarian cancer cannot be
recommended. Successful screening for any malignancy requires detection while the disease is either precancerous or in
its early stages. Although ovarian cancer's pattern of spread is well defined, the natural history of the disease is poorly
understood. The time frame for progression from stage I to IV ovarian cancer remains to be established. The entire
peritoneum is at risk, and peritoneal carcinomatosis may develop even after oophorectomy, or a syndrome of extraovarian
peritoneal carcinomatosis may occur characterized by widespread intraperitoneal epithelial carcinoma in the presence of
histologically normal ovaries. In addition, no premalignant lesion for epithelial ovarian carcinoma has been definitively
identified. Borderline tumors or those with LMP do not progress to invasive malignancies in the majority of cases.
The existing screening techniques, such as ovarian palpation, TVS, and serum CA 125 determinations, are not sufficiently
accurate to recommend general population screening. These tests are all limited by insufficient sensitivity and specificity.
Because surgical intervention and biopsy are frequently required to make the diagnosis of ovarian cancer, the positive
predictive value (PPV) of the screening test is the primary consideration. Excessive cost, morbidity, and even mortality
associated with unnecessary surgeries for a false-positive screening test result have led most investigators to recommend
that at least a 10% PPV be demonstrated.11
Although bimanual pelvic and rectovaginal examinations continue to be routinely recommended for women, ovarian
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palpation has not been established as a useful screening procedure. Most screening studies have used either serum tumor
marker levels or ultrasonography or both. Although serum CA 125 levels correlate with progression or regression of
established disease and are also useful in the preoperative evaluation of a pelvic mass, the test does not have sufficient
specificity to be used as a routine screen for ovarian cancer.12 Besides ovarian cancer, many other conditions can be
associated with an elevated CA 125 level, including cirrhosis, peritonitis, pancreatitis, endometriosis, uterine
leiomyomata, benign ovarian cysts, and pelvic inflammatory disease. Thus, although CA 125 is a useful marker to monitor
an ovarian cancer patient's disease status, it is not an effective biomarker for early detection.
Recent advances in molecular technologies have allowed application of high-throughput techniques to ovarian cancer
biomarker discovery. A number of candidate markers have been discovered that show promise for enhancing the accuracy
of CA 125 levels, such as HE4 (human epididymis 4), osteopontin, mesothelin, and osteoblast-stimulating factor-2.
Algorithms that define the behavior of these markers have also been developed, incorporating biologic characteristics of
the tumor growth and marker behavior.12
In addition, other novel tumor biomarkers for ovarian cancer have been discovered, and a few hold promise for use in
early detection. Lysophosphatidic acid, which had previously been shown to be elevated in malignant ascites, may also be
useful as a predictive biomarker for ovarian cancer, because an elevated level was found in nine of ten patients with
early-stage disease.19 Additional studies of sensitivity and specificity are in progress. Proteomic spectral analysis of sera
from ovarian cancer patients and controls using surface-enhanced laser desorption and ionization time-of-flight mass
spectroscopy has been reported to distinguish between benign and malignant cases, including stage I disease, with 100%
sensitivity.13 Further confirmatory studies are under way at a number of centers.
The two best screening tests currently available are measurement of CA 125 tumor marker levels and TVS.14 Early studies
of TVS suggested a sensitivity of 100% but a specificity of 98%, which is insufficient to achieve a PPV of 10%. More recent
reports suggest that use of color Doppler imaging improves the specificity of TVS, but it is unlikely that a specificity of
99.6% can be achieved. Investigators at the University of Kentucky improved the specificity of TVS by using a morphologic
index. They screened 6470 women, including high-risk premenopausal women and average-risk postmenopausal women.15
Of 90 women who underwent surgery, 6 were found to have an ovarian malignancy, which yields a PPV of 6.7%. One
interval cancer was found at prophylactic oophorectomy 11 months after screening, for a sensitivity of 86%. All but one of
these cancers were stage I, and no deaths due to ovarian cancer were noted in this group.
CA 125 level has been used for many years for evaluation of response to therapy and for surveillance for ovarian cancer
recurrence. In 1985, Bast published the first report of a case in which CA 125 level was elevated before diagnosis of
ovarian carcinoma.15a Since then, CA 125 level has been shown to have high sensitivity as an indicator of ovarian cancer.
For all epithelial ovarian cancers, most of which are diagnosed at a late stage, the sensitivity of CA 125 is approximately
80%. More than 85% of women with advanced ovarian cancer have elevated CA 125 levels; however, only 50% of those with
disease confined to the ovary have elevated levels.11,12 Specificity is poor, however, when CA 125 level is used in this
way. Nearly 6% of women without cancer have elevated levels of CA 125. Thus, the performance of CA 125 as a tumor
marker does not justify its use as a stand-alone screening test, because neither its specificity nor its sensitivity for early-
stage disease are acceptable.16
Because in 20% to 50% of cases CA 125 fails to rise in early-stage disease, complementary markers have been evaluated.
Levels of OVX-1 and macrophage colony-stimulating factor have been found to be elevated in patients with clinically
evident ovarian cancer but normal CA 125 levels, which suggests that these markers may be complementary to CA 125.17
Lysophosphatidic acid level has also been reported to discriminate ovarian cancer cases, including cases with early-stage
disease, from controls.18 None of these tests has been proven to have sufficient sensitivity and specificity for routine use
at the current time. Molecular discoveries by the Early Detection Research Network are likely to yield many potentially
useful markers. Eventually a panel of markers will likely emerge that used together, perhaps with imaging, will yield an
effective screening test for the early detection of ovarian cancer.
Two randomized controlled trials are currently under way to evaluate a multimodal screening approach using both CA 125
and TVS. In the United States, the Prostate, Lung, Colorectal, Ovarian Cancer screening trial uses measurement of CA 125
level (single threshold elevation of more than 35 U/mL) and TVS together, performed annually, as a first-line screen.19 If
either test is positive, the woman is referred for surgical consultation. In this two-arm randomized controlled trial, 74,000
women aged 55 to 74 years have been randomly assigned to the screening arm or to a standard-care control arm. Ten
centers are collaborating in this 14-year trial, which will require 10 years’ average follow-up.
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In a second trial, in the United Kingdom, the primary focus is on ensuring high specificity. A multimodal approach was
explored by Jacobs in a prevalence trial followed by a pilot randomized controlled trial using CA 125 level to select
women for TVS. Jacobs et al. randomly assigned 21,935 average-risk postmenopausal women to undergo three annual
screenings or no screening. The screening protocol used CA 125 level as a first-line screen and referred the woman for TVS
if CA 125 level was above 30 U/mL. If the TVS revealed an ovarian mass, then the woman was referred for surgical
consultation. Findings from this pilot trial were reported in 1999.20 The trial was too small to show efficacy in terms of
mortality reduction, but its results are important because they confirm the findings of the prevalence trial that an
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acceptable PPV is achieved by selecting women for imaging based on elevated CA 125 level. When the decision rule for
surgical referral requires that results of both tests be positive, the PPV is 20%. Furthermore, there were one-half as many
deaths in the screened group as there were among controls, and there was a statistically significant improvement in
survival. Individuals with index cancers survived an average of 72.9 months in the screening group and 41.8 months in the
control group.
This multimodal screening strategy is limited by the sensitivity of the first-line screen, CA 125 level. Accordingly, these
investigators are exploring ways to improve on these results by detecting change over time in the CA 125 values. Skates et
al.21 suggested fitting an exponential model that uses data from several prior CA 125 screens; a result demonstrating an
exponential rise would trigger a call-back for additional testing. Investigators in the United Kingdom are currently testing
this screening strategy in a three-arm randomized controlled trial involving healthy women. The results of both the U.S.
and U.K. trials will not be available for several more years.
HEREDITARY OVARIAN CARCINOMA

Genetic factors (inherited and somatic) as well as hormonal and environmental exposures all contribute to the
development of ovarian cancer. Only 5% to 10% of patients with epithelial ovarian carcinoma likely have inherited a
genetic predisposition to the disease; however, many studies have focused on these individuals in the hopes of gleaning
additional insights into ovarian cancer biology, molecular oncogenesis, early detection, and treatment.
Hereditary ovarian cancer syndromes are linked to genetic mutations inherited in an autosomal dominant manner, and
thus both maternal and paternal family histories must be obtained to determine risk. The breast-ovarian cancer syndrome
accounts for approximately 90% of all hereditary ovarian cancer cases and is most frequently associated with mutations in
the BRCA1 or BRCA2 genes.22 The BRCA1 gene, located on chromosome band 17q12-21, and the BRCA2 gene, located on
chromosome band 13q12-13, were identified and linked to hereditary breast and ovarian cancers in the 1990s. Emerging
evidence suggests that these genes act as tumor suppressor genes and regulate cellular proliferation and DNA repair by
maintaining chromosome integrity.
The presence of a BRCA-associated cancer syndrome is suspected whenever the pedigree reveals three or more affected
relatives with cancer, bilateral or early-onset breast cancer, a proband with both breast and ovarian cancer, or a male
relative with breast cancer. Many mutations have been described, located throughout the BRCA1 and BRCA2 genes, with
nonsense and frameshift mutations being predominant.22 Nonsense mutations occur when a nucleotide substitution results
in a stop codon, and frameshift mutations occur when one or more nucleotides are deleted to produce a downstream stop
codon. Certain ethnic groups have higher frequencies of founder BRCA mutations. Three specific founder mutations,
185delAG BRCA1, 5382insC BRCA1, and 6174delT BRCA2, have been identified in the Ashkenazi Jewish population and are
carried by 2.0% to 2.4% of this population.23 Furthermore, 40% to 60% of epithelial ovarian cancer patients of Jewish
descent carry one of these mutations (irrespective of their family histories). This is compared to a carrier frequency of
approximately 5% among non-Jewish women with ovarian cancer.
The lifetime risk of ovarian cancer for patients with BRCA1 mutations is 20% to 60%, and the risk for BRCA2 mutation
carriers is 10% to 35%. Ovarian cancer associated with germline mutations of BRCA1 appears to present with distinct
clinical and pathologic features compared with sporadic ovarian cancer.24,25 The vast majority of BRCA1-associated
cancers are serous adenocarcinomas, with an average age at diagnosis of 48 years, whereas the mean age for BRCA2-
associated ovarian cancers is 61 years. Furthermore, BRCA-associated cancers may have a more favorable course than
sporadic ovarian cancer. In a study by Rubin et al.24 a median survival of 77 months was reported for 43 patients with
advanced BRCA1-associated disease compared with 29 months for matched controls. Cass et al.26 noted a similar survival
advantage for carriers in their matched cohort and went further to suggest that the improved survival in those with BRCA-
associated ovarian cancers was a result of improved response to platinum-based chemotherapy compared to women who
had sporadic disease. A large prospective study conducted by the Gynecologic Oncology Group (GOG) is currently in
progress to compare the clinical course of sporadic ovarian cancer with that associated with BRCA1 and BRCA2
mutations.25,27
The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome accounts for approximately 5% of all hereditary ovarian
cancer cases. It is an autosomal dominant genetic syndrome in which three or more first-degree relatives have colon
cancer (over 70% of cases in the proximal colon) or endometrial cancer, of whom one is a first-degree relative of the other
two, and two of whom must be diagnosed with cancer before age 50 years. Four genes that are part of the DNA mismatch
repair pathway have now been identified as being responsible for the HNPCC phenotype: hMSH2 (chromosome arm 2p),
hMLH1 (chromosome arm 3p), hPMS1 (chromosome arm 2q), and hPMS2 (chromosome arm 7p).22 The majority of affected
patients are found to have defects in either hMSH2 or hMLH1. An inherited defect in any one of these genes increases an
individual's risk of developing cancer because of an impaired ability to repair somatic genetic mutations. HNPCC syndrome
family members are at risk for cancers at other gastrointestinal sites as well as for tumors in the genitourinary tract and
the ovary.28 The risk of endometrial cancer among women in HNPCC syndrome families is estimated to be 40% to 60% by
age 70, compared to 1.5% in the general population. Limited studies have reported a 3.5-fold increase in the risk of
ovarian cancer in members of these families.
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Although hereditary cancers account for only 10% of malignancies, individual risk assessment and appropriate genetic
testing can identify those individuals with significant lifetime
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risk. Genetic counseling is imperative, and the proper selection of patients for testing is very important. As genetic testing
becomes more readily available to all individuals, clinicians and patients must work together to ensure that the results are
used in a fashion that carefully considers the medical implications as well as any ethical, legal, and psychosocial issues
that may arise. Multidisciplinary services that include pretest and posttest counseling, screening, treatment, and
psychosocial counseling have been established to address each of these aspects of comprehensive care.
The American Society of Clinical Oncology updated its guidelines for genetic testing in 2003.29 All individuals with a
personal or family history suggestive of an inherited cancer susceptibility in whom the test can be adequately interpreted
and for whom the results will influence medical management should be offered testing. First- and second-degree relatives
of an affected individual from a breast–ovarian cancer syndrome family carrying a mutation of the BRCA1 or BRCA2 gene
should be offered genetic testing. Certain ethnic groups, such as Ashkenazi Jews, are at increased risk for carrying a BRCA
mutation, and a lower threshold for genetic testing may be appropriate in some of these individuals. Genetic testing for
the mismatch repair genes should be considered when there is a first-degree relative with a known mutation and when the
patient meets the Amsterdam or the Bethesda criteria for HNPCC syndrome.
A comprehensive family history can provide an estimate of an individual's risk of carrying a genetic mutation; however,
genetic testing provides more accurate information regarding the cancer risks for an individual patient. The best way to
determine if a cancer-associated mutation is present in a family is to test an affected family member, because he or she is
the most likely to carry a deleterious mutation. The first family member to be tested will often need comprehensive gene
sequencing. Other individuals can then be tested for the identified mutation, which may be unique to this particular
family. In the Ashkenazi Jewish population, genetic testing for the three founder mutations is required because the carrier
frequency in this population is high and individuals with both BRCA1 and BRCA2 mutations occasionally have been
reported.
Test results may come back positive or negative for an identifiable mutation, or a mutation of indeterminate clinical
significance may be reported. When a test result is negative, interpretation will depend on the patient's family history. If
an affected family member has tested positive for a mutation, then the patient with the negative result has likely not
inherited the deleterious mutation, and her cancer risk approximates that of the general population. If there is no
documented positive mutation in the family, it is still possible that the patient has a cancer-associated mutation that is
not detectable with current testing. Approximately 12% of current test results are genetic variants or polymorphisms,
reported as of indeterminate clinical significance. Further study of these genetic variants and associated cancer risks in
large populations will help reduce the number of reports of “indeterminate” findings.25
Follow-up and management of patients with an inherited genetic predisposition to ovarian cancer are complex due to the
variable penetrance of genetic alterations and the lack of effective early detection methods. Current consensus
recommendations include at least annual rectovaginal pelvic examinations, serum CA 125 determinations, and TVS14;
however, there is no conclusive evidence that mortality is reduced as a result of these interventions.30 One prospective
study of screening in high-risk women demonstrated a down-staging of the ovarian cancer cases detected; however,
conclusions are limited by small patient numbers.31Table 32.4-2 lists the provisional recommendations for cancer
surveillance for carriers of BRCA1, BRCA2, and HNPCC mutations. Screening and prophylactic surgery for patients with
HNPCC-associated mutations are also based on expert opinion, although colonoscopy and stool occult blood testing have
been shown in randomized clinical trials to reduce the incidence of and mortality from colon cancer.
TABLE 32.4-2. Recommendations for Management of Women at High Genetic Risk for Gynecologic
Malignancies
HNPCC HNPCC
Syndrome/Endometrial Syndrome/Colon
Method Breast Cancer Ovarian Cancer Cancer Cancer
Screening Monthly self- Semiannual/annual Pelvic examination, Colonoscopy

examination rectovaginal TVS every 1–3 y
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pelvic and/or endometrial (beginning age

examination/ biopsy every 1–2 y 20–25 y)
annual (beginning age 30–35
rectovaginal y)
pelvic
examination
Semiannual/annual
clinical
examination
Annual/semiannual
CA 125 level and
TVS screening
(beginning age
25–35 y)
Annual
mammography
(beginning age
25–35 y)
Chemoprevention Consider Consider OCP Consider OCP —

tamoxifen
Prophylactic Counsel regarding Offer PBSO Counsel regarding Counsel

surgery mastectomy ± prophylactic regarding
PBSO hysterectomy/PBSO prophylactic
colectomy
CA 125, cancer antigen 125; HPNCC, hereditary nonpolyposis colorectal cancer; OCP, oral contraceptive pills; PBSO,
prophylactic bilateral salpingo-oophorectomy; TVS, transvaginal ultrasonography.
Evidence suggests that chemoprophylaxis with oral contraceptive pills for 5 years decreases ovarian cancer risk by 50% in
both the general population and in high-risk women.32 A case-controlled study of 207 known BRCA mutation carriers and
their sister controls found a 60% reduction of ovarian cancer risk with oral contraceptive use. Other risk-reducing
strategies such as tubal ligation and hysterectomy have also been demonstrated to reduce the incidence of ovarian cancer
among many high-risk women. Surgery with prophylactic bilateral salpingo-oophorectomy (PBSO) is the most effective
preventative strategy for patients with BRCA mutations to reduce cancer risk.
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Given that the majority of hereditary ovarian cancers occur after the age of 35 to 40 years, PBSO is an option in carefully
selected patients at unequivocally high genetic risk for ovarian cancer who have completed their childbearing or are at
least 35 years of age.33,34 A laparoscopic approach is frequently possible, but the surgical options must be individualized,
as must the decision for concomitant hysterectomy. In any case, the surgical pathologist must be alerted to perform a
careful examination of the patient's ovaries and fallopian tubes given the frequent reports of occult ovarian and tubal
carcinoma occurring in 2% to 10% of PBSO specimens.35,36
The efficacy of PBSO in reducing risk in hereditary breast-ovarian cancer syndrome has been evaluated in several studies.
Prospective studies have documented a significant reduction with PBSO in both ovarian-peritoneal and breast carcinoma
among BRCA mutation carriers. One study of 248 PBSO patients found a 98% decrease in ovarian and primary peritoneal
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cancers and a 50% reduction in subsequent breast cancer compared to age-matched controls.34 Furthermore, studies have
demonstrated that the risk of primary peritoneal carcinomas after PBSO is likely under 5%, and patients should be
counseled regarding this potential risk. It is believed that that all coelomic epithelium, including the peritoneal covering
of the entire abdominal-pelvic cavity, is prone to malignant transformation in BRCA mutation carriers. Several other
significant issues remain unresolved regarding the physiologic adjustments to premature surgical menopause and the
safety of hormone replacement therapy in this group, especially in those at high risk for breast cancer.
STAGING
Ovarian cancer is a surgically staged disease. Thus, it is important for physicians to be thoroughly familiar with the
International Federation of Gynecology and Obstetrics (FIGO) staging system for primary carcinomas of the ovary3 (Table
32.4-3). As described earlier in Pathogenesis, ovarian cancer most frequently spreads by direct extension to neighboring
organs and by exfoliation of cells into the peritoneal cavity. It also disseminates by lymphatic spread, particularly to the
pelvic sidewall lymph nodes (external iliac and obturator chains) and along the gonadal vessels to the upper common iliac
and paraaortic lymph node chains (Fig. 32.4-1). Surgical staging procedures must evaluate sites to which ovarian cancer is
likely to spread.
TABLE 32.4-3. International Federation of Gynecologists and Obstetricians Stage Grouping for
Primary Carcinoma of the Ovary (1998)
Stage Description
I Growth limited to the ovaries.
IA Growth limited to one ovary; no ascites. No tumor on the

external surface; capsule intact.
IB Growth limited to both ovaries; no ascites. No tumor on the

external surface; capsule intact.
ICa Tumor either stage IA or IB but with tumor on the surface of

one or both ovaries, or with capsule ruptured, or with
ascites present containing malignant cells, or with positive
peritoneal washings.
II Growth involving one or both ovaries with pelvic extension.
IIA Extension and/or metastases to the uterus and/or tubes.
IIB Growth involving one or both ovaries with pelvic extension.
IICa Tumor either stage IIA or IIB but with tumor on the surface
of one or both ovaries, or with capsule(s) ruptured, or with
ascites present containing malignant cells, or with positive
peritoneal washings.
III Tumor involving one or both ovaries with peritoneal implants
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outside the pelvis and/or positive retroperitoneal or

inguinal nodes. Superficial liver metastases equals stage III.
Tumor is limited to the true pelvis but with histologically verified
malignant extension to small bowel or omentum.
IIIA Tumor grossly limited to the true pelvis with negative nodes
but with histologically confirmed microscopic seeding of
abdominal peritoneal surfaces.
IIIB Tumor of one or both ovaries with histologically confirmed

implants of abdominal peritoneal surfaces, none exceeding
2 cm in diameter. Nodes negative.
IIIC Abdominal implants greater than 2 cm in diameter and/or

positive retroperitoneal or inguinal nodes.
IV Growth involving one or both ovaries with distant metastasis.

If pleural effusion is present, cytologic test results must be
positive to allot a case to stage IV. Parenchymal liver
metastasis equals stage IV.
aTo evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it is of
value to know if rupture of the capsule was spontaneous or caused by the surgeon, and if the source of
malignant cells detected was peritoneal washings or ascites.
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FIGURE 32.4-1. Ovarian cancer spread pattern. (From Young RC, Perez CA, Hoskins WV. Cancer of the ovary. In:
DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 4th ed. Philadelphia: JB
Lippincott Co, 1993:1226, with permission.)
Complete surgical staging is a necessity to properly evaluate the patient and to determine whether additional therapy
should be recommended. Proper surgical staging requires thorough and complete inspection of the peritoneal cavity and
its contents, as well as evaluation of the retroperitoneal spaces and lymph nodes. When the peritoneal cavity is entered,
any fluid present should be aspirated and sent for cytologic studies. Peritoneal fluid, even if limited to the pelvis, is more
likely to yield malignant cells than are cytologic washings. If no fluid is present, however, one should routinely irrigate the
pelvis and paracolic spaces and send the fluid for cytologic examination. Adhesions should be lysed to restore normal
anatomy, and samples of the adhesions should be sent for pathologic examination.
If intraperitoneal carcinomatosis is not present, it may be most appropriate first to resect the ovarian tumor and then to
proceed with surgical staging to help avoid rupturing of the mass. For women who desire future fertility, when the tumor
is limited to one ovary, staging may be completed without hysterectomy and complete castration. The grossly normal
opposite ovary may undergo biopsy or any visible benign-appearing cysts may be excised. Preservation of fertility should
be considered in any woman of reproductive age with either a borderline malignant tumor of the ovary or an invasive
epithelial cancer grossly confined to one ovary. A frozen-section assessment of any abnormality involving the contralateral
ovary may be helpful in guiding the extent of surgery. Pelvic and paraaortic retroperitoneal lymph nodes are removed in
all patients whose tumors do not grossly extend outside of the pelvis. Any enlarged pelvic retroperitoneal lymph nodes are
removed, regardless of their location, to achieve optimal cytoreduction. Lymphadenectomy is an important part of the
staging of ovarian cancers, particularly when the disease is grossly limited to one ovary. In this situation, up to 20% of
women have been found to have paraaortic lymph node metastases.37
To fully assess and resect disease in the upper abdomen, it is frequently necessary to extend the vertical incision above
the umbilicus. If gross disease is not present in the omentum, an infracolic omentectomy is sufficient for diagnostic
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purposes.
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When the omentum is caked with tumor, the omentum should be excised from the greater curvature of the stomach as
completely as possible (Fig. 32.4-2). The upper abdominal evaluation continues with a careful inspection of the right
hemidiaphragm and liver serosa and parenchyma. The spleen is then carefully inspected, as is the left diaphragm. If
splenectomy is required to achieve optimal surgical cytoreduction, then this should be considered.38 Preoperative imaging
can often help predict splenic involvement so that pneumococcal vaccine (Pneumovax) can be given preoperatively. If this
has not been done and splenectomy is performed, then Pneumovax should be administered postoperatively to protect
against future infections with encapsulated bacteria.
FIGURE 32.4-2. Excising omentum off stomach. (From Young RC, Perez CA, Hoskins WV. Cancer of the ovary. In:
DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 4th ed. Philadelphia: JB
Lippincott Co, 1993:1226, with permission.)
The paracolic spaces and large bowel are then carefully inspected. The small intestine and its mesentery are evaluated,
and any implants present are removed. If luminal narrowing, especially in the area of the terminal ileum, or any other
potentially obstructing lesion is present, a small bowel resection and reanastomosis should be performed. Similarly, if
tumor appears to invade the large bowel transluminally, a resection may be required, although often, with the larger
diameter of the colon and the typical growth pattern of ovarian cancer, this can be avoided. In the face of advanced-stage
disease, lymphadenectomy is performed only if the visible disease is less than 2 cm (stage IIIB or lower) or if grossly
enlarged nodes are discovered on inspection of the retroperitoneum.39 In postmenopausal women or in women in whom
fertility is no longer desired, one should routinely perform a bilateral salpingo-oophorectomy and total abdominal
hysterectomy at the time of staging. The hysterectomy is performed because the serosal surface of the uterus is a large
peritoneal surface for implantation of malignant cells. In addition, field effects may occur whereby the epithelium of the
fallopian tubes or uterus is involved with premalignant or malignant processes as well. These latter changes may not be
grossly recognized at the time of surgery.
Under-staging occurs approximately 30% of the time, especially when the preoperative diagnosis is that of a benign
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process. In many cases, this leads to use of abdominal incisions that do not allow complete surgical staging even when the
diagnosis of a malignancy is recognized intraoperatively. At other times, under-staging or incomplete staging is due to a
lack of familiarity with accepted surgical staging procedures.40
The issue of inadequately staged early ovarian cancer is often a difficult one. The simplest solution for such patients is to
recommend complete surgical staging via laparotomy or laparoscopy performed by a gynecologic oncologist. However, if
this is not possible or practical, an alternative is to obtain a CT scan to try to identify the presence of any subclinical
bulky disease. If the CT scan and CA 125 level are normal, and the tumor was of LMP and limited to one ovary, no further
therapy is recommended. If there was bilateral involvement and one ovary was left in situ, the patient should be
counseled regarding her risk for recurrence, and if fertility is no longer desired, the contralateral ovary should be
removed. If the ovarian tumor is a high-grade invasive epithelial malignancy, chemotherapy is required, but the exact
stage of the tumor is important in determining the number of cycles of chemotherapy that are recommended.
In the event that any gross disease is detectable on the CT scan, a surgical procedure to remove gross disease should be
performed. Postoperative reevaluation and staging by laparotomy or laparoscopy may be performed.41 Earlier papers on
laparoscopic surgical staging revealed that as many as 30% to 40% of patients originally thought to have FIGO stage I or II
disease actually had disease in the upper abdomen. The choice of surgical approach will be in large part dependent on the
extent of
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disease seen on imaging, individual patient characteristics, and the skills and experience of the surgeon. Developments in
laparoscopic techniques allow paraaortic lymph node dissections and omentectomies to be performed by this method.42
PROGNOSTIC FACTORS
At the conclusion of a comprehensive laparotomy, the clinical and pathologic findings are used to select appropriate
postoperative therapy. In addition, new prognostic factors are being evaluated that may be used to identify groups of
patients for whom more specific biologic treatments or more aggressive therapy is indicated.
Clinicopathologic findings determined to be clinically useful include the following:
FIGO stage
Histologic subtype
Histologic grade
Factors associated with tumor dissemination
Malignant ascites or malignant peritoneal washings
Tumor excrescences on ovarian surface or ruptured capsule
Volume of residual disease after cytoreductive surgery
The tumor stage remains the most important prognostic variable. Few trials provide an accurate assessment regarding the
long-term survival of patients with early-stage ovarian cancer because earlier studies often included patients with
inadequately staged disease. Patients with stage I disease with well or moderately well-differentiated tumors have a
greater than 90% 5-year survival rate.43 Patients with stage I disease with poor prognostic features are often included in
treatment protocols for patients with stage II disease. This group of tumors has been termed early-stage disease with
unfavorable characteristics. However, limited information is available regarding the actual survival impact of some of the
factors used to characterize disease as having an unfavorable prognosis. Rupture of the capsule increases the stage to IC.
In a Swedish series, however, no adverse effect on survival could be established for patients with early-stage disease in
whom the capsule was ruptured during surgery.44 Furthermore, the adverse effect of malignant ascites is well
established; however, there is limited information regarding the prognostic significance of positive results of peritoneal
cytologic examination. Dense tumor adherence to surrounding structures and the pelvic sidewall should now also be
considered an adverse prognostic factor for patients with early-stage tumors because such patients have at least stage II
disease.45 Tumor size, bilaterality, and cytologically negative ascites have no prognostic significance. The most reliable
long-term survival data on accurately staged early-stage ovarian cancer is derived from studies of the GOG. In these
studies, patients with unfavorable-prognosis early-stage ovarian cancer have a 5-year survival rate of approximately
80%.43
Patients with stage III disease have a 5-year survival rate of approximately 35% that is dependent in large part on the
volume of disease present in the upper abdomen. Patients with stage IV disease have less than a 10% 5-year survival rate.
Volume of residual disease after cytoreductive surgery for patients with advanced ovarian cancer has a significant impact
on survival. After the administration of postoperative platinum-based combination chemotherapy, 4-year survival rates for
patients with optimal stage III disease (defined as only microscopic residual disease) is approximately 60%.10,46
The true prognostic impact of histologic subtype and grade in patients with epithelial ovarian cancer remains to be
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determined. In patients with early-stage ovarian cancer, grade is an accepted determinant of risk and is used to assign
postoperative therapy. Studies have also identified an adverse prognostic effect of clear cell histologic type in early-stage
ovarian cancer.43,47 In patients with advanced-stage disease, mucinous and clear cell histologic types also have been
shown to have an adverse prognostic significance. In a GOG analysis, no negative results were obtained in second-look
laparotomies in patients with mucinous or clear cell tumors. Some studies also have demonstrated that histologic grade
has an impact on survival in patients with advanced-stage disease.
Serum CA 125 levels frequently reflect the volume of disease and, for this reason, in multivariate analysis preoperative
levels have not exerted an independent prognostic effect on survival.48 However, postoperative CA 125 levels were shown
to be an independent prognostic variable. Most studies also have demonstrated that serum CA 125 levels after three cycles
of chemotherapy are accurate predictors of the probability that a patient will achieve a complete remission. However, the
CA 125 level after three cycles of chemotherapy cannot be used as a guide for treatment decisions because of the lack of
predictive power.
The prognostic significance of age on survival of patients with ovarian cancer has been recognized.49 Median survival is at
least 2 years longer in women younger than age 65 years than in those older than age 65 years.
The prognostic significance of DNA ploidy and S-phase fraction has been examined in ovarian cancer. Investigators in
Europe have now included aneuploidy in their criteria for selection of patients with high-risk early-stage ovarian cancer
for adjuvant therapy.50 Controversy remains, however, as to the nature of the relationship between histologic grade and
degree of aneuploidy.
A series of new molecular factors have been proposed to have prognostic significance in ovarian cancer (Table 32.4-4).
26,51,52,53 These factors include markers of proliferation, drug resistance markers, serum cytokine levels, levels of
growth factor receptors or substances involved in signal transduction pathways, expression of genes associated with
metastases, and oncogene expression. Most of these factors have been identified in retrospective studies without
multivariate analysis or confirmation in larger studies. Many of these factors were discovered during experimental studies
of ovarian cancer biology, and none of these markers is routinely used to select therapy for patients with ovarian cancer
at the current time. Ongoing investigations are using microarray analysis to identify gene profiles that may be useful for
predicting prognosis and response to therapy.54,55
TABLE 32.4-4. Experimental Prognostic Factors in Ovarian Cancer
MORPHOMETRY
DNA PLOIDY AND S-PHASE FRACTION
DRUG RESISTANCE MARKERS
P-glycoprotein immunoreactivity
Glutathione S-transferase pi
c-erbB-2
BRCA1 and BRCA2
Multidrug resistance proteins (Lrp)
Nucleotide excision DNA repair genes ERCC1 and XPAC
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BAX
ONCOGENE
Mutant p53 expression
AKT-2
MARKERS OF PROLIFERATION
Ki-67
Proliferating cell nuclear antigen
MARKERS OF TUMOR SPREAD
Metastasis-related genes (nm23-H1)
Cathepsin D
Urokinase-type plasminogen activators
Colony-stimulating factor 1
CD44 molecules
CYTOKINE LEVELS AND OTHER ACTIVE PROTEINS
Heat-shock protein
Interleukin-6
Platelet-derived growth factor
MANAGEMENT OF EARLY-STAGE DISEASE

A subset of patients with early-stage ovarian cancer has been shown not to require any additional postoperative therapy
after tumor resection and comprehensive staging. Patients with stage IA or IB disease with well or moderately well-
differentiated tumors have a 5-year survival rate of more than 90% without any adjuvant treatment.43 Patients with
favorable-prognosis early-stage ovarian cancer (stage IA and IB with grade 1 and 2 tumors)
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were randomly assigned in an earlier GOG study to receive no treatment or oral intermittent melphalan (0.2 mg/kg daily
for 5 days) with repeat cycles every 4 to 6 weeks for a total of 12 courses or 18 months of therapy. At a median follow-up
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of more than 6 years, only six deaths have been reported in 81 patients: four in the observation group and two in the
group receiving melphalan. Disease-free survival and overall survival is shown in Figure 32.4-3. Patients with favorable-
prognosis early-stage ovarian cancer can be spared the acute and chronic toxicities of chemotherapy, including
myeloproliferative disorders such as leukemia.
FIGURE 32.4-3. Disease-free (A) and overall (B) survival of patients with early-stage ovarian cancer. The top two
curves represent patients with favorable prognoses randomly assigned to receive observation or melphalan. The
lower two curves represent patients with unfavorable prognoses randomly assigned to receive either phosphorus 32
(32P) or melphalan. (From 43, with permission.)
The optimum treatment of early-stage ovarian cancer patients with unfavorable prognosis remains an area of controversy.
Opinions differ as to not only what modality of treatment should be used (chemotherapy, external-beam radiotherapy, or
intraperitoneal radioisotope therapy) but also whether treatment should be immediate or should be delayed until disease
progression. Furthermore, as noted in Prognostic Factors, consensus has not been established as to the prognostic
significance of some clinicopathologic features, such as positive peritoneal cytologic examination and a surgically ruptured
capsule with contamination of the pelvis with cyst fluid. Clinicopathologic factors currently used by the GOG to define
unfavorable-prognosis early-stage disease include FIGO stage II and IC, clear cell histology, and grade 3 tumors.
The results of two randomized European trials [International Collaborative Ovarian Neoplasm Trial 1 (ICON1) and Adjuvant
ChemoTherapy in Ovarian Neoplasm Trial (ACTION)] have, for the first time, provided data demonstrating that initiation of
adjuvant chemotherapy in patients with high-risk early-stage ovarian cancer can exert a favorable impact on both
progression-free and overall survival.56,57,58 The two studies, with a total population of 925 patients, differed somewhat
in eligibility criteria, requirements for surgical staging, and the specific adjuvant chemotherapy program used. However,
the trials asked the same question: Does the administration of platinum-based chemotherapy after surgery for high-risk
early-stage ovarian cancer improve survival, compared to observation until objective evidence of disease progression?
The combined analysis of the trials revealed a statistically significant improvement in progression-free survival and overall
survival associated with initiation of platinum-based treatment immediately after surgery. Although these data provide
strong support for the conclusion that patients with high-risk early-stage ovarian cancer should be offered adjuvant
chemotherapy,
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some have suggested that chemotherapy may not be required in patients who have undergone optimal surgical staging.
However, this conclusion is based on a retrospective analysis of a subset of patients entered into these early-stage trials,
and caution is advised in drawing definitive conclusions based on any such evaluation.
The GOG trial compared three versus six cycles of carboplatin plus paclitaxel adjuvant chemotherapy in high-risk early-
stage ovarian cancer in an effort to determine if the shorter treatment program may provide equivalent efficacy.
Unfortunately, the preliminary results of this study suggest that a definitive answer to this question will not be
provided.59 Although there was a 33% reduction in the risk of recurrence associated with the administration of six cycles
compared to three cycles, this difference did not reach the study requirement for a 50% reduction in recurrence to reach
statistical significance. However, many oncologists will reasonably conclude that this level of reduction in the risk of
disease recurrence with three additional cycles of carboplatin and paclitaxel justify the added time, effort, and toxicity
associated with the longer treatment regimen.
The current GOG trial for patients with early-stage ovarian cancer with unfavorable prognosis compares three cycles
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against six cycles of a treatment with paclitaxel and carboplatin. The details of this combination are discussed later.
It is apparent that the optimum postoperative treatment for patients with early-stage ovarian cancer with unfavorable
prognostic features remains to be established. Pending the results of the ongoing clinical trials, treatment options include
chemotherapy with cisplatin or carboplatin, total abdominal and pelvic irradiation, and paclitaxel-based chemotherapy. In
addition, a no-treatment option can be considered, although this choice has been shown to be associated with a decrease
in survival in one large trial.56,57,58 Second-look operations after completion of adjuvant therapy are not routinely
recommended, especially for patients with early-stage disease.
External-Beam Radiotherapy
Although cisplatin- or paclitaxel-containing chemotherapy has become the standard initial treatment for patients with
unfavorable-prognosis early-stage ovarian cancer in all but a few centers, a number of studies have demonstrated that
carefully applied whole abdominal radiotherapy is also a highly effective treatment for some patients.
Early nonrandomized studies suggested that pelvic disease control and survival were improved when patients with early-
stage ovarian carcinoma were treated with postoperative pelvic irradiation. In particular, patients with stage II disease
had consistently better survival rates if the pelvis was treated.60 However, these studies also demonstrated the
importance of the coelomic pattern of metastatic spread, which limited the benefit of pelvic irradiation.
On the basis of these findings and reports of encouraging responses of ovarian carcinoma to alkylating agents, two groups
of investigators at the M. D. Anderson Cancer Center and Princess Margaret Hospital60a,61 conducted prospective trials
that compared pelvic and whole abdominal irradiation with pelvic irradiation and single-agent chemotherapy. The M. D.
Anderson study included patients who had stage I to III ovarian carcinomas with less than 2 cm of residual disease after
surgery. Treatment was delivered with cobalt 60 using a moving strip technique, because contemporary treatment
machines could not treat the entire abdomen in a single field. The authors reported that survival rates were similar for
patients treated in the two arms, but the rate of serious bowel complications was higher for patients who received whole
abdominal irradiation. It was concluded that chemotherapy was a superior treatment, and subsequent clinical trials at the
M. D. Anderson Cancer Center and throughout the United States focused on the search for more effective chemotherapy.
Four years later, Dembo and associates61 published the results of a similar prospective randomized study conducted at
the Princess Margaret Hospital in Toronto. Patients with stage IB or II ovarian cancer were randomly assigned to one of
three treatment arms: pelvic irradiation, pelvic plus whole abdominal irradiation, or pelvic irradiation plus single-agent
chemotherapy. Patients with “asymptomatic” stage III disease were randomly assigned only between the last two arms.
Although the treatment arms were similar to those of the M. D. Anderson trial, the details of the treatments differed
significantly from that study. Patients on the chemotherapy arm received chlorambucil, an alkylating agent that has since
been demonstrated to yield poorer response rates than melphalan. The total dose of abdominal strip irradiation (22.5 Gy)
and the daily fraction size (2.25 Gy) were less than those used in the M. D. Anderson trial, but the liver was not shielded
and particular care was taken to include the domes of the diaphragm in the treatment fields.62
Of 190 patients entered on the study, 132 had a hysterectomy and bilateral salpingo-oophorectomy performed at their
initial laparotomy. Of these 132 (who were considered to have minimal residual disease), the 50 who received whole
abdominal irradiation had significantly better rates of survival and abdominal disease control than did patients who
received pelvic irradiation with chlorambucil (Table 32.4-5). Although the study has been criticized for using inconsistent
surgical staging methods, it undoubtedly demonstrates the efficacy of abdominopelvic irradiation for at least some subsets
of patients with minimal residual disease. Subsequent analysis of patients treated at Princess Margaret
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Hospital demonstrated that patients who had grade 1; stage I or II, grade 2; or stage I or II, grade 3 disease and no gross
residual tumor after surgery were most likely to have a prolonged disease-free interval after abdominopelvic irradiation
(Table 32.4-6). 61,63
TABLE 32.4-5. Survival Rates and Relapse Sites for 116 Patients with Stage IB, Stage II, and
Asymptomatic Stage III Ovarian Cancer Who Had a Total Hysterectomy and Bilateral Salpingo-
Oophorectomy at Initial Operation
No. with Recurrence
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Treatment No. of Patients Pelvis Abdomena 4-Y Survival Rateb(%)
Pelvic RTc 31 8 (27%) 8 (27%) 50
Pelvic RT plus chlorambucil 51 10 (20%) 13 (25%) 55
Pelvic plus whole abdominal RT 50 11 (22%) 0 (0) 81
RT, radiation therapy.
aP<.01.
bP<.02.
cStages IB and II only.
TABLE 32.4-6. Proportion of 325 Patients in Whom Disease Recurred after Treatment with
Abdominopelvic Irradiation between 1971 and 1981
Proportion with Disease Recurrence
Stage Gross Residual Disease Grade 1 Grade 2 Grade 3
I No — .21 (33) .30 (27)
II No/uncertain .09 (32) .29 (35) .47 (36)
II Yes .17 (12) .38 (16) .86 (14)
III No/uncertain .20 (10) .67 (18) .67 (15)
III Yes .40 (15) .79 (24) .84 (38)
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Note: Numbers in parentheses are the number of patients treated in each group.
Differences in the chemotherapy and radiotherapy techniques described earlier may explain the apparently contradictory
results of the two trials. An imbalance in the proportion of stage IA patients may have favored the chemotherapy arm in
the M. D. Anderson trial, but subset analysis by stage also failed to suggest an advantage for whole abdominal irradiation.
The high total dose and fraction size per strip used at M. D. Anderson may explain the high rate of severe enteric
complications compared with the 3% to 4% rate reported at Princess Margaret Hospital.
A number of other reports document that patients with postoperative residual disease have been cured with
abdominopelvic irradiation alone; relapse-free survival rates of 40% to 60% at 10 to 15 years have been reported for
patients with residual gross disease measuring less than 2 cm (Table 32.4-7). 63 Collectively, these studies demonstrate
the efficacy of abdominopelvic irradiation and its superiority over pelvic radiotherapy alone. They also indicate that
irradiation alone is insufficient treatment for most patients with gross residual disease, particularly when the residuum is
extrapelvic.
TABLE 32.4-7. Evidence for Cure of Ovarian Cancer by Abdominopelvic Radiotherapy: Long-Term
Outcome in Patients with Stage II and III Disease and Macroscopic Residuum
Size of Residuum
Study Center <2 cm >2 cm End Point
Princess Margaret Hospital63 38 (91) 6 (91) 10-y relapse-free rate
Stanford64 50 (42) 14 (54) 15-y failure-free rate
Salt Lake City65 62 (12) 0 (10) 10-y relapse-free survival
Walter Reed Hospital66 42 (24) 10 (20) 10-y survival rate
Yale67 41 (27) — ∼6-y surviving fraction
Note: Numbers in parentheses are the number of patients treated in each group.
There have been few direct comparisons between abdominopelvic irradiation and modern cisplatin- or paclitaxel-based
chemotherapy. Although retrospective studies do not demonstrate a clear advantage of one treatment over the other for
patients with minimal residual disease, physician biases are strong, and several multi-institutional trials addressing this
question have been closed prematurely because of inadequate patient accrual. In 1993, Redman and coworkers68
published the results of a randomized trial comparing abdominopelvic irradiation with single-agent cisplatin in 40 patients
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with microscopic residual disease, stages IC to III. The 5-year survival rates were 58% and 62% in the two arms,
respectively, but the power of the study was weak because of the small number of patients. In 1994, Chiara and
colleagues69 reported results of a second study comparing whole abdominal radiotherapy with cisplatin and
cyclophosphamide in 70 patients with high-risk stage I or II disease. This study was compromised by poor accrual and
protocol violations. Eight (24%) of the 34 patients assigned to receive radiotherapy were treated with chemotherapy.
Projected 5-year survival rates for those randomly assigned to receive radiation (34 patients) or chemotherapy (36
patients) were 53% and 71%, respectively (P = .16). In a secondary analysis, the death rates for the 44 patients who
received chemotherapy and the 25 who received radiation therapy were similar (27% and 32%, respectively; P = .7).
These studies still leave us with an incomplete understanding of the role of radiotherapy in initial management of ovarian
cancer, however. Although pelvic irradiation was routinely added to early treatments with single alkylating agents, it
generally has been abandoned since platinum-containing regimens became standard. Early studies of pelvic radiation
therapy alone and the success of whole abdominal plus pelvic irradiation in selected patients indicate that radiation is an
active agent and suggest that pelvic irradiation may be a useful addition to chemotherapy for selected patients who have
a high risk of pelvic recurrence. However, no study has ever been done to determine whether pelvic irradiation could
improve the control rates achieved with modern chemotherapy.
Whole Abdominal Radiotherapy

The cobalt 60 moving strip technique was developed at the M. D. Anderson Cancer Center in the 1960s to improve the
acute tolerance of patients to large whole abdominal fields of radiation. The abdomen was divided into horizontal strips of
2.5 cm each. Two to four contiguous strips were treated each day, with exposure moving down gradually until the whole
abdomen had received the prescribed dose of radiation. Subsequent studies suggested that large stationary megavoltage
fields could be tolerated, and they were technically less difficult to deliver. In 1983, Dembo and coworkers69a reported a
randomized comparison of open field whole abdominal irradiation (22 Gy in 22 fractions) and the moving strip technique
(22.5 Gy in 10 fractions per strip), demonstrating lower complication rates and comparable tumor control with the simpler
open field technique.
The high rate of subdiaphragmatic recurrences observed after treatment with early “whole abdominal” fields that did not
completely cover the diaphragm illustrates the critical importance of covering the entire peritoneal cavity. In a review of
a prospective multi-institutional trial, Klaassen and colleagues62 reported a significantly poorer survival rate for patients
whose whole abdominal radiation fields were found to deviate seriously from protocol specifications. In a more recent
report, Firat et al.70 suggested that the rates of abdominal disease control and survival can be improved if patients
receive more than
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30 Gy to the whole abdomen, although the rate of major complications was also much higher in patients who received
these higher doses.
Patients should always undergo simulation using fluoroscopy, and fields should provide a 1-cm margin on the maximum
cephalad excursion of the diaphragmatic domes under quiet respiration. It is often necessary to flash the lateral
abdominal wall and to include the entire bony pelvis in whole abdominal fields to avoid excluding peritoneal surfaces. In
obese patients with poor abdominal tone, the fields may need to extend laterally beyond the bony pelvis. This is
particularly true when the patient is treated in the prone position. The thickness of the abdominal wall should be
considered in choosing the energy of the radiation beam. When fields are designed using CT scans of the whole abdomen,
coverage of peritoneal surfaces can be assured. The total dose of whole abdominal irradiation varies between 22 and 30
Gy depending on the fractionation scheme, use of concurrent chemotherapy, and patient tolerance. Posterior kidney
blocks are placed to limit the renal dose to 15 to 18 Gy, and a portion of the liver may be shielded during part of the
treatment to limit the dose to 22 to 25 Gy. The true pelvis is usually treated to a higher dose of 45 to 50 Gy, either after
whole abdominal irradiation or concurrently as a field within a field (not to exceed a total daily dose to the pelvis of 180
cGy). Martinez and coworkers64 have suggested boosting the dose to the paraaortic nodes and medial diaphragms with a
T-shaped field in selected patients. Chemotherapy that is given before or after irradiation can influence normal tissue
tolerance and should be considered in estimations of organ tolerance.
Intraperitoneal Radioisotope Therapy

The characteristic transcolonic pattern of dissemination of ovarian cancer first led clinicians to treat patients with
intraperitoneal isotopes in the 1950s, and this treatment is still used by some practitioners for a selected group of patients
with minimal disease. The isotope that is generally used is chromic phosphate (32P). 32P decays with a half-life of 14.3
days, emitting β-particles with a mean energy of 0.69 MeV. Because the average penetration of these particles in soft
tissue is less than 1 to 2 mm, treatment with 32P is inappropriate for patients who have macroscopic residual disease.
Because the goal is to distribute the isotope evenly over peritoneal surfaces, patients with intraabdominal adhesions that
inhibit the flow of the isotope-containing fluid are poor candidates for this treatment. Intraabdominal distribution is
usually evaluated before treatment by scanning the patient after an intraabdominal injection of technetium 99m sulfur
colloid. If a good distribution is confirmed, the patient is treated with 10 to 20 mCi of 32P diluted in saline and then is
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positioned to optimize distribution. It is estimated that this dose delivers 20 to 40 Gy of radiation to the peritoneal
surface. However, nonuniform distribution can produce variations in the dose of tenfold or more.
An early GOG randomized trial,43 reported in 1990, demonstrated 5-year survival rates of 81% and 78% for patients
treated with melphalan and 32P, respectively; four patients (6%) treated with 32P required an operation for small bowel
obstruction, and two patients (3%) treated with melphalan developed leukemia. The authors concluded that
intraabdominal 32P was the preferred treatment for these patients because of its limited toxicity and no known risk for
causing leukemia. In a subsequent GOG study,71 intraabdominal 32P therapy was compared with three cycles of cisplatin
and cyclophosphamide in patients with high-risk early-stage disease. There was no significant difference in the risk of
recurrence (35% and 28%, respectively; P = .15) or in the probability of survival (P = .43) for patients treated with 32P and
chemotherapy. One toxicity-related death was reported in each treatment arm. Of 118 patients treated with
chemotherapy, 69%, 8%, and 16% had grade 3 or 4 leukopenia, thrombocytopenia, or gastrointestinal toxicity,
respectively; of 106 patients treated with 32P, 3 experienced small bowel perforations during catheter insertion, which in
one case may have contributed to the treatment-related death on that arm. The authors concluded that platinum-based
chemotherapy should be standard because of the complications of 32P administration and the trend toward a lower risk of
recurrence with chemotherapy.
Two other randomized studies have compared 32P with cisplatin-containing chemotherapy.72,73 These also failed to
demonstrate a significant difference in survival between the two treatments. Vergote and colleagues72 randomly assigned
347 patients who had no gross residual disease after laparotomy to receive intraperitoneal 32P (7 to 10 mCi) or cisplatin
(six courses of 50 mg/m2 each). The estimated 5-year survival rates were 83% and 81%, respectively (P = .6). Although the
dose of 32P was relatively low, 12 (9%) of 136 patients who had this treatment experienced small bowel obstructions
compared with 2% of patients treated with cisplatin. For this reason, these authors also recommended platinum-based
chemotherapy as standard treatment.
The most common complication of 32P administration is transient abdominal pain, which occurs in 15% to 20% of patients.
Chemical or infectious peritonitis is a rare complication that occurs in 2% to 3% of patients. The most serious late
complication of treatment is small bowel obstruction, which has been reported in 5% to 10% of patients treated with 32P
alone. This risk increases to an unacceptable rate of 20% to 30% when intraperitoneal 32P is combined with external-beam
radiotherapy, an approach that is no longer recommended.
TREATMENT OF ADVANCED-STAGE OVARIAN CANCER

The recommended treatment strategy for patients with advanced-stage ovarian cancer (stage III or stage IV disease) is
similar: optimal cytoreductive surgery to remove all visible tumor, whenever feasible, followed by platinum- and taxane-
based chemotherapy.
Cytoreduction
Aggressive surgery to remove all grossly visibile tumor (i.e., cytoreductive surgery or tumor debulking surgery) has been an
integral part of the initial treatment for advanced ovarian cancer for almost 30 years.76 The theoretical benefits of
cytoreductive surgery are to remove large necrotic tumors with poor blood supplies and to remove large tumors that are
in a slower growth phase, which leaves behind tumors that are more sensitive to the effects of chemotherapy. Optimal
cytoreduction has been defined differently through the years, but at the current time, cytoreduction with residual disease
under 1 cm is most widely accepted. Several reports have demonstrated that the size of the largest residual disease
correlates with progression-free and overall survival.46,47,77 Theoretically, all patients with stage III and IV disease are
candidates for cytoreductive surgery; however, in some cases, clinical assessment dictates that neoadjuvant
chemotherapy
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should be initially prescribed. For example, patients with a poor performance status who cannot undergo an aggressive
surgical procedure or, in some cases, stage IV patients with parenchymal liver disease, enlarged retrocrural or
supraclavicular lymph nodes, mediastinal metastases, and parenchymal lung metastases may not be candidates for
optimal cytoreductive surgery. Women with stage IV disease based only on the presence of malignant pleural effusion
have been able to undergo optimal cytoreductive surgery. Studies have suggested that an optimal surgical cytoreductive
procedure should be performed in women with stage IV disease even when parenchymal liver disease is recognized
preoperatively.74,75 In patients who underwent optimal cytoreduction with residual tumor of less than 1 to 2 cm
maximum diameter, the median survival varied from 25 to 40 months, whereas among those who underwent suboptimal
cytoreduction, median survival times were 10 to 18 months. Interestingly, in three of the four prospective randomized
trials conducted by the GOG, the patients with stage IV disease undergoing optimal cytoreduction had survival superior to
that of patients with stage III ovarian cancer who underwent optimal cytoreduction.46
Successful surgical management of stage III or IV ovarian cancer requires meticulous attention to surgical techniques to
avoid complications and a thorough knowledge of abdominal and pelvic anatomy to allow the successful accomplishment
of cytoreductive surgery. In general, it is wisest to start with an incision in the lower abdomen to free the pelvis of
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cancer, then work up into the upper abdomen to attempt to clear it of cancer, then complete the procedure with
paraaortic and pericaval retroperitoneal lymph node sampling or resection if optimal cytoreduction has been accomplished
within the peritoneal cavity. The goal of optimal cytoreductive surgery is complete removal of all palpable or visible
tumor. A minimal goal of cytoreductive surgery is to reduce the residual tumor to less than 1 cm and preferably to less
than 0.5 cm in maximum diameter.
When the abdominal cavity is entered, normal anatomy is restored by lysing adhesions and freeing organs from adherent
tumor. Frequently the pelvis is completely filled with tumor. By identifying the round ligaments and suture ligating and
dividing them, the pelvic retroperitoneum can be entered and the external iliac arteries and veins, the hypogastric
arteries, and the ureters can be rapidly identified. Accomplishing this allows ligation of the infundibulopelvic ligaments
with the ovarian vessels; resection of peritoneum, along with the attached vessels down to the tumor mass; and dissection
of the ovarian mass off of, or with, the underlying peritoneum to elevate the mass from the pelvic sidewall. By dividing
the utero-ovarian ligaments and fallopian tubes, one can then remove the mass. At times, it may be necessary to resect
small bowel or sigmoid colon in continuity with the ovarian mass. An end-to-end or side-to-side anastomosis restores
bowel continuity. Less frequently a colostomy is necessary. Once each of the ovaries has been removed, a hysterectomy is
performed. At times, ovarian cancers infiltrate the uterus and it is necessary to take the uterus out en bloc with the
ovarian tumor. Implants in the cul-de-sac may be resected using retroperitoneal dissection. Sigmoid colon implants usually
involve epiploic appendices, which can be resected without performing a sigmoid colon resection. Retroperitoneal lymph
nodes are routinely removed from the external iliac artery and vein, hypogastric arteries, and the obturator fossa. An
appendectomy is routinely performed.
After resection of the pelvic disease, a complete omentectomy is performed and large masses implanting on peritoneal
surfaces, including the diaphragm, are removed. Once the abdomen has been cleared of disease or the maximum residual
disease is less than 1 cm, the fat pad overlying and surrounding the aorta and vena cava is removed, as are lymph nodes
involved with metastatic disease in this area. In general, if large residual tumor volume is left within the peritoneal
cavity, there is not much benefit in resecting retroperitoneal disease. However, when intraperitoneal disease has
undergone optimal cytoreduction to less than 1 cm maximal residual tumor volume, retroperitoneal lymphadenectomies
are appropriate.
Impact of Primary Cytoreductive Surgery

The clinical rationale for cytoreductive surgery has been ascribed to Griffiths,76 who demonstrated in 1975 that survival
was directly affected by the initial degree of cytoreductive surgery in women with advanced-stage ovarian cancer. In a
retrospective review, patients with no residual disease had a mean survival of 39 months compared with 29 months for
those with residual disease of less than 0.5 cm, 18 months for those with residual disease of 0.6 to 1.5 cm, and 11 months
for those who did not have cytoreduction below 1.5 cm. None of the latter patients survived beyond 26 months. Women
who underwent optimal cytoreductive surgery had survival rates similar to those of women who had minimal-size
abdominal metastases at the initial surgery. Subsequent to Griffiths's report, numerous series have confirmed that
aggressive cytoreductive surgery to 2 cm of residual tumor or less significantly enhances survival for patients. Most
patients participated in trials in which multidrug chemotherapy was used, generally involving cisplatin-based
chemotherapy. A review of nine studies in which primary cytoreductive surgery resulted in disease of less than 2 cm or
greater than 2 cm demonstrated a mean survival in the group with optimal cytoreduction of 29.4 months compared with
13.4 months in the group in whom cytoreductive surgery was suboptimal76,77,78,79,80,81,82,83,84 (Table 32.4-8).
TABLE 32.4-8. Effect of Residual Disease at the Conclusion of Primary Cytoreductive Surgery on
Survival
Investigators Treatment Residual Disease (cm) Survival (Mo)
Griffiths (1975)76 L-PAM 0 39
0–0.5 29
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0.6–1.5 18
>1.5 11
Hacker et al. (1983)77 Varied <0.5 40
0.6–1.5 18
>1.5 6
Vogl et al. (1983)78 CHAP <2 >40
>2 16
Pohl et al. (1984)79 Varied <2 45
>2 16
Delgado et al. (1984)80 Varied <2 45
>2 16
Redman et al. (1986)83 CAP <3 >3 3826
Conte et al. (1986)84 CAP, CP <2 >40
>2 16
Neijt et al. (1991)82 CHAP or CP <1 40
>1 21
Piver et al. (1988)81 PAC <2 48
>2 21
Totals Mean, 36.7 (optimal)
Mean, 16.6 (suboptimal)
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CAP, cyclophosphamide, doxorubicin(Adriamycin), and cisplatin; CHAP, cyclophosphamide,

hexamethylmelamine, doxorubicin, and cisplatin; CP, cyclophosphamide and cisplatin; L-PAM, melphalan;
PAC, cisplatin, doxorubicin, and cyclophosphamide.
(Modified from Young RC, Perez CA, Hoskins WV. Cancer of the ovary. In: DeVita VT Jr, Hellman S, Rosenberg
SA, eds. Cancer: principles and practice of oncology, 4th ed. Philadelphia: JB Lippincott Co, 1993:1226, with
permission.)
Two metaanalyses gave conflicting views on the survival impact of cytoreductive surgery.85,86 Hunter et al.85 reviewed a
total of 58 separate studies encompassing 6962 patients to determine whether maximal cytoreductive surgery benefits the
survival of women with
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advanced ovarian cancer. These authors looked at the median survival times of groups of women with advanced ovarian
cancer and used multiple linear regression techniques to analyze the effects on median survival. The variables studied
were the proportion of each cohort undergoing maximal cytoreductive surgery, the use of cisplatin chemotherapy, the
dose intensity of the chemotherapy, the proportion of each cohort with stage IV disease, and the year of publication of
the study. The use of cisplatin chemotherapy resulted in an increased survival time of 53% [95% confidence interval (CI),
35% to 73%]. For each 0.2-U increase in dose intensity, the increase in median survival time was 11.1% (95% CI, 6% to 17%;
P = .001). Stage IV disease had a negative impact on survival. For each 10% increase in the number of stage IV patients in
the study, a negative survival increase of 2.6% (95% CI, -0.1% to -5.4%) was found. For each 10% increase in the percentage
of women who underwent maximal cytoreductive surgery, the increase in survival was only 4.1% (95% CI, -0.6% to 9.1%; P
= .089) (Fig. 32.4-4). This study concluded that cytoreductive surgery has only a small effect on the survival of women
with advanced ovarian cancer and that the type of treatment used (i.e., cisplatin) was far more important.
FIGURE 32.4-4. Graph of log median survival time (MST; in months) versus percent maximal cytoreductive surgery
(MCS) for 76 cohorts for which dose intensity could be calculated after adjustments for effects of dose intensity,
percentage of patients with stage IV disease, and use of platinum chemotherapy. (From 85, with permission.)
Three GOG studies give important insight into the impact of cytoreductive surgery in advanced ovarian cancer. The first
demonstrated that removing all gross tumor defines true optimal cytoreductive surgery. Women treated with cisplatin-
based chemotherapy who had no gross disease left had a progression-free interval of 42 months compared with 20 months
for those with residual disease of less than 1 cm.87 The second study revealed that women who had 1 to 2 cm of residual
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tumor had a significant survival improvement compared with those who had more than 2 cm of residual tumor.88 This
third study refuted early data suggesting that women undergoing optimal cytoreductive surgery have survival similar to
that of patients initially found at surgery to have low-volume disease.46 The latter study reported on 348 women with 1
cm or less residual tumor, 200 of whom initially had abdominal disease of 1 cm or less. When implants were present on
parietal or visceral peritoneum, even when cytoreduction was optimal, survival rates significantly decreased. Indeed, the
best survivals observed for patients with stage III disease were in those whose initial macroscopic tumor was smaller than
1 cm in the omentum and associated with either no disease or microscopic disease in other abdominal sites (P = .0001).
Those with the poorest survival had tumors initially larger than 1 cm involving omentum and had gross disease in other
abdominal sites (Fig. 32.4-5). This study refutes early data suggesting that women undergoing optimal cytoreductive
surgery have the same survival as those patients initially found at surgery to have low-volume disease. The study
demonstrates that biologic factors responsible for bulk disease may be as important as technical ability to resect the
disease.
FIGURE 32.4-5. Survival time by initial maximum omental (Omen.) and abdominal (Abdom.) tumor diameter. Micro,
microscopic. (From 46, with permission.)
Bristow et al.10 performed a metaanalysis of data for 81 cohorts of patients with advanced-stage ovarian cancer (more
than 6800 patients) to assess the survival effect of maximal cytoreductive surgery during the platinum-based
chemotherapy era. They found a statistically significant positive correlation between percent maximal cytoreduction and
log median survival time, and this correlation remained significant after controlling for all other variables (P <.001) (Fig.
32.4-6). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. The
relationship between platinum dose intensity and log median survival time was not statistically significant in this study.
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FIGURE 32.4-6. Impact of surgical cytoreduction on survival. Simple linear regression analysis: de-logged median
survival time plotted against percent maximal cytoreductive surgery. Gray area, maximal cytoreductive ≤25% and
>75%; crosshatched area, corresponding range of median survival times. (From 10, with permission.)
Aggressive cytoreductive surgery incurs complications. Chen and Bochner89 reported on 60 patients who underwent
optimal cytoreductive surgery. These patients had a 5% operative morbidity. Blythe and Wahl90 looked at quality of life in
patients with optimal residual disease (less than 2 cm in diameter) and suboptimal residual disease (more than 2 cm in
diameter) and found that 75% of the group with optimal residual disease were judged to have good or good to fair quality
of life, but only 18% of the group with suboptimal residual disease achieved this quality of life. It has been argued that
perhaps those women who are able to undergo optimal cytoreduction have biologically less virulent disease than those
patients in whom optimal cytoreductive surgery cannot be achieved. This question has yet to be answered because there
are no data from prospective randomized trials available.
CT scans have been used to identify tumor distribution and the extent of ovarian cancer metastases. In some cases, CT
findings suggest metastatic disease that is not amenable to optimal surgical cytoreduction such as parenchymal liver
disease and porta hepatis infiltration.91 Although it is sometimes possible to resect tumor in these sites, many of these
patients are left with a suboptimal result, and thus neoadjuvant chemotherapy has often been recommended. The initial
experience with neoadjuvant chemotherapy in the management of women who have advanced disease that does not
appear to be surgically resectable or who have evidence for stage IV disease suggests that it may be as effective as the
conventional approach of chemotherapy after suboptimal cytoreductive surgery.92 Interval debulking surgery is then
performed after three or four cycles of chemotherapy in those patients who demonstrate response to therapy.93 Potential
advantages of neoadjuvant chemotherapy appear to be a much more rapid improvement in quality of life, a less expensive
treatment program for patients, and, when surgery is ultimately performed, an easier operation requiring shorter
hospitalization. Prospective randomized trials incorporating neoadjuvant chemotherapy in the management of advanced-
stage ovarian cancer are definitely needed.
Chemotherapy
Chemotherapeutic agents from a wide variety of different classes have been shown to produce responses in patients with
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ovarian cancer. Numerous combination chemotherapy regimens have been studied, and individual drugs have been
compared with combinations. Since the mid-1990s, the combination of a platinum agent and a taxane has been accepted
as the standard of care in the United States.
The major importance of cisplatin in the management of ovarian cancer was summarized in a metaanalysis of 45
randomized trials that compared primary treatment with regimens containing this agent with regimens that did not
include the drug.94 A modest survival advantage for platinum-based combination programs compared to single-agent
cisplatin was also revealed in this analysis.
The next highly relevant development in the management of ovarian cancer was the introduction of carboplatin into the
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oncologist's armamentarium as a less toxic analogue of cisplatin. Several prospective randomized trials, and the results of
a large metaanalysis, have confirmed the equivalence of single-agent carboplatin and cisplatin, and of combination
cisplatin versus carboplatin non–taxane-containing primary chemotherapy regimens in advanced ovarian cancer.95,96,97
Several trials have specifically examined the benefits of extending treatment with cisplatin-based chemotherapy beyond 5
or 6 cycles to 10 or 12 cycles.98,99 Unfortunately, the studies only showed that such treatment increased toxicity but did
not improve either progression-free or overall survival.
Other studies have examined the role of cisplatin dose intensity in ovarian cancer. A retrospective review of 33 published
trials suggested that a greater dose intensity (expressed as milligrams per square meter per week) may be associated with
superior outcome.100 However, several prospective phase III randomized studies have failed to reveal an advantage for
increasing cisplatin dose intensity beyond 75 mg/m2 delivered every 3 weeks.101,102,103,104
As with cisplatin, retrospective data have suggested a modest dose-response curve for carboplatin in ovarian cancer
treatment.105 Several phase III randomized trials have examined the importance of carboplatin dose intensity in ovarian
cancer and have failed to demonstrate the superiority of increasing the carboplatin area under the curve (AUC) from 4 to
8 (when patients also received cyclophosphamide)106 or escalating the AUC from 6 to 12 (when given as single-agent
therapy).107
The issue of a potential role for an anthracycline in combination with a platinum agent and cyclophosphamide has
remained an incompletely answered question in the management of ovarian cancer. For example, a GOG trial compared
the two-drug combination of cisplatin and cyclophosphamide to a three-drug regimen of cisplatin, cyclophosphamide, and
doxorubicin (Adriamycin; PAC) in a trial involving 349 patients.108 There was no difference in response rate, progression-
free survival or overall survival between the two study arms. However, two metaanalyses of published randomized trials
have provided support for the conclusion suggesting a 5% to 7% survival advantage for combination regimens that included
doxorubicin compared to those that did not contain the drug.109,110 A large phase III randomized trial (ICON2) that
directly compared single-agent carboplatin to a PAC regimen failed to demonstrate any survival advantage (progression-
free or overall) for the combination doxorubicin-containing program.111 That this study has not ended the controversy
surrounding the use of anthracyclines in ovarian cancer is shown by the fact that several recently completed (but not yet
reported) and ongoing trials are specifically examining a role for either epirubicin or liposomal doxorubicin in this clinical
setting.
Before the introduction of paclitaxel into the management of advanced ovarian cancer, the randomized trial experience
noted earlier resulted in the routine use of several primary chemotherapy regimens for this malignancy. These included
either cisplatin (75 mg/m2) or carboplatin (AUC = 5 to 7) delivered with cyclophosphamide (600 to 750 mg/m2). In Europe,
it was not uncommon for a PAC regimen to be used.
In the 1980s, the taxanes (paclitaxel, docetaxel) were shown to possess significant activity against platinum-resistant
ovarian cancer.112,113,114 Based on this experience, two phase III randomized trials were initiated that compared a
cisplatin-paclitaxel regimen to a cisplatin-cyclophosphamide regimen (Table 32.4-9). The GOG study115 randomly assigned
patients with suboptimally resected stage III and IV ovarian cancer to one of these two chemotherapy combinations and
showed that women treated with the paclitaxel-containing program experienced a statistically significantly higher
objective response rate as well as improved progression-free and overall survival (38 vs. 24 months) (Fig. 32.4-7).
TABLE 32.4-9. Randomized Trials of Paclitaxel plus Platinum in Advanced Ovarian Cancer
No. of CCR PFS OS

Trial and Randomization Reference
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Median Median
Patients/Stage (%) (Mo) (Mo)
GOG 111 115 386; Suboptimal

stage II and IV
Cisplatin (75 mg/m2) plus 51 18 38

paclitaxel (135 mg/m2 in 24 h)

cyclophosphamide (750
mg/m2)
OV-10 116 668; Stage IIB–IV


mg/m2)
GOG 132 117 —
Cisplatin (75 mg/m2) plus NA 14.1 26.6

Paclitaxel (200 mg/m2) NA 11.4 26
Cisplatin (100 mg/m2) NA 16.4 30.2
ICON3 118 2074; Stage I–IV
Carboplatin (AUC = 5–6) plus NA 17.3 36.1

paclitaxel (175 mg/m2)
Carboplatin (AUC = 5–6) or NA 16.1 35.4

cisplatin (50 mg/m2) plus
doxorubicin (50 mg/m2) plus
mg/m2)
AUC, area under the curve; CCR, clinical complete remission; GOG, Gynecologic Oncology Group; ICON3,
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International Collaborative Ovarian Neoplasm trial 3; NA, not available; OS, overall survival; PFS, progression-
free survival.
FIGURE 32.4-7. Disease-free (A) and overall (B) survival of patients with suboptimally resected stage III and IV
ovarian cancer randomly assigned to treatment with cisplatin plus cyclophosphamide (solid line) or cisplatin plus
paclitaxel (dotted line). (From 115, with permission.)
These impressive results were confirmed in a trial conducted in Europe and Canada that used a similar but not identical
study design.116 In this later trial the paclitaxel was delivered as a 3-hour infusion (175 mg/m2) whereas in the GOG study
the agent was administered over 24 hours (135 mg/m2). In addition, a much larger percentage of patients in the
European-Canadian study received paclitaxel as a second-line therapy than in the GOG trial. Despite this fact, this study
also revealed a statistically significant improvement in both progression-free and overall survival associated with the
paclitaxel-containing program.116
Of note, the 3-hour paclitaxel infusion regimen, in combination with cisplatin, resulted in a very high incidence of grade 3
peripheral neuropathy (20% to 25%). A substantially lower risk of this toxic effect was observed in the GOG trial (4%), in
which the paclitaxel was administered as a 24-hour infusion.
Several additional trials examining a role for paclitaxel in treatment of advanced ovarian cancer are worthy of discussion.
After the completion of the study noted earlier, the GOG decided to directly compare single-agent cisplatin (100 mg/m2),
single-agent paclitaxel (200 mg/m2 over 24 hours), or the combination of cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2
over 24 hours).117 When the results of this trial were analyzed, it was determined that approximately 50% of patients in
the single-agent arms actually received the alternative agent before documented disease progression. This is the most
likely explanation for the fact that survival was essentially the same in all three study arms, despite the fact that there
was a superior objective response rate to both platinum-containing regimens (67%), compared to single-agent paclitaxel
(42%). One important conclusion of this study is that the results support the argument that sequential treatment with a
platinum agent, followed by paclitaxel, is therapeutically equivalent to combination therapy with the two drugs in
advanced ovarian cancer.
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A large (2000-patient) European phase III randomized trial (ICON3) compared a “control” regimen of either single-agent
carboplatin or PAC to an “experimental” program of carboplatin and paclitaxel. The study failed to reveal a difference in
survival between either control arm and the experimental arm.118 A number of theories have been proposed to explain
the difference in outcome between this study and the two previously mentioned trials that compared cisplatin plus
cyclophosphamide and cisplatin plus paclitaxel.115,116 Perhaps the most likely explanation is the fact that one-third of
the patients on the control arms of ICON3 ultimately received paclitaxel. Thus, as in the previously mentioned three-arm
GOG study,117 this outcome provides support for the hypothesis that the sequential administration of the two active
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agents is therapeutically equivalent to combination drug delivery.
Due to the more favorable toxicity profile of carboplatin, compared to cisplatin, it was natural that investigators desired
to use the newer platinum agent with paclitaxel,119 assuming equivalent efficacy could be documented. Three phase III
randomized trials have been reported that directly compared a carboplatin-paclitaxel regimen to cisplatin plus paclitaxel
(Table 32.4-10). 120,121,122 As might have been anticipated, the studies have revealed equivalent progression-free and
overall survival for the regimens, with a generally more favorable toxicity profile associated with the carboplatin-based
programs. Of note, the studies demonstrated that it was possible to administer
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paclitaxel over 3 hours in combination with carboplatin with an acceptable incidence of neurotoxicity, in contrast to the
situation with cisplatin, in which a 24-hour infusion regimen was required.
TABLE 32.4-10. Randomized Trials of Carboplatin plus Paclitaxel versus Cisplatin plus Paclitaxel
No. of PFS Median OS Median

Trial and Randomization Reference Patients/Stage (Mo) (Mo)
GOG 158 120 792; Optimal stage

III
Carboplatin (AUC = 7.5) plus 20.7 57.4

Cisplatin (75 mg/m2) plus 19.4 48.7

paclitaxel (135 mg/m2)
AGO 121 798; Stage IIB–IV
Carboplatin (AUC = 6) plus 17.2 43.3

Cisplatin (75 mg/m2) plus 19.1 44.1

NETHERLANDS-DENMARK 122 208; Stage IIB–IV
Carboplatin (AUC = 5) plus ND ND

Cisplatin (75 mg/m2) plus ND ND

AGO, Arbeitsgemeinschaft Gynaekologische Onkologie; AUC, area under the curve; GOG, Gynecologic
Oncology Group; ND, no difference reported; OS, overall survival; PFS, progression-free survival.
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The preceding data support the conclusion that there are two acceptable standard paclitaxel-containing combination
chemotherapy regimens that may be used for primary treatment of advanced ovarian cancer: cisplatin (75 mg/m2) plus
paclitaxel (135 mg/m2 over 24 hours) or carboplatin (AUC = 5.0 to 7.5) plus paclitaxel (175 mg/m2 over 3 hours). In
general, the carboplatin-based regimen is preferred due to reduced toxicity (e.g., emesis, neutropenia, nephrotoxicity)
and the ability to deliver a shorter paclitaxel infusion. In individuals for whom there is concern regarding the ability to
tolerate a combination regimen (e.g., marginal performance status, significant comorbid medical conditions, advanced
age) it is reasonable to initiate treatment with single-agent carboplatin and either add paclitaxel to the regimen at a later
point or deliver the drugs in sequence.
The preliminary report of a randomized trial comparing a carboplatin (AUC = 5) plus paclitaxel (175 mg/m2) regimen to
carboplatin (AUC = 5) plus docetaxel (75 mg/m2) has suggested equivalent efficacy (objective response rate in patients
with measurable disease, median progression-free survival) for the two programs.123 Data regarding median overall
survival are not yet available. As might have been anticipated, the toxicity profiles of the two carboplatin-based regimens
were different, with more grade 4 neutropenia seen with the docetaxel-containing regimen and a greater incidence of
grade 2 or 3 neuropathy with the paclitaxel-containing program. These data indicate that a carboplatin-docetaxel
combination is an acceptable alternative for primary chemotherapy for advanced ovarian cancer.
A number of important questions remain regarding the optimal use of paclitaxel as a component of primary therapy for
ovarian cancer. These include the issue of the value of dose intensity of this agent124 and the potential clinical utility of a
lower-dose weekly schedule.125 Phase II trials have demonstrated the activity of weekly paclitaxel in ovarian cancer
resistant to both platinum and paclitaxel (every-3-week schedule). The question of whether a weekly regimen can
enhance the cytotoxic potential of this agent when delivered as primary therapy for advanced ovarian cancer is worthy of
examination in a randomized trial. Several novel taxane preparations that appear to produce equivalent efficacy and
reduced toxicity compared to paclitaxel are currently undergoing phase I and II testing. It is important ultimately to
compare one or more of these agents with standard treatment using carboplatin and paclitaxel in phase III randomized
trials.
The provocative results of a randomized trial conducted by the Southwest Oncology Group and the GOG have raised the
important issue of the duration of paclitaxel therapy in advanced ovarian cancer.126 In this trial women with advanced
disease who had demonstrated a clinically defined complete response were randomly assigned to receive either 3 cycles
or 12 cycles of single-agent paclitaxel (175 mg/m2 over 3 hours) delivered on a schedule of every 28 days. The study was
stopped early by the Data Safety Monitoring Committee when an interim analysis revealed a 50% reduction in the risk of
recurrence associated with the 12-month maintenance strategy (median progression-free survival 28 months vs. 21 months
in the 3-month maintenance arm; P = .0023). At the time of study closure there was no difference in overall survival
between the two regimens, but follow-up to address this point was very limited. Further exploration in appropriately
designed randomized trials of the issue of the duration of treatment for patients responding to, and tolerating, therapy is
clearly indicated, because it remains the case that 70% to 80% of women with advanced ovarian cancer who achieve a
clinically defined complete response and 50% to 60% of those who achieve a surgically defined complete response
ultimately experience relapse of their disease.
Management after Induction Chemotherapy

The majority, almost 80%, of previously untreated patients with advanced-stage disease achieve a clinical complete
remission after platinum and taxane induction chemotherapy. Clinical complete remission is defined as no evidence of
disease on physical examination or by radiographic studies, together with a normal CA 125 level. However, between 50%
and 75% of patients with advanced disease ultimately experience relapse from a clinical remission. Even patients who are
surgically confirmed to be in complete remission (negative second look) still remain at high risk, with a relapse rate of 30%
to 50% after platinum-based chemotherapy.
Second-Look Surgery
Second-look surgery is a carefully planned systematic surgical approach to evaluate patients who have completed the
planned
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course of chemotherapy and who, by clinical examination, measurement of CA 125 level, and diagnostic imaging studies,
are free of persistent cancer. The purpose of the second-look operation is to assess the pathologic or microscopic response
to therapy by completely exploring the abdominal cavity and sampling any abnormalities found or performing biopsy of
peritoneal surfaces where microscopic ovarian cancer is most likely to be found, or both.127 Although the intent of
second-look surgery is to improve survival by instituting additional therapy if any persistent cancer is discovered, to date,
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second-look procedures have not demonstrated any survival advantage and thus are no longer standard of care. In some
subgroups of patients or as part of a clinical trial design, a secondary surgical assessment may still be included in the
treatment management plan. In other individual cases, second-look procedures may be performed to help determine
prognosis, although their therapeutic value has not been validated.
At the current time, when second-look surgery is performed, a laparoscopic approach is most frequently used. This
approach allows complete visualization of the peritoneal cavity and in most cases provides sufficient ability to obtain the
necessary biopsy specimens.128 Washings of the pelvis and abdomen are performed, followed by lysis of adhesions, which
are sent for histologic assessment. Sampling then begins in the pelvis with peritoneal biopsy specimens taken from the
areas of the round ligaments and the infundibulopelvic ligaments, from the bladder flap peritoneum, and from the cul-de-
sac peritoneum. The retroperitoneal spaces are examined, and any residual lymph node or fatty tissues surrounding the
external iliac artery, vein, or hypogastric artery are sampled. Studies comparing the diagnostic accuracy of laparoscopic
reassessment to reassessment via laparotomy have demonstrated equivalent ability to detect disease and predict future
recurrence. Furthermore, the minimally invasive approach has proven to be more cost effective, with less associated
morbidity and mortality.128
Radiotherapy after Chemotherapy

Numerous small phase I and II studies have used whole abdominal irradiation as salvage treatment for patients with
minimal residual disease after chemotherapy. Some authors have reported 3-year progression-free survival rates as high as
25% to 35% and occasional 10- to 15-year disease-free survivors among patients treated with abdominal irradiation after an
incomplete response to chemotherapy.129,130,131,132 However, others have reported high complication rates and have
been discouraged by the short duration of most remissions, particularly in patients with high-grade disease or macroscopic
residual tumor.133,134
Although irradiation of the abdomen and pelvis may cure a small proportion of patients who have residual disease after
chemotherapy, the control rates appear to be much poorer than those reported for patients treated with initial radiation
for a similar volume of residual disease. A number of factors may contribute to these disappointing results. Patients who
have not responded completely to chemotherapy may have disease that is inherently more aggressive than that of patients
chosen for primary treatment with whole abdominal irradiation. Radiotherapy is often compromised because of poor
hematologic tolerance after aggressive chemotherapy, which further decreases the probability that the tumor will be
sterilized. It also has been suggested that cytoreductive treatments (surgery, irradiation, or chemotherapy) may stimulate
the proliferation of clonogenic tumor cells. Consequently, to overcome rapid repopulation, higher doses of radiation may
be required to sterilize tumor cells that remain after a course of chemotherapy.
Hoskins et al.135 have reported encouraging results for a regimen that integrated whole abdominal irradiation in the
initial treatment of patients with minimal residual disease after cytoreduction. In their study, radiation was given after
the first three of six cycles of cisplatin and cyclophosphamide. Comparison with the results for similar patients treated
during a later time with six cycles of chemotherapy alone favored the alternating regimen, particularly for patients with
stage I disease (P = .04).
Several randomized trials have compared whole abdominal irradiation with additional consolidative chemotherapy for
patients with minimal disease after surgical cytoreduction and platinum-containing chemotherapy. Bruzzone et al.136
randomly assigned patients who had minimal or no residual disease after chemotherapy (doxorubicin, cyclophosphamide,
and cisplatin or carboplatin) to receive whole abdominal irradiation or three more cycles of chemotherapy. The study was
closed after accruing only 41 patients because disease progression had been observed in 55% of patients treated with
radiation versus 29% of those treated with additional chemotherapy (P = .08). The authors recommended treatment with
chemotherapy, but the small number of patients and short median follow-up weakened the conclusions of their study. In
another study by Lambert et al.,137 254 patients with stage IIB to IV disease received five monthly courses of carboplatin
and second-look laparotomy. The 117 patients who had residual disease of 2 cm or less after secondary cytoreduction
were then randomly assigned to receive either five additional courses of carboplatin or whole abdominal irradiation (24 Gy
in 5 weeks). The authors reported no statistical difference in survival time or disease-free survival rates between the two
treatment arms. In a third trial, Pickel's group137a randomly assigned 64 patients who had a complete clinical response
after surgery and chemotherapy (carboplatin, epirubicin, and prednimustine) to receive whole abdominal irradiation or no
further treatment. No second-look laparotomy was performed. In this study, patients who had consolidation with radiation
therapy had a significantly better 5-year survival than patients who had chemotherapy alone (59% vs. 33%; P = .03).
More recently, Sorbe et al.138 reported results of a trial that included 172 patients with FIGO stage III ovarian carcinoma
who had pathologic complete response or surgical complete response (microscopic residual only) after initial surgical
cytoreduction and four cycles of chemotherapy [cisplatin (50 mg/m2/cycle) with either doxorubicin or epirubicin].
Patients who had microscopic residual disease at second-look surgery received additional treatment with whole abdominal
radiation therapy (20 Gy to the whole abdomen with an additional 20.4 Gy to the lower abdomen and pelvis) or six
additional cycles of chemotherapy. The outcome for patients in this subgroup was not correlated with the type of
consolidation treatment. Another group of 98 patients who had a pathologic complete response after initial therapy was
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then randomly assigned to receive additional chemotherapy, radiation therapy, or no further treatment. These patients
had a significantly better progression-free survival rate if they had whole abdominal radiation (56%) than if they had
chemotherapy (36%) or no additional treatment (33%) (P = .03). At 5 years, the overall survival rates were 69%, 57%, and
65% for the radiation, chemotherapy, and control arms, respectively (P = .08). Severe late intestinal complications
occurred in 10% and 4% of patients treated with radiation and chemotherapy, respectively. This trial is the first to
demonstrate a
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benefit from consolidation with radiation therapy. The exclusion of patients who had macroscopic residual disease
probably improved the chance of demonstrating a benefit from radiation therapy and may explain the difference between
the results of this trial and the results of that reported by Lambert et al.137 However, the number of patients in this trial
was small, and the overall survival comparison, although encouraging, did not achieve statistical significance. It can also
be argued that more intensive initial chemotherapy (e.g., six cycles of carboplatin and paclitaxel) might have improved
the relapse-free survival in the control arm, diminishing the advantage of radiation therapy. Clearly there is room to
improve the outcome of this group of patients; although the results of the trial by Sorbe et al.138 may not be definitive,
they do suggest the need for further study of the question.
Although most research emphasis has been on the use of whole abdominal irradiation, several authors have reported cases
of long-term disease-free survival in patients who have received radiation treatment to smaller fields for locally relapsed
or persistent disease.139,140 Although these experiences are anecdotal, they do suggest that local field radiation therapy
may be of benefit to some patients.
TREATMENT OF RECURRENT OVARIAN CANCER

The selection of treatment modalities and drug regimens for patients with recurrent ovarian cancer is based on the initial
chemotherapy regimen used and on the nature of the initial response to treatment. Patients with recurrent ovarian cancer
can be broadly divided into two subsets with markedly different prognoses. Patients whose disease recurs after a disease-
free interval of less than 6 months have a worse prognosis that approaches that of patients who progress while on their
initial chemotherapeutic regimen. In contrast, patients who have a disease-free interval of longer than 6 months or 1 year
have a markedly improved prognosis, primarily because of the increased efficacy of salvage chemotherapy. Among
patients with a long disease-free interval, secondary cytoreductive surgery can be considered in select subsets of patients.
Secondary Cytoreductive Surgery

Primary cytoreductive surgery has well-documented benefits in the management of advanced ovarian cancer. The
possibility that secondary cytoreductive surgery (i.e., surgery performed to remove known persistent or recurrent disease
after initiation chemotherapy) may be beneficial to patients has been suggested by numerous authors.141,142,143 Most of
these reports show that a statistically significant survival advantage can be gained for patients in whom an optimal
secondary surgical result is achieved. Predictive factors for achieving an optimal secondary debulking include a longer
disease-free interval (more than 12 months), focal tumor distribution (one or two sites), and initial optimal
cytoreduction.141
Berek et al.142 reported that secondary cytoreductive surgery could be performed in 12 of 32 patients (38%), and their
tumors were reduced to less than 1.5 cm of residual disease. The median survival for that group was 20 months, compared
to 5 months for the 20 patients whose disease could not be optimally cytoreduced. The patients most likely to undergo
optimal cytoreductive surgery were those who previously had optimal primary cytoreduction, less than 1000 mL of ascites,
and a tumor size of less than 5 cm at the second operation. The interval from the primary to secondary surgery should be
longer than 12 months. Factors that did not have an impact on secondary cytoreductive surgery included patient age,
tumor grade, type of chemotherapy, and the presence or absence of bowel obstruction. Subsequently, Segna et al.143
reported their experience with secondary cytoreductive surgery. They too were able to show that, if optimal secondary
cytoreductive surgery could be performed, patients lived longer before succumbing to ovarian cancer. Factors that
influenced successful efforts in cytoreductive surgery were a time interval of more than 1 year between the original
operation and the secondary cytoreductive surgery and performance of optimal cytoreductive surgery at the initial
operation.
In 1995, Vaccarello et al. reported on 57 patients with recurrent ovarian cancer.144 This population experienced relapse a
median of 33 months after documented complete surgical response to primary cytoreduction and platinum-based therapy
(negative second-look laparotomy). Thirty-eight patients (67%) underwent laparotomy at the time of recurrence, of whom
36 had bulky disease (larger than 0.5 cm) before resection. Of the 23 patients in whom debulking surgery was undertaken,
14 (61%) completed surgery with optimal residual disease (smaller than 0.5 cm). The median survival for patients
undergoing optimal debulking was significantly better (41 months; P <.0001) than that for patients undergoing suboptimal
debulking (23 months) or those not undergoing exploration (9 months). In multivariate analysis, the only factor that was
found significantly to affect survival was tumor debulking to less than 0.5 cm. The authors concluded that secondary
cytoreductive surgery benefits those patients who had a good response to primary surgery and chemotherapy followed by
a substantial disease-free interval after negative second-look laparotomy, because these qualities would predict a good
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response to second-line therapy.
The ideal methodology for assessing the value of secondary debulking for patients with recurrent ovarian cancer would be
a prospective trial comparing results for patients randomly assigned to surgical and nonsurgical arms followed by
equivalent salvage chemotherapy. Thus far, such a protocol has not been undertaken. However, a prospective trial
reported by Eisenkop et al. further supports surgical debulking of recurrent disease.145 Secondary cytoreduction was
prospectively performed on 36 patients who had a minimum disease-free interval of 6 months before relapse of ovarian
cancer. The mean disease-free interval was 22 months (range, 6 to 43 months). All patients had undergone a primary
surgical effort and received platinum-based chemotherapy. At the time of secondary surgery, all 36 patients had recurrent
disease measuring more than 1 cm (greatest dimension of largest tumor nodule), with 64% having disease larger than 6
cm. Using an aggressive surgical approach, these authors were able to remove all macroscopic disease in 30 patients
(83%); however, 14 patients required a modified posterior exenteration to achieve an optimal (microscopic residual only)
resection. Morbidity occurred in 30.1% of patients, and there was one postoperative mortality (2.8%). Although a control
population of patients with recurrent ovarian cancer not undergoing surgery was not available for comparison, survival
analysis demonstrated a dramatic advantage for patients undergoing optimal resection compared to those left with
macroscopic tumor. Median survivals for these two groups were 43 and 5 months, respectively (P = .01). Multivariate
analysis revealed that, in addition to the amount of disease after secondary cytoreductive surgery, patient performance
status and a longer disease-free interval (more than 36 months) were also independently predictive of improved survival.
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The majority of these published reports show a statistically significant survival benefit for patients undergoing optimal
debulking of recurrent ovarian cancer. Data indicate that the magnitude of this benefit is inversely proportional to the
volume of “optimal” residual disease and directly related to the duration of complete clinical remission (Table 32.4-11).
TABLE 32.4-11. Survival after Secondary Cytoreduction for Ovarian Cancer
Study Median No. of Residual Survival Measure P

DFI (Mo) Patients Disease (Mo) Value
Eisenkop et 22 30 Microscopic 43 Median <.01

al., 1995145
6 Macroscopic 5 Median
Vacarello et 20 14 <0.5 cm >41a Median <.0001

al., 1995144
24 >0.5 cm 23
Segna et al., Not 61 <2 cm 27.1 Median .0001

1993143 stated
39 >2 cm 9
Janicke et al., 16 14 Microscopic 29 Median .004

1992146
12 >2 cm 9
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4 <2 cm 3
DFI, disease-free interval before recurrence.
aMedian survival not reached (75% probability of surviving 41 mo).
Interval Cytoreduction after Neoadjuvant Chemotherapy

Neijt et al.147 compared the survival of women who underwent optimal cytoreductive surgery with the survival of women
who had an unsuccessful optimal cytoreductive procedure but in whom, generally after three cycles of cisplatin-based
chemotherapy, a secondary cytoreductive surgery was attempted. Those patients who underwent optimal secondary
cytoreductive surgery had a statistically better survival rate than those who were unable to undergo optimal secondary
cytoreductive surgery. However, those patients who underwent optimal secondary cytoreduction did not have a survival
rate comparable to that of patients who had optimal cytoreduction performed at the initial operation (Fig. 32.4-8).
FIGURE 32.4-8. Survival after cytoreductive surgery leading to tumor residuals of 1 cm or smaller at the staging
laparotomy or during chemotherapy (intervention cytoreductive surgery). (From 147, with permission.)
Van der Burg et al.93 reported on the experience of the European Organization for Research and Treatment of Cancer
with debulking surgery after induction chemotherapy for advanced ovarian cancer. Three hundred and nineteen of 425
patients with advanced epithelial ovarian cancer who had more than 1 cm in diameter of residual tumor after primary
surgery received three cycles of cyclophosphamide and cisplatin and were randomly assigned to undergo secondary
cytoreductive surgery or no surgery. Both groups received additional chemotherapy. The progression-free and overall
survival rates were both significantly higher in the group that underwent surgery (P = .01) (Fig. 32.4-9). The difference in
survival was 6 months. At 2 years after initial diagnosis, 56% of those who underwent surgery were alive, as opposed to
46% of those who did not. In an update, the 5-year survival rate was found to be 23% for the surgery group and 12% for the
nonsurgery group.148 A multivariate analysis determined that debulking surgery was an independent prognostic factor for
survival (P = .012). After adjustment for all other prognostic factors, the risk of dying was reduced by 33% (95% CI, 10% to
50%; P = .008). This study statistically confirmed improved survival with optimal secondary cytoreductive surgery.
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However, secondary cytoreductive surgery does not make up for inadequate cytoreductive surgery performed at the initial
operation.
FIGURE 32.4-9. Survival of patients with advanced epithelial ovarian cancer who did not have debulking surgery
and of patients who had such surgery, according to whether the lesions were smaller than 1 cm in diameter before
cytoreduction, smaller than 1 cm after cytoreduction (optimal), or larger than 1 cm after cytoreduction
(suboptimal). (From 93, with permission.)
Palliative Surgery
Palliative surgery may be necessary in women with advanced ovarian cancer. This surgery may involve a colostomy for
relief of a
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large bowel obstruction, lyses of adhesions, and surgical management of small bowel obstruction. Small bowel obstruction
is a common complication as ovarian cancer advances and becomes refractory to chemotherapy. In considering surgery to
relieve small bowel obstruction, the time from the original diagnosis and treatment of the ovarian cancer to the time of
the obstruction is important, as is the adequacy of the initial cytoreductive surgery. Women who present with small bowel
obstruction during the initial course of chemotherapy and who have not undergone optimal cytoreductive surgery
generally have biologically aggressive tumors in the treatment of which the role of surgery of the small bowel is minimal.
A palliative gastrostomy tube may be most appropriate in this situation, and frequently this can be inserted endoscopically
or under radiographic (CT) guidance. In contrast, women who have had prolonged periods of freedom from disease,
usually lasting more than 1 year from the original diagnosis, do benefit from small bowel surgery to relieve obstruction.
However, a pseudo–small bowel obstruction pattern can be seen in women with advanced ovarian cancer with
intraabdominal carcinomatosis, which occurs when ovarian cancer cells infiltrate the myenteric plexus of the small bowel.
Surgery generally plays no role in management of these patients. Medical treatment with metoclopramide, which
improves motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions, may at
times be helpful. Large bowel obstruction, particularly sigmoid colon obstruction, is relieved by performing a colostomy
and can provide significant prolongation of life and improved quality of life if the disease is confined to the pelvis.
Chemotherapy for Recurrent Disease

Patients with ovarian cancer who had a response to chemotherapy and then experienced relapse after a platinum-free
interval of more than 6 months are considered platinum sensitive, with the likelihood of achieving a secondary response
increasing as the duration of the platinum-free interval lengthens.149 Single-agent carboplatin has a more favorable
toxicity profile than cisplatin and remains the preferred platinum compound for treatment of recurrent disease. The
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probability of response to second-line chemotherapy is related to other clinical factors, in addition to the platinum-free
interval. Eisenhauer et al.150 identified three factors as independent predictors of response in a multivariate analysis of
data for 704 patients who received prior treatment with platinum-based chemotherapy: serous histology, number of
disease sites, and tumor size.
Retreatment with carboplatin-paclitaxel combination chemotherapy also has been shown to favorably impact survival in
patients with recurrent ovarian cancer.151 However, it is possible that the same long-term survival rates could have been
achieved by use of these drugs in sequence.
For patients who do not respond to platinum- or paclitaxel-based retreatment or who developed resistance to these drugs
when they are used as second-line agents, numerous other agents have been shown to have activity. However, response
rates are significantly lower in patients who have platinum- or paclitaxel-resistant ovarian cancer, and these patients
should be encouraged to enter experimental clinical trials. Drugs that have been shown to be active in patients with
platinum- and paclitaxel-resistant ovarian cancer include topotecan,152 oral etoposide,153 gemcitabine,154 liposomal
doxorubicin,155 vinorelbine,156 and altretamine.149
Hormonal therapy has long been used in the treatment of patients with refractory ovarian cancer.157 The overall response
rate of progestational agents and antiestrogens has been 10% to 15%. Hormonal therapy continues to be a viable
therapeutic option for patients who cannot tolerate or have experienced unsuccessful treatment with numerous cytotoxic
regimens. Tamoxifen also has been recommended as the initial salvage therapy for patients who have a rising CA 125 level
as the only manifestation of their disease. Although a rising CA 125 level in a patient in clinical complete remission is
highly predictive of a symptomatic recurrence (median time to physical or radiographic evidence of recurrent disease is 4
to 6 months), there is no evidence that immediate treatment with salvage chemotherapy is more effective than reserving
such treatment for the time when other manifestations of recurrent disease appear. A trial is ongoing in Europe in which
patients with elevated marker levels are randomly assigned to receive immediate systemic therapy or treatment at the
time of symptomatic progression.
Radiation Therapy for Recurrent Disease

Although rarely curative, radiation therapy can play an important role in palliation for patients with incurable ovarian
cancer. Symptoms from a growing pelvic mass frequently dominate the final months of life for patients with terminal
ovarian cancer, causing pain, bleeding, and rectal narrowing. Palliative pelvic radiotherapy can provide rapid relief and,
in some cases, may prevent or delay the need for diverting colostomy.
Palliative treatment courses are designed to be convenient and to achieve rapid symptom relief. At the M. D. Anderson
Cancer Center, palliation of pelvic disease has been achieved using two single-fraction treatments of 10 Gy each to the
true pelvis delivered 1 month apart.161 Treatment is delivered using 18- to 25-MeV photons. In a report of 42 patients
who had advanced ovarian cancer and were treated with this approach, Adelson and coworkers158 reported that tumors in
19% of patients partially or completely responded to irradiation after one fraction and 75% responded after two fractions.
Toxicity was minimal if treatment was limited to two fractions (20 Gy). However, they reported major hemorrhagic
complications in four of eight patients who survived more than 6 months after receiving three fractions. The Radiation
Therapy Oncology Group investigated the efficacy of a multiple daily-fraction split-course regimen (14.8 Gy delivered at
3.7 Gy/fraction in 2 days) in patients with advanced pelvic malignancies.159 Treatment was repeated every 2 to 4 weeks
for a total dose of up to 44.4 Gy. A complete or partial tumor response was reported in 34% of patients (42% of those
completing three courses), and toxic effects were acceptable. The interval between fractions had no significant influence
on the response rate.
Other authors have reported relief of pelvic pain, bleeding, large bowel obstruction, pulmonary compromise, bone pain,
and other symptoms of metastatic disease with radiotherapy using a variety of fractionation schemes.139,140 Patients
with isolated cerebral metastases should be treated with combined surgical resection, postoperative whole brain
irradiation, and chemotherapy, if possible.181 With this treatment, some patients survive for more than 3 years. Radiation
therapy alone frequently relieves symptoms from brain metastasis but survival is usually shorter than 6 months.
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Intraperitoneal Chemotherapy
Pharmacokinetic modeling studies, based on knowledge of the anatomy and physiology of the peritoneal cavity and
biologic behavior of ovarian cancer, have suggested that direct intraperitoneal antineoplastic drug delivery is a rationale
management strategy for this malignancy.160 Phase I studies have confirmed the pharmacokinetic advantage and
established the local toxicity profile associated with intraperitoneal drug delivery of a number of agents with known
activity in ovarian cancer (Table 32.4-12).
TABLE 32.4-12. Pharmacokinetic Advantage Associated with Intraperitoneal Administration of
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Selected Cytotoxic Agents
Agent Peak Peritoneal Cavity to Plasma Concentration Ratio
Doxorubicin 474
Mitoxantrone 620
Cisplatin 20
Carboplatin 18
Mitomycin 71
5-Fluorouracil 298
Methotrexate 92
Paclitaxel 1000
Thirty percent to 40% of patients with small volume disease (microscopic cancer or largest residual tumor nodule of less
than 0.5 to 1.0 cm in maximum diameter) after platinum-based primary chemotherapy have been shown to achieve a
surgically defined partial or complete response when treated with cisplatin-based intraperitoneal drug delivery.161 Other
agents examined for their potential clinical usefulness when delivered by the intraperitoneal route as second-line
treatment of ovarian cancer include carboplatin,162 paclitaxel,163 interleukin-2 (IL-2),164 interferon-α,165 and
interferon-γ.166
Unfortunately, there have been no randomized trials examining the second-line treatment of ovarian cancer using the
intraperitoneal route of drug delivery. Thus, it remains unknown if patients treated by this technique experience better
outcomes than with systemic drug administration.
Three randomized trials have now been reported, however, that directly compared intravenous to intraperitoneal cisplatin
as primary therapy for ovarian cancer.167,168,169
Taken together, these data support the clinical usefulness of the intraperitoneal delivery of cisplatin as primary treatment
for small-volume advanced ovarian cancer. However, the toxicity of cisplatin-based therapy, with 24-hour intravenous
infusional paclitaxel, is not insignificant. A trial examining intraperitoneal administration of carboplatin with 3-hour
intravenous administration of paclitaxel, compared to systemic administration of both agents, will be conducted by the
GOG in the near future. It is hoped that this study will be able to provide a definitive answer to the question of whether
regional drug delivery has a role in the primary chemotherapeutic management of advanced ovarian cancer.
EXPERIMENTAL THERAPIES
High-Dose Chemotherapy with Hematologic Support

Standard-dose chemotherapy produces response rates in more than 70% of patients with advanced ovarian cancer.
However, most patients develop disease recurrence, at which point salvage therapy has limited curative potential.
Because of the high response rate to standard-dose chemotherapy and because of retrospective studies identifying a
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relationship between dose intensity and response, numerous clinical studies have evaluated the use of high-dose
chemotherapy with hematologic support.170,171,172 To date, no role has yet been established for high-dose
chemotherapy with hematologic support in the routine treatment of patients with advanced ovarian cancer. However, this
remains an area of active clinical investigation.
New Drug Combinations

With the large number of active compounds available for treatment of recurrent disease, numerous new potential
combinations and sequences are reasonable to evaluate. Currently, preclinical models have not been shown to be
predictive in identifying the clinical activity of new combinations. Empirical phase I and phase II trials have been
conducted and have been followed by prospective randomized comparisons of three-drug combinations and sequential
therapy to determine if there is any clinical benefit to the combination of paclitaxel and carboplatin compared with
standard treatment. The results of these trials are eagerly awaited.
Novel Drug Strategies in Treatment of Ovarian Cancer

A number of trials examining the use of highly novel biologic agents in the management of ovarian cancer have been
initiated over the past few years. Ongoing trials include evaluation of monoclonal antibodies, epidermal growth factor
receptor inhibitors (e.g., Iressa, C-225), immunomodulators, antiangiogenesis agents, and the addition of interferon-γ to a
carboplatin-paclitaxel regimen as primary treatment of ovarian cancer.
It is important that biologic agents with potential activity against ovarian cancer be specifically evaluated in this setting
before any conclusion is drawn regarding possible efficacy. For example, although the important clinical activity of
trastuzumab in breast cancer has clearly been documented,173 when this agent was tested in ovarian cancer an objective
response rate of only 7% was observed.174 Furthermore, only 11% of patients with ovarian cancer who were screened for
overexpression of HER2 (2+ or 3+ by immunohistochemistry) were found even to be candidates to receive the agent.
Both systemic175 and intraperitoneal176 administration of IL-12 has been examined in women with advanced ovarian
cancer. Although minimal objective activity was observed, a substantial percentage of patients achieved apparent
stabilization of the disease process. This observation is consistent with proposed antiangiogenesis properties of IL-12.
OvaRex (MAb B43.13), a monoclonal antibody against CA 125, has been explored for its potential clinical activity in several
trials.177,178 It has been suggested that the antibody will bind to circulating CA 125 to form a complex that then elicits
an immune response against CA 125–containing ovarian cancer cells.179 It is hoped that ongoing studies will define a
possible role for this antibody in the management of ovarian cancer.
TLK-286, a prodrug activated in vivo to become an alkylating agent, has been shown to be active (15% objective response
rate) in platinum-resistant ovarian cancer.180 The dose-limiting toxicity is bone marrow suppression. The efficacy of this
drug, in comparison to standard second-line treatment of ovarian cancer, is currently being evaluated in a phase III
randomized trial.
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Immunotherapy and Gene Therapy in Ovarian Cancer

Genetic alterations in oncogene and suppressor gene function and the immunobiology of ovarian cancer are reviewed
elsewhere in this text. Abnormalities in the function of suppressor genes, particularly TP53, are common in ovarian
cancer. Cisplatin sensitivity is associated with TP53 function, with loss of function usually resulting in resistance. Loss of
TP53 function may inhibit the drug-induced pathways of apoptosis. In experimental models of gene therapy, sensitivity to
cisplatin can be restored in resistant cell lines by reintroduction of p53 into tumor cells.181
An additional potential gene therapy in ovarian cancer relates to molecular chemotherapy in which a gene product can
selectively sensitize tumor cells to an agent that is not ordinarily toxic. Adenovirus-mediated delivery of herpes simplex
virus thymidine kinase has been shown to selectively synthesize human ovarian cancer cells to ganciclovir, and clinical
evaluation of this combination is planned.
Immunotherapy for ovarian cancer has evolved from the administration of nonspecific immunostimulants such as
Corynebacterium parvum to more specific therapies targeting antigens and surface receptors present on tumor cells. The
use of IL-2, either as a single agent administered intraperitoneally or as part of adoptive immunotherapy together with
lymphokine-activated killer cells, has been studied extensively in ovarian cancer patients. In initial studies with IL-2 and
lymphokine-activated killer cells, peritoneal toxicity was unacceptable. Subsequent trials with lower doses of IL-2
produced acceptable toxicity, and the preliminary report described apparent durable responses in selected patients with
recurrent ovarian cancer treated with intraperitoneal IL-2.
Antibody conjugates (either with antineoplastic drug, biologic toxin, or radioisotope) also have been evaluated in early
trials in ovarian cancer patients. Prolonged survival was observed in a pilot study in which patients with small volume
residual disease were treated with iodine 131–labeled monoclonal antibody directed against an ovarian cancer
41 of 42 10/01/18, 00:57
phosphatase,182 and a larger confirmatory trial of this conjugate is currently nearing completion.
42 of 42 10/01/18, 00:57

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Ovid: Cancer: Principles & Practice of Oncology http://ovidsp.tx.ovid.com/sp-3.27.2b/ovidweb.

Editors: DeVita, Vincent T.; Hellman, Samuel; Rosenberg, Steven A.

HISTOLOGIC CLASSIFICATION OF EPITHELIAL TUMORS

TABLE 32.4-1. World Health Organization Classification of Malignant Ovarian Tumors

COMMON EPITHELIAL TUMORS

Malignant serous tumor

Adenocarcinoma, papillary adenocarcinoma, papillary cystadenocarcinoma

Surface papillary carcinoma

Malignant adenofibroma, cystadenofibroma

Malignant mucinous tumor

Malignant adenofibroma, cystadenofibroma

Malignant endometrioid tumor

Malignant adenofibroma, cystadenofibroma

Endometrioid stromal sarcoma

Mesodermal (müllerian) mixed tumor: homologous and heterologous

Clear cell (mesonephroid) tumor, malignant

Carcinoma and adenocarcinoma

Brenner tumor, malignant

Mixed epithelial tumor, malignant

SEX CORD–STROMAL TUMORS

Granulosa–stromal cell tumor

Granulosa cell tumor

Tumor in the thecoma-fibroma group

Androblastoma: Sertoli-Leydig Cell Tumor

Tubular androblastoma, Sertoli cell tumor (tubular adenoma of Pick)

Sertoli-Leydig cell tumor (tubular adenoma with Leydig cells)

Leydig cell tumor, hilus cell tumor

Poorly differentiated (sarcomatoid)

With heterologous elements

Germ cell tumor

Endodermal sinus tumor

LIPID (LIPOID) CELL TUMORS

Mature dermoid cyst with malignant transformation

Monodermal and highly specialized

Struma ovarii and carcinoid

Mixed with dysgerminoma or other form of germ cell tumor

DIAGNOSIS AND SYMPTOMS

SCREENING AND EARLY DETECTION

HEREDITARY OVARIAN CARCINOMA

Screening Monthly self- Semiannual/annual Pelvic examination, Colonoscopy

pelvic and/or endometrial (beginning age

Chemoprevention Consider Consider OCP Consider OCP —

Prophylactic Counsel regarding Offer PBSO Counsel regarding Counsel

I Growth limited to the ovaries.

IA Growth limited to one ovary; no ascites. No tumor on the

IB Growth limited to both ovaries; no ascites. No tumor on the

ICa Tumor either stage IA or IB but with tumor on the surface of

II Growth involving one or both ovaries with pelvic extension.

IIA Extension and/or metastases to the uterus and/or tubes.

IIB Growth involving one or both ovaries with pelvic extension.

III Tumor involving one or both ovaries with peritoneal implants

outside the pelvis and/or positive retroperitoneal or

IIIB Tumor of one or both ovaries with histologically confirmed

IIIC Abdominal implants greater than 2 cm in diameter and/or

IV Growth involving one or both ovaries with distant metastasis.

Clinicopathologic findings determined to be clinically useful include the following:

Factors associated with tumor dissemination

Malignant ascites or malignant peritoneal washings

Tumor excrescences on ovarian surface or ruptured capsule

Volume of residual disease after cytoreductive surgery

TABLE 32.4-4. Experimental Prognostic Factors in Ovarian Cancer

DNA PLOIDY AND S-PHASE FRACTION

DRUG RESISTANCE MARKERS

BRCA1 and BRCA2

Ovid: Cancer: Principles & Practice of Oncology

Ovid: Cancer: Principles & Practice of Oncology