Patofisiologi

Most theories of the pathophysiology of ovarian cancer include the concept that it begins with

the dedifferentiation of the cells overlying the ovary. During ovulation, these cells can be

incorporated into the ovary, where they then proliferate. Ovarian cancer typically spreads to the

peritoneal surfaces and omentum.

Ovarian carcinoma can spread by local extension, lymphatic invasion, intraperitoneal

implantation, hematogenous dissemination, and transdiaphragmatic passage. Intraperitoneal

dissemination is the most common and recognized characteristic of ovarian cancer. Malignant

cells can implant anywhere in the peritoneal cavity but are more likely to implant in sites of

stasis along the peritoneal fluid circulation. As discussed later, these mechanisms of

dissemination represent the rationale to conduct surgical staging, debulking surgery, and

intraperitoneal administration of chemotherapy. In contrast, hematogenous spread is clinically

unusual early on in the disease process, although it is not infrequent in patients with advanced

disease.

Epithelial ovarian cancer

Epithelial tumors represent the most common histology (90%) of ovarian tumors. Other

histologies include the following:

Sex-cord stromal tumors

Germ cell tumors

Primary peritoneal carcinoma

Metastatic tumors of the ovary

Epithelial ovarian cancer is thought to arise from epithelium covering the ovaries, which is

derived from the coelomic epithelium in fetal development. This coelomic epithelium is also

involved in formation of the Müllerian ducts, from which the Fallopian tubes, uterus, cervix, and

upper vagina develop.

Five main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the

cervix, uterus, and fallopian tube, as follows:

Serous (from fallopian tube)

Endometrioid (endometrium)

Mucinous (cervix)

Clear cell (mesonephros)

Brenner

Some variation is observed in the patterns of spread and disease distribution within the various

histologic subtypes.

Epithelial tumors are found as partially cystic lesions with solid components. The surface may be

smooth or covered in papillary projections (see the image below), and the cysts contain fluid

ranging from straw-colored to opaque brown or hemorrhagic.

An enlarged ovary with a papillary serous carcinoma on the

surface.

Epithelial ovarian cancer most often spreads initially within the peritoneal cavity (see the images

below). Metastatic disease often is found on the peritoneal surfaces, particularly on the

undersurface of the diaphragms, the paracolic gutters, the bladder, and the cul-de-sac. Other

common sites are the surface of the liver, the mesentery and serosa of the large and small bowel,

in the omentum, the uterus, and para-aortic and pelvic lymph nodes.

Laparotomy on a patient with intermittent small bowel

obstruction. A loop of small bowel (bottom of frame) is adherent to a poorly differentiated

primary epithelial ovarian carcinoma (left of frame) that has spread to involve the pelvic

sidewall, the bladder peritoneum, the serosa of the uterus, and the fallopian tube.

Metastases from epithelial ovarian carcinoma involving the omentum.

Outside the peritoneal cavity, epithelial ovarian cancer may spread to the pleural cavity, lungs,

and groin lymph nodes. Presence of pleural effusion does not necessarily indicate disease in the

chest, and malignancy can be diagnosed only cytologically. Mucinous tumors tend to form large

dominant masses, while papillary serous tumors have a more diffuse distribution and are more

commonly bilateral. Endometrioid and clear-cell variants more commonly exhibit local invasion,

retroperitoneal disease, and hepatic metastases.

Li et al suggested a tubal origin of ovarian-serous cancers rather than through Müllerian

metaplasia from ovarian surface epithelium.

Etiology

The precise cause of ovarian cancer is unknown, but several risk and contributing factors have

been identified.

Hippisley-Cox and Coupland developed an algorithm to determine risk of breast cancer in

women with and without symptoms.[2] , In their cohort study, 10% of women with the highest-

predicted risk had 63% of all ovarian cancers diagnosed over the next 2 years.

Reproductive factors

Parity is an important risk factor. The risk of epithelial ovarian cancer is increased in women

who have not had children and possibly those with early menarche or late menopause. Women

who have been pregnant have a 50% decreased risk for developing ovarian cancer compared

with nulliparous women. Multiple pregnancies offer an increasingly protective effect. Oral

contraceptive use decreases the risk of ovarian cancer.

These factors support the idea that risk for ovarian cancer is related to ovulation. Two theories

regarding this relationship have been proposed. The incessant ovulation theory suggests that

repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair

results in genetic alterations within the surface epithelium. The gonadotropin theory proposes

that persistent stimulation of the ovaries by gonadotropins, coupled with local effects of

endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity.

Thus, the probability of ovarian cancer may be related to the number of ovulatory cycles, and

conditions that suppress the ovulatory cycle may play a protective role. Ovulation suppression

has been shown to decrease cancer incidence. Although treatment with agents that induce

ovulation in women with infertility has been suggested to increase the incidence of epithelial

ovarian cancer, this is unproven.

Genetic factors

Family history plays an important role in the risk of developing ovarian cancer. The lifetime risk

for developing ovarian cancer is 1.6% in the general population. This compares with a 4-5% risk

when 1 first-degree family member is affected, rising to 7% when 2 relatives are affected. From

5-10% of cases of ovarian cancer occur in an individual with a family history of the disease.

Only a small percentage of these patients have an inherited genetic abnormality, and the risk of

this occurrence increases with the strength of the family history. Hereditary epithelial ovarian

cancer occurs at a younger age (approximately 10 years younger) than nonhereditary epithelial

ovarian cancer, but the prognosis may be somewhat better.

Integrated genomic analyses by the Cancer Genome Atlas Research Network have revealed high-

grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors. The

findings also include the low prevalence but statistically recurrent somatic mutations in 9 further

genes, including NF1, BRCA1, BRCA2, RB1, and CDK12, along with 113 significant focal DNA

copy number aberrations and promoter methylation events involving 168 genes. Pathway

analyses revealed defective homologous recombination in about half of all tumors, and that

NOTCH and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.[3]

At least 2 syndromes of hereditary ovarian cancer are clearly identified, involving either (1)

disorders of the genes associated with breast cancer, BRCA1 and BRCA2, or (2) more rarely,

genes within the Lynch II syndrome complex. Breast/ovarian cancer syndrome is associated with

early onset of breast or ovarian cancer. Inheritance follows an autosomal dominant transmission.

It can be inherited from either parent. Most cases are related to the BRCA1 gene mutation.

BRCA1 is a tumor suppressor gene that inhibits cell growth when functioning properly; the

inheritance of mutant alleles of BRCA1 leads to a considerable increase in risk for developing

ovarian cancer.

Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some

populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi

Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal

epithelial ovarian cancer, the likelihood of a female relative having an affected BRCA1 or

BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in

relatives postmenopausally.

Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast

cancer and a 15-45% risk of developing epithelial ovarian cancer. Those with a BRCA2 gene

mutation have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of

developing epithelial ovarian cancer. Families with BRCA2 mutations are at risk for developing

cancer of the prostate, larynx, pancreas, and male breast.

Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of

breast and ovarian cancers; however, in an investigation of a common genetic variation at the

9p22.2 locus, a decreased risk of ovarian cancer was noted in carriers of a BRCA1 or BRCA2

mutation.[4]

Families with Lynch II syndrome or hereditary nonpolyposis colorectal cancer are characterized

by a high risk for developing colorectal, endometrial, stomach, small bowel, breast, pancreas,

and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes.

Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

Women with a history of breast cancer have an increased risk of epithelial ovarian cancer.

In a study by Rafner et al, whole-genome sequencing identified a rare mutation in BRIP1, which

behaves like a classical tumor suppressor gene in ovarian cancer.[5] This allele was also

associated with breast cancer.

Previous hormone therapy

A nationwide prospective cohort study over 10 years that included all Danish women aged 50-79

years concluded that risk for ovarian cancer is increased with hormone therapy, regardless of

duration of use, formulation, estrogen dose, regimen, progestin type, and administration route.[6]

Nearly 1 million women without hormone-sensitive cancer or bilateral oophorectomy were

followed. In an average of 8 years of follow-up, 3068 ovarian cancers were detected, of which

2681 were epithelial cancers.

Current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 (95%

confidence interval [CI], 11.26-1.51) compared with women who never took hormone therapy.

Risk declined as years since last hormone use increased. Incidence rates in current and never

users of hormones were 0.52 and 0.40 per 1000 years, respectively. This translates to

approximately 1 extra ovarian cancer for approximately 8300 women taking hormone therapy

each year.

Other factors

Lactose consumption and the use of talcum powder on the vulva and perineum may be

associated with increased risk of epithelial ovarian cancer.

Diagnostic Considerations

The normal functioning ovary produces a follicular cyst 6-7 times each year. In most cases, these functional masses are self-limiting and resolve within the duration of a normal menstrual cycle. In rare situations, they persist longer or become enlarged. At this point, they represent a pathological condition.

Evaluation of adnexal masses

Adnexal masses present a diagnostic dilemma; the differential diagnosis is extensive, with most masses representing benign processes.[18, 19, 20] However, without histopathologic tissue diagnosis, a definitive diagnosis is generally precluded. Physicians must evaluate the likelihood of a pathologic process using clinical and radiologic information and balance the risk of surgical intervention for a benign versus malignant process.

Since ovaries produce physiologic cysts in menstruating women, the likelihood of a benign process is higher. In contrast, the presence of an adnexal mass in prepubertal girls and postmenopausal women heightens the risk of a pathologic etiology.

For more information, see Adnexal Tumors.

Differentials

Malignant gastric tumors Adnexal Tumors Anovulation Appendiceal tumors Appendicitis, Acute Ascites Benign lesions of the uterine corpus Bladder distention/urinary retention Borderline Ovarian Cancer Bowel/omental adhesions Cervicitis Colon cancer Colon Cancer, Adenocarcinoma Colonic Obstruction Ectopic Pregnancy Embryologic remnants Endometriosis Fecal impaction Gastric adenocarcinoma Gastric Cancer Hydrosalpinx/pyosalpinx Irritable Bowel Syndrome Low-lying cecum

Metastatic gastrointestinal carcinoma Ovarian Cysts Ovarian torsion Pancreatic Cancer Pelvic abscess Pelvic Inflammatory Disease Pelvic kidney Peritoneal Cancer Peritoneal cyst Rectal Cancer Retroperitoneal mass Urachal cyst Urinary Tract Obstruction Uterine anomalies Uterine Cancer Uterine fibroids Uterine Leiomyoma (Fibroid) Imaging

History

Assessment of women for their risk of ovarian cancer necessitates obtaining a careful family history of both male and female relatives, including those relatives without cancer. (See Etiology) If possible, obtain verification of the histologic diagnoses. The counsel of a trained geneticist is ideal. Significant problems are involved in the counseling of women and their families with regard to genetic testing and its implications. Carriers of mutations may be detected through laboratory analysis of the genetic structure of white blood cells.

Epithelial ovarian cancer presents with a wide variety of vague and nonspecific symptoms, including bloating, abdominal distension or discomfort, pressure effects on the bladder and rectum, constipation, vaginal bleeding, indigestion and acid reflux, shortness of breath, tiredness, weight loss, and early satiety. The patient may feel an abdominal mass.

A case-control study showed that symptoms independently associated with the presence of ovarian cancer were pelvic and abdominal pain, increased abdominal size and bloating and difficulty eating or feeling full.[13] Another study reported that gastrointestinal (GI) symptoms such as nausea and vomiting, constipation, and diarrhea, or other digestive disorders were associated with later-stage disease.[14] Presentation with swelling of a leg due to venous thrombosis is not uncommon. Paraneoplastic syndromes due to tumor-mediated factors lead to various presentations.

A prospective case-control study of 1,709 women visiting primary care clinics found that the combination of bloating, increased abdominal size, and urinary symptoms was found in 43% of those with ovarian cancer but in only 8% of those presenting to primary care clinics.[15]

Physical Examination

Physical findings are uncommon in patients with early disease. Patients with more advanced disease may present with ovarian or pelvic mass, ascites, pleural effusion, or abdominal mass or bowel obstruction.

Approach Considerations

Presence of advanced ovarian cancer is often suspected on clinical grounds but can be confirmed only pathologically by removal of the ovaries or, when disease is advanced, by sampling tissue or ascitic fluid.

Routine imaging is not required in all patients in whom ovarian cancer is highly suggested. If diagnostic uncertainty is present, a pelvic ultrasound or CT scan of the abdomen and pelvis is warranted.[21, 22] Chest radiographs are common and considered routine. CT scan of the chest is seldom indicated.

MRI can increase the specificity of imaging evaluation in cases where the ultrasound appearance of the lesion is indeterminate.[23] MRI is not definitive, however. On MRI, endometriotic cysts with enhanced mural nodules are a hallmark of ovarian cancer, but they may also be a feature of benign neoplasms and even inflammatory diseases. Large contrast-enhanced nodules on large endometriotic cysts in an elderly patient are more likely to indicate malignancy.[24]

When imaging studies demonstrate an adnexal mass, the decision whether to observe the patient with repeat imaging or to proceed to surgical evaluation must take into account not only the imaging characteristics but also the patient's medical history, physical examination results, and cancer antigen 125 (CA125) level.[25] Tumor markers such as CA125 are not good discriminators of benign lesions from malignant lesions in premenopausal women but have better accuracy in postmenopausal women.

In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be indicated, including one of the following:

Upper and/or lower endoscopy Barium enema Upper GI series

Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended. In most cases, this approach may only serve to delay diagnosis and treatment of ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, the patient should undergo a laparotomy for diagnosis and staging. An FNA or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass.

Screening

Ovarian cancer does not lend itself to screening because it has a relatively low prevalence within the general population and no proven precursor lesion exists that can be detected and treated to prevent the cancer from occurring. No approved screening method is available for ovarian cancer.

The U.S. Preventive Services Task Force (USPSTF) recommends against screening for ovarian cancer in the general population. The USPSTF found fair evidence that although screening with serum CA125 level or transvaginal ultrasonography can detect ovarian cancer at an earlier stage, earlier detection is likely to have a small effect, at best, on mortality from ovarian cancer. In addition, because of the low prevalence of ovarian cancer and the invasive nature of diagnostic testing, the USPSTF concluded that the potential harms outweigh the potential benefits.[26] A randomized trial in a US population found that simultaneous screening with ultrasonography and CA125 did not reduce ovarian cancer mortality, and evaluation of false-positive results was associated with complications.[27]

Currently, the National Cancer Institute (NCI) recommends that high-risk women should seek advice from their physician and consider having annual ultrasonographic examination, annual CA125 testing, and be considered for oophorectomy or participation in a clinical trial. The NCI recommends no screening methodology for women at normal risk for epithelial ovarian cancer, but these women should also be considered for research protocols seeking improved detection methods.

Studies are trying to improve the accuracy of screening for early-stage ovarian cancer. Most are targeting perimenopausal or postmenopausal women or those with a family history of epithelial ovarian cancer. Many studies are using a combination of ultrasound, serum CA125 testing, and other tumor markers. Large prospective trials include the United Kingdom Collaborative Trial of Ovarian Cancer Screening, a European trial of ovarian cancer screening, and the National Institutes of Health Prostatic, Lung, Colorectal and Ovarian (NIH-PLCO) cancer study. The primary outcome measure of the latter study is mortality from ovarian and fallopian tube cancer on 10-year follow-up.

Considerable interest has developed in the characterization of computer-analyzed protein patterns in the blood as a way of improving screening for ovarian cancer. Such methods are currently undergoing intensive research and clinical validation, and they may hold hope for the future.

Lachance et al tested a nomogram for estimating the probability of ovarian cancer. The model had a sensitivity of 90% and a specificity of 73%, which may provide a further tool to aid in ensuring referral.[28]

In a study by van Nagell et al, asymptomatic women who underwent annual sonographic screening achieved increased detection of early stage ovarian cancer, with an increase in 5-year disease-specific survival.[29]

Tumor Markers

Tumor markers are glycoproteins that are usually detected by monoclonal antibodies. Each tumor marker has a variable profile of usefulness for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. They are produced by tumor cells in response to cancer or certain benign conditions and indicate biological changes that signal the existence of malignancy. These soluble molecules can usually be detected in elevated quantities in the blood, urine, or body tissues of patients with certain types of cancer.

The levels of tumor marker are not altered in all cancer patients, especially in early stage cancer. The level of some tumor markers can be elevated in patients with noncancerous conditions. Following the development of monoclonal antibodies, many new tumor markers have been discovered during the past 2 decades. Some tumor markers can be used for screening, diagnosis, management, determining response, and recurrence. Some markers show promise as prognostic indicators.

Due to the location of ovarian tumors within the abdominal cavity, making a preoperative pathological diagnosis of cancer is difficult without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA125, in addition to diagnostic imaging, is useful in the diagnosis of ovarian cancer.

CA125 is a glycoprotein antigen detected by using mouse monoclonal antibody OC125 raised from an ovarian cancer cell line. CA125 is not specific for epithelial ovarian cancer and is elevated in other benign and malignant conditions, including menstruation; endometriosis; pelvic inflammation; liver, renal, and lung disease; and cancer of the endometrium, breast, colon, pancreas, lung, stomach, and liver. It is also elevated in 6% of women who do not have epithelial ovarian cancer. Although CA125 is elevated in 83% of women with epithelial ovarian cancer, it is elevated in only 50% of those with stage I disease.

A monoclonal antibody-based immunoassay for CA125 has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA125 in serum has generally reflected persistence of disease at second-look surveillance procedures. However, CA125 levels can return to within normal limits and residual disease can be found at laparoscopy or laparotomy. CA125 is not useful when used alone as a single one-time test for ovarian cancer screening, but it may have increased value when serial measurements are performed over time and if it is incorporated into a risk of ovarian cancer algorithm. CA125 shows promise for distinguishing benign from malignant pelvic masses. Several trials are ongoing to determine the potential of CA125 in combination with other markers to increase earlier detection of occult ovarian cancer.[18]

A study by Hirai et al found that stage IA ovarian cancers with normal CA125 levels are usually smaller, have slightly different histopathologic type distribution, and have less solid components than cancers with elevated CA125 levels.[30]

A study by Buys et al found that among women in the general US population, screening simultaneously with CA125 and transvaginal ultrasonography did not reduce ovarian cancer mortality compared with usual care. Moreover, diagnostic evaluation after a false-positive result was associated with complications.[31]

Besides CA125, other markers have been investigated, including lysophosphatidic acid, tumor-associated glycoprotein 72 (TAG 72), OVX1, and macrophage colony-stimulating factor (M-CSF). Newer experimental markers have been identified through various laboratory techniques. These markers include mesothelin, human epididymis protein 4, kallikrein, and haptoglobin-alpha. A study by No et al found that p-4EBP1 expression was associated with poor prognostic factors and that overexpression may be a prognostic biomarker.[32] Tapia et al report that p-trkA may be a potential new tumor marker and that nerve growth factor may act as a direct angiogenic factor.[33]

A study by Lin et al found that the adjusted hazard ratio for ovarian cancer in women with pelvic inflammatory disorder was 1.92. This suggests that pelvic inflammatory disorder may be a useful marker for ovarian cancer.[34]

No marker is completely specific; therefore, diagnostic immunohistochemistry testing must be used in conjunction with morphologic and clinical findings.

Please go to the main article on Gynecologic Tumor Markers for more information.

Urinalysis

Urinalysis should be obtained to rule out other possible causes of abdominal or pelvic pain, such as urinary tract infections or kidney stone.

Imaging in Ovarian Cancer

Imaging studies used in ovarian cancer include ultrasonography, chest radiography, and magnetic resonance imaging (MRI). Positron emission tomography (PET) scanning does not have an established role in the diagnosis of primary ovarian malignancy.

Ultrasonography is the most useful initial investigation in a patient found to have a pelvic mass. This may define the morphology of the pelvic tumor. In addition, it can determine whether large masses are present in other parts of the abdomen, including in the liver. Chest radiography is useful in helping exclude pulmonary spread of malignant diseases of the ovary. The primary advantage of using MRI in the evaluation of ovarian masses is the ability to employ this modality in the characterization of tissue. The presence of fat, hemorrhage, mucin, fluid, and solid tissue within an ovarian mass can be determined with the aid of MRI. The ability to characterize tissue in this way is most useful in determining whether a mass is definitely benign.

GI Tract Workup

In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be indicated, including one of the following:

Upper and/or lower endoscopy Barium enema Upper GI series

Biopsy

Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended. In most cases, this approach may only serve to delay diagnosis and treatment of ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, the patient should undergo a laparotomy for diagnosis and staging.

FNA or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass.

Mammography

The preoperative workup also should include mammography for women older than 40 years who have not had one in the preceding 6-12 months. This is especially important in women with estrogen-producing tumors because these may increase the risk of breast malignancies.

Additionally, breast cancers can metastasize to the ovaries and are often bilateral. Mammography can help rule out the possibility of a nongynecologic primary neoplasm in the breast.

Tumors of Low Malignant Potential

All histologic subtypes of EOC have serous, mucinous, endometrioid, clear cell, and Brenner LMP variants, with the essential feature being that no invasion occurs. Mucinous and serous types are most common (see Images below). Invasion is difficult to interpret in mucinous tumors, and the requisite microscopic feature is epithelial stratification exceeding 3 cell layers with associated nuclear atypia. Ovarian tumors require very careful pathologic examination, with sufficient numbers of sections taken to ensure adequate assessment. Particular care must be taken with frozen section interpretation of large mucinous tumors at the time of surgery.

This photo shows a large, smooth-surfaced tumor replacing the ovary. This tumor appeared complex upon preoperative ultrasonography. Final histologic studies indicated the

tumor was a mucinous carcinoma of low malignant potential. Inside of

a large, smooth-surfaced tumor replacing the ovary. Final histologic studies indicated the tumor was a mucinous carcinoma of low malignant potential. Note the multiple cysts with thick septa between. This tumor was extensively sectioned and was a mucinous carcinoma of low malignant potential.

Serous LMP tumors usually are unilocular, more often bilateral than mucinous LMP tumors, and filled with clear serous fluid. The external surface normally is smooth, but excrescences on the outside surface and papillary projections on the inside may be observed. Mucinous LMP tumors are multicystic with a smooth outer surface. Both types may be large.

LMP tumors can metastasize throughout the abdominal cavity and elsewhere. Metastases can be differentiated microscopically as those without invasion and those with invasion.

Malignant Germ Cell Tumors

If a malignant GCT is suspected at presentation, blood should be examined for tumor markers, including bHCG, alpha-fetoprotein, and lactate dehydrogenase. In premenarchal girls found to have an adnexal mass, perform karyotyping to determine the status of the sex chromosomes.

Other investigations include chest x-ray for lung metastases and ultrasound to help define the morphology of the pelvic tumor, to help evaluate the kidneys for evidence of ureteric obstruction, and to help detect ascites and the presence of metastases in the liver and retroperitoneum. Preoperative CT scan or MRI may document intra-abdominal disease, including liver or lymph node metastases that are deemed undetectable on ultrasound imaging.

With immature teratomas, tumor markers are not elevated unless the tumor contains elements of other GCTs. The cardinal histologic feature is immature elements, mostly of neural tissue.

Approach Considerations

In women who present with GI carcinomatosis but without an obvious pelvic mass, an extensive

search often fails to identify a primary tumor. These patients can be presumed to have ovarian

carcinoma or primary peritoneal carcinoma and treated with cytoreductive surgery followed by

platinum-based chemotherapy.

Surgery is the initial treatment of choice, provided patients are medically fit. Patients who are not

fit for surgery may be given chemotherapy and considered for surgery later. The aim of surgery

is to confirm the diagnosis, define the extent of disease, and resect all visible tumor. The role of

cytoreduction was demonstrated by Griffiths in 1975 and has been confirmed by many others.

A retrospective analysis from Lin et al found that epidural anaesthesia and analgesia for ovarian

serous adenocarcinoma surgery was associated with reduced mortality during the initial years of

follow-up.[35]

Choosing Appropriate Surgery

Appropriate surgery depends on whether or not disease is visible outside the ovaries. It is

essential that where no disease is visible outside the ovaries, the patient be adequately surgically

staged because the incidence of microscopic metastases is significant. Surgery for patients with

stage IV disease should be individualized, particularly when disease is in the liver and above the

diaphragm. Patients who are in stage IV because of small-volume disease in the liver, abdominal

wall, or lung should undergo cytoreductive surgery if medically fit.

If there is no visible disease outside an ovary, aspirate ascitic fluid for cytology studies. Perform

peritoneal washings for cytology if ascites is not present. Remove the ovary and ovarian tumor

intact. Perform diaphragmatic scraping or biopsy for cytology studies. Obtain peritoneal biopsy

specimens. Perform a subcolic omentectomy. Obtain bilateral para-aortic and pelvic node

samples. Obtain biopsy samples of adhesions or other suspicious areas.

If the patient does not desire future fertility, perform a total abdominal hysterectomy and excise

the opposite ovary. Remove the appendix if mucinous tumor is present.

If macroscopic disease is visible outside of the ovary, all visible tumor should be removed. This

may require extensive surgery, including bowel resection, excision of peritoneal implants, liver

resection, omentectomy, and splenectomy.

The extent of bowel resection should depend on the role this plays in achieving maximal

cytoreduction.

Surgical Staging

The standard care for ovarian cancer includes surgical exploration for primary staging and for

cytoreduction or debulking. If the disease appears to be confined to the pelvis, comprehensive

surgical staging is indicated.

The incision for surgery should be midline abdominal. In young women with early-stage disease,

a transverse incision may be considered. Careful inspection and/or palpation of the abdominal

contents should be performed, including all peritoneal surfaces, the liver, large and small bowel

and mesentery, stomach, appendix, kidneys, spleen, retroperitoneal spaces, and all pelvic

structures.

The staging procedure should include the following:

Peritoneal cytology

Multiple peritoneal biopsies

Omentectomy

Pelvic and para-aortic lymph node sampling.

Cytoreductive Surgery

This should be performed by a gynecologic oncologist at the time of initial laparotomy. The

volume of residual disease at the completion of surgery represents one of the most powerful

prognostic factors. According to the 2011 National Comprehensive Cancer Network (NCCN)

ovarian cancer guidelines, residual disease of less than 1 cm is evidence of optimal

cytoreduction, although the greatest possible effort should be made to remove all obvious

disease. As of this guideline, distal pancreatectomy may be considered in all stages for optimal

surgical cytoreduction.[36]

Patients with advanced ovarian cancer are classified in 3 groups as follows, based on the

postoperative residual tumor:

Good risk - Microscopic disease outside the pelvis (stage IIIa) or macroscopic disease

less than 2 cm outside the pelvis (stage IIIb)

Intermediate risk - Macroscopic disease less than 2 cm outside the pelvis only after

surgery

Poor risk - Macroscopic disease more than 2 cm after surgery or disease outside the

peritoneal cavity

Interval Debulking

Interval debulking can be performed in patients who were not adequately debulked at the time of

initial surgery. It should also be considered in those patients in whom an initial debulking

surgery was not attempted.

Patients receive 3 cycles of postoperative chemotherapy. Approximately 60% of patients are then

able to undergo optimal resection. Surgical treatment is followed by 3 more cycles of

chemotherapy.

A European prospective, randomized, clinical trial demonstrated that this approach improves the

outcome of patients with advanced ovarian cancer.[37] However, this was not confirmed in a study

conducted in the United States.[38] A major difference between both studies was the extent of the

initial debulking procedure. In the US study, initial optimal debulking was attempted in all

patients. A meta-analysis found no conclusive evidence regarding the possible survival benefit of

interval debulking but noted apparent benefit only in patients whose primary surgery was not

performed by gynecologic oncologists or was less extensive.[39]

Laparoscopic Surgery

According to guidelines developed by the American College of Obstetricians and Gynecologists,

laparoscopy may be used for diagnostic purposes in a patient with low risk for ovarian cancer

and to remove cystic masses. The mass must be 10 cm or smaller as viewed by a sonogram, must

have a distinct border and no solid parts, and must not be associated with ascites. The serum

CA125 level must be normal (< 35 U/mL), and the patient must have no family history of

ovarian cancer. If a chance exists that ovarian cancer may be present, surgery is best arranged in

conjunction with a specialist in gynecologic cancer surgery. The patient can then undergo all

necessary surgery for her cancer under a single anesthetic, without delay.

As part of initial treatment of epithelial ovarian cancer, laparoscopic surgery may be performed

for early stage disease when no disease is visible outside of the ovaries. Its use in more advanced

disease, when spread is visible outside the ovaries, is more limited due to the scope of

cytoreductive surgery necessary and the risk of port-site recurrence. Laparoscopy also has a role

in second-look inspection and in the staging of apparently early-stage disease found by chance

during another surgery.

The 2011 NCCN ovarian cancer guidelines state that minimally invasive surgery may be

considered in selected patients with Stage 1 disease. This is particularly true where an incidental

finding of ovarian cancer was made during prophylactic oophorectomy.[36]

Secondary Surgery

An assessment by Park et al found that secondary cytoreductive surgery is safe and effective in

patients with platinum-sensitive recurrent ovarian cancer. The surgery was most beneficial in

patients who had remained disease free for more than 24 months after primary treatment and in

those who achieved optimal cytoreduction.[40]

Chemotherapy Regimens

Only a small percentage of women with epithelial ovarian cancer can be treated with surgery

alone. These include patients with stage IA grade 1 and stage IB grade 1 serous, mucinous,

endometrioid, and Brenner tumors. Clear-cell carcinomas are associated with a significantly

worse prognosis in stage I, and patients with this histologic subtype should be considered for

chemotherapy at all stages.

Patients not treated with chemotherapy should be monitored closely at regular intervals with

clinical examination, serum CA125 estimation, and ultrasonography if an ovary is still present.

Surgery to remove the uterus and residual ovary should be considered when the patient no longer

desires to remain fertile.

The 2011 NCCN ovarian cancer guidelines recommend pelvic examinations at least every 2-3

cycles in women receiving primary chemotherapy.[36]

Higher-risk early-stage disease includes all histologic subtypes with stage IA and stage IB grade

2 and all stage I grade 3. These patients should be treated with front-line chemotherapy with a

taxane/platinum combination for a minimum of 3 courses. They should consider participating in

clinical trials.

All patients with stage II cancer and greater should receive front-line chemotherapy and should

strongly consider participation in clinical trials.

Standard therapy for all patients with advanced disease following surgery is a taxane/platinum

combination, usually carboplatin and either paclitaxel or docetaxel for a minimum of 6 courses;

however, this may be changing soon. Carboplatin given at an area under the curve (AUC) of 6-

7.5 mg/mL/min (using the Calvert formula for calculating total dose of carboplatin: Total dose

(mg) = target AUC x (GFR + 25), where GFR = glomerular filtration rate, taken to be the

creatinine clearance in mL/min and AUC in mg/mL/min.

The normal range of AUC for treatment of ovarian carcinoma varies from 5-8. Patients who have

received extensive prior chemotherapy or radiation should start with an AUC of less than 5.

Paclitaxel and docetaxel are usually dosed at 175 mg/m2 and 60-75 mg/m2 respectively. Cisplatin

at 50-75 mg/m2 can be substituted for carboplatin. Increasing the dose intensity of cisplatin did

not improve progression-free survival or overall survival compared with standard chemotherapy.[41] Docetaxel in combination with carboplatin has been shown to provide equivalent survival

rates with less neurotoxicity but greater neutropenia.

Standard postoperative chemotherapy is combination therapy with platinum and paclitaxel.

Cisplatin and paclitaxel or carboplatin and paclitaxel are accepted alternatives. Randomized

studies have proven that both regimens result in equivalent survival rates. However, because of a

more tolerable toxicity profile, the combination of carboplatin and paclitaxel is preferred. If

patients are treated with cisplatin, paclitaxel should be administered as a 24-hour infusion to

decrease the risk of neurotoxicity. Another alternative is to combine carboplatin with docetaxel.

The combination of paclitaxel and carboplatin is customarily given every 3 weeks (day 1 of a 21-

d cycle). Because the addition of other drugs to this regimen has proved disappointing,

Katsumata et al studied the use of a dose-dense regimen, in which paclitaxel is given on days 1,

8, and 15 and carboplatin is given on day 1.[42] Compared with the conventional regimen, the

dose-dense regimen resulted in longer median progression-free survival (28.0 mo versus 17.2

mo) and higher overall survival at 3 years (72.1% versus 65.1%). Early discontinuation was

more common with the dose-dense regimen, and these patients were more likely to experience

toxicity, especially neutropenia and anemia.

A study by Morgan et al found that first-cycle maximum tolerated dose of intraperitoneal

carboplatin combined with intravenous paclitaxel did not predict the tolerability of the regimen

over multiple cycles. An intraperitoneal dose of carboplatin at area under the curve (AUC) of 6

in combination with paclitaxel can be administered with a high rate of completion over multiple

cycles. Neutropenia is a frequent dose-limiting toxicity; thus, adding hematopoietic growth

factors may permit a high completion rate while maintaining this dose.[43]

Patients receiving adjuvant intraperitoneal chemotherapy are more likely to have recurrences

outside the abdominal cavity, according to a study by Tanner et al.[44]

In a study by Kurtz et al, patients aged 70 years or older experienced more neuropathy and had a

higher incidence in the carboplatin-paclitaxel group.[45] As with all study patients, the therapeutic

index was better among elderly women with platinum-sensitive recurrent ovarian cancer who

received carboplatin-pegylated liposomal doxorubicin than among those who received

carboplatin-paclitaxel.

The 2011 NCCN ovarian cancer guidelines panel recommends the use of dose-dense paclitaxel

as the first-line treatment of stage II, III, or IV epithelial ovarian cancer. However, clinicians

should inform their patients about the high toxicity of this newly added regimen so they can

weigh the benefits and risks of the therapy.[36]

Postoperative chemotherapy is indicated in all patients with ovarian cancer except those who

have surgical-pathologic stage I disease with low-risk characteristics. A meta-analysis suggests

that postoperative platinum-based chemotherapy prolongs both progression-free survival and

overall survival in the majority of patients with early-stage ovarian cancer. However, these

authors also noted strong evidence that optimal surgical staging identifies patients who are at low

risk and have little or nothing to gain from adjuvant chemotherapy.[46]

Many women experience symptoms of ovarian dysfunction (ie, amenorrhea and hot flashes)

during treatment with chemotherapy. The younger the woman at the time of treatment, the more

likely the return of normal ovarian function and the more tolerant the ovaries are to higher doses

of alkylating agents.

An increase in congenital anomalies in babies conceived following treatment with chemotherapy

does not seem to occur. The necessity for chemotherapy during a preexisting pregnancy

fortunately is rare, but antifolate drugs such as methotrexate probably should be avoided during

the first trimester.

Intraperitoneal chemotherapy

Use of chemotherapy agents instilled into the peritoneal cavity has the theoretical advantage that

much higher concentrations can be obtained locally without the risk of adverse systemic effects;

however, the agents are unable to penetrate more than a few millimeters. At least 3 randomized

studies comparing chemotherapy regimens, including the intraperitoneal route with the

intravenous route, have shown a survival advantage for the arms receiving intraperitoneal

chemotherapy.

The most recent Gynecologic Oncology Group protocol #172 published in January 2006 showed

that following optimal cytoreductive surgery women with advanced epithelial ovarian cancer

randomized to receive part of their chemotherapy with cisplatin and paclitaxel intraperitoneally

had a median progression-free interval and median overall survival approximately 5 months and

16 months greater than those women receiving standard intravenous chemotherapy. Thus,

intraperitoneal chemotherapy should be strongly considered for the treatment of front-line

disease following surgery where 5mm or less-residual disease exists and perhaps, for more

advanced cancers.

This route of chemotherapy may cause more side effects for the patient and administration

requires the placement of a subcutaneous tube into the peritoneal cavity (an intraperitoneal port);

this is associated with a number of complications including infection, blockage, retraction out of

the peritoneal cavity, and discomfort. Nevertheless, randomized studies show a survival benefit

and disease-free survival benefit and the National Cancer Institute has suggested that all women

with optimally cytoreduced disease should at least be offered intraperitoneal treatment.

Results from randomized clinical trials suggest that in patients with optimally debulked disease,

intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous

administration.[47] Recent meta-analyses confirm that intraperitoneal administration of

chemotherapy is associated with an improvement in survival.[48, 49] However, this approach is also

associated with more toxicity. The National Cancer Institute released a clinical announcement

supporting the use of intraperitoneal chemotherapy in optimally debulked ovarian cancer.[50]

Jaaback et al found that intraperitoneal chemotherapy increases overall survival and progression-

free survival in advanced ovarian cancer; however, catheter-related complications and toxicity

must be considered in the treatment decision.[51]

Neoadjuvant chemotherapy

This is given to patients with disease that is initially considered inoperable or if the patient is

unfit for surgery at the time of diagnosis. If the patient has a good response to 3 or more cycles

of chemotherapy, interval debulking surgery may be performed followed by further

chemotherapy. Overall, patients treated with this approach likely have an inferior outcome to

patients undergoing initial maximal cytoreductive surgery followed by chemotherapy.

Patients with advanced ovarian cancer who are not candidates for surgical cytoreduction may be

treated initially with 2-3 cycles of conventional chemotherapy and can then be reevaluated for

surgical cytoreduction. However, optimal initial cytoreduction remains the standard of care for

most patients.

A study by Joly et al found that pegylated liposomal doxorubicin with carboplatin instead of

paclitaxel was associated with a low rate of hypersensitivity reaction among patients with

relapsed ovarian cancer.[52] In a separate study by Pignata et al, pegylated liposomal doxorubicin

with carboplatin produced a similar response rate to carboplatin with paclitaxel; the authors

conclude that it could be an alternative to standard therapy.[53]

Neoadjuvant chemotherapy followed by interval surgery provided equivalent outcomes to

standard primary surgery followed by chemotherapy in women with stage III and IV ovarian

cancer.[54]

According to the 2011 NCCN ovarian cancer guidelines, a patient should be evaluated for

neoadjuvant chemotherapy by a fellowship-trained gynecologist oncologist before being

considered a nonsurgical candidate.[36]

Maintenance chemotherapy

Most patients with ovarian cancer achieve a complete clinical response after debulking surgery

and platinum-based chemotherapy. However, 50% experience relapse and ultimately die of the

disease. Therefore, strategies to decrease the risk of recurrence have been investigated. A phase

III randomized trial exploring the impact of 12 monthly cycles of paclitaxel as maintenance

chemotherapy was discontinued by the Data Safety and Monitoring Committee when a

prospectively defined interim analysis revealed a highly statistically significant improvement in

progression-free survival; an ongoing phase III trial is addressing the question of whether this

maintenance strategy has a significant effect on overall survival.[55]

A meta-analysis indicated that continuing chemotherapy improved progression-free survival and

overall survival, especially if complete response was reached after primary therapy.

Second-line chemotherapy

Recurrent ovarian cancer is classified into 2 categories, depending on the length of time the

patient remained disease-free after completing chemotherapy: (1) relapse that occurs more than 6

months after initial chemotherapy is considered platinum-sensitive; (2) earlier relapse is

considered platinum-resistant. Patients with platinum-sensitive disease may exhibit a good

response if rechallenged with a platinum-based regimen.[56, 57] The probability of response

increases with the duration of the disease-free interval.

Results from clinical trials suggest that combination chemotherapy offers an improvement in

response rate, progression-free survival, and overall survival. Several chemotherapy agents elicit

a response in patients whose disease is resistant to platinum-based therapies. These include

liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, docetaxel, and vinorelbine. Other

agents that may be used are ifosfamide, 5-fluorouracil with leucovorin, and altretamine

(Hexalen). Tamoxifen, an oral antiestrogen, exhibits modest activity but has a favorable toxicity

profile.

The addition of gemcitabine to carboplatin plus paclitaxel did not improve overall survival or

progression-free survival; therefore, it is not a good candidate for a third non-cross-resistant drug

in the treatment of advanced ovarian cancer.[58] In a phase 3 randomized study, topotecan and

cisplatin followed by carboplatin and paclitaxel were more toxic and without improved efficacy.[59]

A randomized multicenter phase II trial of the North-Eastern German Society of Gynecological

Oncology Ovarian Cancer Study Group indicated similar effectiveness and less toxicity in

platinum-resistant recurrent ovarian cancer for weekly topotecan compared to conventional 5-

day schedules.[60]

A study by Haldar et al found that epithelial growth factor inhibitors, including pertuzumab, may

add activity to standard chemotherapy among women with platinum-resistant ovarian cancer.[61]

Consolidation chemotherapy

Ovarian cancer has a very high response rate when treated front-line; despite this, most patients

develop recurrent cancer. Many have shown interest in research into treatments to prevent or

prolong the interval of recurrence (such as consolidation therapy). A Gynecologic Oncology

Group protocol was discontinued when a statistical improvement in disease-free survival was

demonstrated in patients receiving 12 months versus 3 months of additional monthly paclitaxel

after initial therapy. However, questions remain about this study, which was not completed as

designed. Since no consensus on management in this situation exists, patients should be

encouraged to participate in clinical trials of consolidation therapy.

Hyperthermic intraperitoneal chemotherapy

The instillation into the peritoneal cavity of chemotherapeutic agents in a solution heated to

between 40°C and 43°C was first introduced in an attempt to induce longer survival in patients

with gastric carcinomas that had spread to the peritoneal cavity. Considerable experimental

evidence shows that not only is heat alone tumoricidal, but it also increases the activity of many

different chemotherapeutic agents, several of which have activity in ovarian cancer.

Ovarian cancer is a good theoretical target for surgical debulking combined with hyperthermic

chemotherapy because it combines 3 separately useful modalities: surgical debulking,

intraperitoneal chemotherapy, and heat. No randomized, phase III studies have been performed

in ovarian cancer cases and more research is warranted.

Radiation Therapy

Radiation has not been widely accepted as a routine treatment modality in the initial treatment of

patients with epithelial ovarian cancer, despite reports of efficacy for higher-risk stage I and II

disease and in stage III disease where small-volume residual disease is present after surgery. In

selected cases, pelvic diseases may respond to palliative dosing regimens with minimal toxicity.

Estrogen Replacement Therapy

The safety of estrogen replacement therapy (ERT) after treatment for epithelial ovarian cancer

has not been tested in a randomized trial, but current evidence suggests that the benefits of ERT

outweigh the risks.

Younger women with endometrioid subtypes are of concern because these tumors theoretically

are estrogen-sensitive. If estrogen is used in such patients, a progestogen probably should be

given with it.

Experimental Medications

Several recent case reports have raised the possibility of the use of hormonal therapy in the

management of recurrent granulose-theca cell tumors. Responses to medroxyprogesterone

acetate, GnRH agonists, and megestrol (Megace)[23] have all been reported in a small number of

patients with progressive disease not responsive to chemotherapy.

Several recent reports have documented the use of the aromatase inhibitor anastrozole, which

inhibits the conversion of androstenedione to estrone, in the management of patients who

previously received surgery and chemotherapy.[62] Several patients with recurrent disease

demonstrated normalization of their serum inhibin, decrease in tumor size, and an increase in

disease-free survival. Several authors have recommended aromatase inhibitors as a treatment

strategy for recurrent and refractory disease. Currently, however, the number of cases is too

small to draw any conclusions, and the use of aromatase inhibitors should be considered strictly

experimental.

The OCEANS phase III study reported that when bevacizumab (Avastin) was combined with

chemotherapy, a 52% risk reduction for recurrence in disease progression was observed

(HR=0.48, P < .0001) compared with women who received chemotherapy alone. The study

included women with recurrent, platinum-sensitive ovarian, peritoneal, or fallopian tube

carcinoma, who received bevacizumab in combination with carboplatin and gemcitabine

followed by continued use of bevacizumab alone until disease progression. Other results of the

trial include a median progression-free survival of 12.4 months, compared with 8.4 months in

women who received chemotherapy alone. Additionally, the overall response rate of tumor

shrinkage was 79% in women receiving the bevacizumab-based regimen, compared with 57% in

those who received chemotherapy alone.[63]

A study by Stone et al concluded the presence of a paracrine circuit, wherein increased

production of thrombopoietic cytokines in tumor and host tissues leads to a paraneoplastic

thrombocytosis, which fuels tumor growth. Targeting these cytokines may have therapeutic

potential.[64]

Second-Look Laparotomy

Second-look laparotomy is a surgical procedure performed within a few weeks following initial

treatment of epithelial ovarian cancer when no disease is evident on clinical examination, by

CA125, or radiology. The aim is to inspect the abdominal cavity for disease and, when no

macroscopic disease is found, perform peritoneal washings and extensive biopsies for pathologic

assessment for microscopic disease. Some years ago this surgery went out of fashion in many

centers because no effective treatment was available for those found to have disease present

following front-line therapy, and, thus, the evaluation did not improve prognosis. Of those

patients who had completely negative findings at second-look surgery (a complete pathologic

response), 56% had recurrence by 5 years and 60% by 10 years. In the Gynecologic Oncology

Group Study #172, despite the improvement in overall survival rate, 65% of these patients

developed recurrence within the time period of the study.[47]

Efforts are now underway to find effective methods of delaying or preventing recurrence

following front-line therapy. The best way to determine that a woman is pathologically disease-

free is a second surgery because regular clinical investigations are far from accurate. It may be

possible to perform this evaluation adequately using the laparoscope in many instances.

Management of Recurrent Disease

In most patients presenting with advanced epithelial ovarian cancer, the disease recurs, and the

prognosis for these patients is poor. The goal of further therapy is to achieve a response to

treatment and to prolong meaningful quality survival.

Treatment of recurrent disease may involve surgery, chemotherapy, and radiation. Participation

in clinical trials should be considered. If a localized mass is present, surgery may play a role

prior to the initiation of further chemotherapy. Response is more likely in patients who

previously had a good response to first-line therapy and who had a long interval between the

completion of initial therapy and the time of recurrence.

Patients whose previous response to platinum agents was good and who have gone at least 6

months since completing initial therapy may be re-treated with a taxane together with carboplatin

or cisplatin. Patients with platinum-resistant disease who respond poorly to treatment with

platinum agents initially and who have a short interval to recurrence do poorly. These patients

particularly should be offered participation in clinical trials, if available. Agents with some

activity in this situation include topotecan, etoposide, liposomal doxorubicin, and docetaxel and

altretamine. Single-agent therapy is usually given for recurrent disease, although combination

therapy is becoming more popular and several combinations have been reported.

Antiangiogenesis agents, such as bevacizumab, and hormonal agents, such as tamoxifen and

anastrozole, may have a role to play.

The 2011 NCCN ovarian cancer guidelines encourage participation in clinical trials of

bevacizumab, which is showing promising results. Increased progression-free survival has been

seen in patients receiving bevacizumab as first-line therapy and as maintenance therapy,

compared with standard chemotherapy alone.[36]

A study by O’Malley et al found that a combination of paclitaxel and bevacizumab significantly

increased progression-free survival, including a trend toward improved overall survival, among

women previously heavily treated for recurrent epithelial ovarian cancer.[65]

Samples of recurrent tumor or ascitic fluid can be sent to one of several laboratories for

chemotherapeutic assay. This assay involves culturing tumor cells in media containing a range of

chemotherapy agents. This allows chemotherapy agents to be offered to patients with the greatest

potential for activity, and, conversely, this allows drugs associated with extreme resistance to be

avoided.

Patients who were initially sensitive to platinum-containing chemotherapy have overall response

rates of 30-60%, with an overall survival of 12-48 months, whereas patients resistant to

chemotherapy have expected response rates of 12-32%, with an overall survival of 7-12 months.

The finding of elevated CA125 in the serum in the absence of clinical or radiographic disease is

a relatively common situation in patients with epithelial ovarian cancer following initial

treatment. Treatment of these patients is controversial.

However, the 2011 NCCN ovarian cancer guidelines panel recommends evaluation for CA125

tumor marker with each follow-up visit.[36]

The standard treatment for ovarian cancer starts with staging and cytoreductive surgery. Based

on the surgical staging, patients are classified as having limited disease (stages I and II) or

advanced disease (stages III and IV).

Low risk for recurrence is indicated by the following:

Grade 1 or 2 disease

No tumor on external surface of the ovary

Negative peritoneal cytology

No ascites

Tumor growth confined to the ovaries

High risk for recurrence is indicated by the following:

Grade 3 disease

Preoperative rupture of the capsule

Tumor on the external surface of the ovary

Positive peritoneal cytology

Ascites

Tumor growth outside of the ovary

Clear cell tumors

Surgical stage II

Palliative Care

When potentially curative treatment options are unavailable or are ineffective, the clinical goal

changes from cure to palliation.

Recurrent ovarian cancer is seldom curable. Second-line, third-line, or even fourth-line

chemotherapy is often administered in a palliative fashion, both to diminish symptoms and to

prolong life. When chemotherapy is considered for patients with good performance status, it is

most appropriate to offer enrollment in formal clinical studies such as those coordinated by the

Gynecologic Oncology Group. Recently, oral thalidomide has shown activity in heavily

pretreated patients with ovarian cancer when compared with traditional intravenous

chemotherapy.[66] When chemotherapeutic options are exhausted or the adverse effects are not

worth the small potential for benefit, other means of palliating symptoms of progressive ovarian

cancer are necessary.

Ovarian cancer spreads regionally in the form of scattered deposits of tumor on all surfaces in the

peritoneal cavity. Morbidity and mortality as a direct result of this process are far more common

than symptoms related to recurrence, specifically at the primary tumor site or in distant extra-

abdominal sites.

Bowel obstruction

Bowel obstruction is a common terminal effect of progressive ovarian cancer. Rectosigmoid

obstruction in the face of progressive disease is best palliated with a transverse loop colostomy.

Often, a small incision at the stoma site is all that is necessary to identify the dilated proximal

colon and to elevate it through the anterior abdominal wall. The stoma starts to function

immediately, and patients can eat and return to their baseline functional status soon. Cecostomy

tube placement can be used to vent the large intestine in colonic obstruction. However,

cecostomy sites are prone to recurrent obstruction from solid stool and tube placement is most

appropriate in those patients with extremely short life expectancies.

Small bowel obstruction is more challenging. Multiple areas of partial small bowel obstruction

are typically not amenable to surgical correction. Tumor implants on the bowel surface and

mesentery cause adhesions and impede peristalsis. Infrequently, an isolated small bowel

obstruction can be managed with bowel resection and reanastomosis. More commonly, palliation

is achieved with a percutaneous gastrostomy tube draining by gravity or with a nasogastric tube

on suction. Medical management may also be beneficial to decrease gastrointestinal secretions

with somatostatin combined with erythromycin to improve motility in the management of small

bowel obstruction.

Ascites

Ascites can result from widespread microscopic and macroscopic tumor infiltration over the

peritoneum, preventing absorption of peritoneal fluid. This symptom can become quite troubling

when progressive disease is unresponsive to chemotherapy. Patients complain of pain, early

satiety, vomiting, fatigue, and shortness of breath. Diuretics are of limited efficacy in relieving

malignant ascites, and relief is best obtained by repetitive paracentesis. Placement of a

semipermanent drainage tube, Pleurx, has been FDA approved for symptomatic relief in patients

with recurrent ascites. The eventual metabolic impact is depletion of albumin. However, the

immediate temporary improvement in patient comfort usually takes precedence over long-term

nutritional status for a patient who is terminally ill.

Anorexia

Anorexia seldom occurs without a component of bowel obstruction or ascites. For anorexia

without associated bowel obstruction, treatment with megestrol acetate or steroids can stimulate

appetite and lead to an increased sense of well-being. Parenteral nutritional support might be

appropriate as a short-term measure perioperatively following relief of bowel obstruction or

other intervention. However, long-term parenteral nutritional support is seldom an appropriate

measure in a patient with incurable malignant impairment of bowel function.

Constipation

Constipation may be an adverse effect of narcotic analgesics or colonic dysmotility from tumor

involvement. Treatment options range from behavioral changes to medicinal agents. When

possible, an increase in fluid intake and exercise can be of benefit, as does close attention to

bodily signals of defecation. More useful to the patient with cancer is the addition of fiber,

colonic stimulants, and laxatives to their regimen.

For narcotic-induced constipation, stool softeners should be combined with stimulant laxatives

such as docusate sodium tablets and senna or bisacodyl tablets. Cascara, a liquid cathartic

derived from tree bark, is also useful. For patients with obstipation or for those in whom the

above measures are inadequate, enemas and suppositories are helpful. Enema choices include

warm tap water, phosphate/biphosphate, soapsuds, milk and molasses, and mineral oil. Bisacodyl

or glycerin suppositories are also useful. Saline laxatives draw fluid into the intestine, causing

distention and reflex peristalsis. Saline laxatives include magnesium sulfate, milk of magnesia,

magnesium citrate, Phospho-soda, and sodium phospate. Prolonged use of these agents may

cause fluid and electrolyte imbalance and should be avoided in malnourished patients.

Stimulant laxatives include senna, bisacodyl, cascara, castor oil, phenolphthalein, Miralax, and

danthron. These drugs may ultimately contribute to a loss of normal bowel function and cause

laxative dependence, but this issue is often unimportant in the palliative care setting. Lubricating

agents include oral ingestion of mineral oil. Prolonged use of mineral oil may lead to

malabsorption of fat-soluble vitamins. Lactulose draws water into the intestinal lumen, softens

stools, and increases defecation frequency. Excessive use can lead to fluid and electrolyte

imbalance. Polyethylene glycol electrolyte solution is useful for stimulating defecation with

minimal fluid or electrolyte imbalance.

Fatigue and dyspnea

Fatigue or dyspnea secondary to anemia can be treated with blood transfusions or erythropoietin.

Transfusions provide immediate improvement, whereas erythropoietin injections may take weeks

to improve fatigue.

To see complete information on Palliative Care of the Patient With Advanced Gynecologic

Cancer, please go to the main article by clicking here.

Ovarian Cysts

Most ovarian cysts are functional in nature and resolve with minimal treatment. However,

ovarian cysts can herald an underlying malignant process or, possibly, distract the emergency

clinician from a more dangerous condition, such as ectopic pregnancy, ovarian torsion, or

appendicitis. When ovarian cysts are large, persistent, or painful, surgery may be required,

sometimes resulting in removal of the ovary.

Tumors of Low Malignant Potential (Borderline Tumors)

The accepted initial treatment for LMP tumors is surgical removal of the tumor and biopsies.

Surgery begins with a full assessment of the pelvis and abdominal contents as for epithelial

ovarian cancer and is carried out as described below.

Patients who are premenopausal and desire preservation of fertility can be treated with unilateral

oophorectomy alone. In selected cases, ovarian cystectomy may be enough for stage IA serous

tumors of LMP. Hysterectomy and removal of the other ovary can be performed if the patient no

longer desires to remain fertile.

When complete surgical staging is performed in patients with LMP tumors, some patients with

disease originally thought to be confined to the ovaries are found to have disease that has spread.

However, the value of this has not been defined in early-stage disease.

In advanced disease, patients should undergo cytoreductive surgery, as for invasive epithelial

ovarian cancer, to remove all visible tumor.

The postoperative management protocol is far from clear. To date, no medical therapy has been

shown to clearly improve outcomes. Chemotherapy and radiation therapy are not indicated for

LMP tumors following complete resection for stage I and II disease. In cases where disease has

spread from the ovaries at the time of surgery, and particularly where implants are found to be

invasive, chemotherapy can be considered, but data establishing its efficacy are absent.

Regular follow-up care includes clinical examination and serum CA125 estimation, especially if

the original tumor was serous and/or the CA125 was elevated. If a patient retains 1 or both

ovaries, annual ultrasound examination may be indicated (see Workup).

LMP tumors do not recur in most patients. When they do, initial debulking surgery usually is

indicated. Chemotherapy has no proven role.

Malignant Germ Cell Tumors

Surgery is the initial treatment for GCTs, and, in young patients, this can be conservative, with

preservation of the uterus and contralateral ovary, because chemotherapy is very effective.

Second-look surgery generally is not indicated following initial treatment.

For a tumor that possibly is a dysgerminoma, surgery is the initial management. Assessment of

the abdominal and pelvic contents is made as for EOC.

Where no macroscopic disease exists outside the ovary, unilateral oophorectomy should be

performed, excising the tumor intact and without rupture. Staging procedures include washings,

omental biopsy, and sampling of paraaortic and pelvic lymph nodes. The opposite ovary should

be carefully inspected, and a biopsy should be performed if necessary. However, in young

patients, the uterus and opposite ovary should be left in situ.

If disease is present outside the ovary, an effort should be made to remove all visible tumor while

maintaining fertility for the patient. In a young patient, debulking disease from the contralateral

ovary, without performing oophorectomy, should be acceptable.

Many patients present having already undergone a unilateral oophorectomy that diagnosed the

dysgerminoma. Consideration should be given to staging these patients, laparoscopically if

possible, if a negative result will spare the patient from receiving chemotherapy. If chemotherapy

will be given regardless, initial staging surgery is not warranted.

Adequately staged dysgerminoma patients with stage IA disease can be monitored without

further therapy, whatever the size of the primary tumor. However, 15-20% of tumors recur,

mostly in the first 2 years after treatment.

All dysgerminoma patients at a stage greater than IA require combination chemotherapy, with

the most accepted regimen in the United States being bleomycin, etoposide, and cisplatin (BEP).

In patients with advanced disease, the combination of vincristine, actinomycin D, and

cyclophosphamide (VAC) has been used following BEP as consolidation therapy.

Dysgerminoma is very radiosensitive, but radiation rarely is used, especially in young patients,

because of its effect on future fertility. Stage IA disease is associated with a 5-year survival rate

of higher than 95%, but even with advanced disease, the 5-year survival rate is good following

surgery and chemotherapy.

In the premenopausal patient who has an immature teratoma, treatment should include unilateral

oophorectomy and surgical staging. The contralateral ovary rarely is involved, and biopsy of the

other ovary is not necessary. If a patient no longer desires to remain fertile or is postmenopausal,

hysterectomy with removal of both ovaries is sensible.

Patients with stage IA grade 1 immature teratoma do not need adjuvant therapy postoperatively.

The standard of care for high-grade stage I disease postoperatively has been chemotherapy with

BEP. Evidence is accumulating that such patients can be treated more conservatively following

surgery, provided good follow-up care is maintained. Patients with stage IA grade 2 disease can

be monitored only. The conservative management of stage IA grade 3 is more controversial.

No tumor markers exist for immature teratoma, and follow-up care should include clinical

examination together with ultrasound at regular intervals. Second-look laparoscopy or

laparotomy may be considered, particularly in patients who had macroscopic residual disease at

the end of surgery. Immature teratoma may be associated with the development of benign

teratomatous masses and peritoneal glial implants that may remain for a long time. All masses at

second surgery should be removed to be sure that no immature (malignant) elements are present.

If such elements are present, the patient should have further chemotherapy with VAC.

The prognosis for immature teratoma depends on the extent of the tumor and the grade. Stage I

grades 1 and 2 have almost 100% survival. Patients with incompletely resected tumor have a

50% chance of survival.

A study by Rungruang et al found that women upstaged to IIIC by retroperitoneal involvement

had better outcomes than those with intraperitoneal tumors, suggesting a unique subset of stage

III patients, according to the International Federation of Gynecology and Obstetrics ovarian

cancer surgical staging system.[67]

Endodermal sinus cell tumors secrete alpha-fetoprotein. Following standard surgery, all patients

should be treated with BEP. Other chemotherapy regimens may be necessary.

Sex-Cord Stromal Tumors

Although granulosa cell tumors are malignant and Sertoli-Leydig cell tumors less so, they

behave in a much less malignant fashion than epithelial ovarian cancers.

Juvenile granulosa cell tumor is usually unilateral and confined to the ovary and can be managed

with surgery alone.

For Sertoli-Leydig cell tumors, the surgery is unilateral oophorectomy, and, if patients'

childbearing has been completed, total hysterectomy and bilateral oophorectomy is performed.

The overall 5-year survival rate is 70-90%.

Rare Tumors

Small-cell carcinoma is treated with surgery and chemotherapy, but the prognosis is poor.

Mixed mesodermal sarcoma or carcinosarcoma should be treated with surgery (see Epithelial

Ovarian Cancer - Treatment), followed by platinum-containing chemotherapy. Prognosis is poor.

Treatment of metastatic tumors of the ovary relates to the primary site.

Assessment of Response to Therapy and Relapse

Normalization of tumor marker values may indicate cure despite radiographic evidence of

persistent disease. In this situation, the residual tumor is frequently nonviable. Sometimes, tumor

marker levels may rise after effective treatment (due to cell lysis), but the increase may not

portend treatment failure. A consistent increase in tumor marker levels, combined with lack of

clinical improvement, may indicate treatment failure. Residual elevation after definitive

treatment usually indicates persistent disease.

The following tumor markers are helpful in assessing response to chemotherapy and in

determining relapse when monitoring patients with complete remission. Further studies are

needed to determine the role of these markers.

Squamous cell carcinoma antigen

The squamous cell carcinoma antigen level can be increased in patients with epidermoid

carcinoma of the cervix, benign tumors of epithelial origin, and benign skin disorders.

Carcinoembryonic antigen

Most epithelial neoplasms of the ovary also express carcinoembryonic antigen (CEA). The

neoplasms include, with decreasing intensity and frequency, Brenner, endometrioid, clear cell,

and serous tumors. CEA is frequently present in patients with cancer that has metastasized to the

ovary because the primary cancer is generally mammary or gastrointestinal in origin and these

tumors frequently contain CEA.

Alpha-fetoprotein

Alpha-fetoprotein (AFP) is a normal fetal serum protein synthesized by the liver, yolk sac, and

gastrointestinal tract that shares sequence homology with albumin. AFP is a major component of

fetal plasma, reaching a peak concentration of 3 mg/mL at 12 weeks of gestation. Following

birth, AFP rapidly clears from the circulation because its half-life is 3.5 days. AFP concentration

in adult serum is less than 20 ng/mL.

Most endodermal sinus tumors of the ovary express AFP. AFP is present within the cytoplasm of

tumor cells and in the characteristic hyalin globules observed in the endodermal sinus tumor.

AFP is also expressed by ovarian embryonal cell carcinoma, immature teratomas, and

polyembryomas.

Lysophosphatidic acid

Lysophosphatidic acid stimulates cancer cell proliferation, intracellular calcium release, and

tyrosine phosphorylation, including mitogen-activated protein kinase activation.

Lysophosphatidic acid has been shown to be a multifunctional signaling molecule in fibroblasts

and other cells. It has been found in the ascitic fluid of patients with ovarian cancer and is

associated with ovarian cancer cell proliferation.

MIB-1

MIB1-determined tumor growth fraction has recently been studied as an additional tool for the

decision of adjuvant therapy in patients with very early stages of ovarian carcinomas. In one

study, MIB1 predicted tumor recurrences in 84% of the ovarian cancers.

L1 (CAM)

According to Daponte et al, L1 (CAM) immunoreactivity correlates with stage and grade of

ovarian cancer. It increases from benign tumors to early carcinomas and to advanced stage

carcinomas progressively and significantly. L1 (CAM) expression represents a novel diagnostic

marker in serous ovarian neoplasms that shows characteristics of tumor progression. L1

expression is associated with chemotherapy response.[68]

Consultations

Consult a gynecologic oncologist if ovarian cancer is suspected. The question of when to obtain

preoperative consultation with a gynecologic oncologist can be difficult to delineate. A good rule

of thumb is that all postmenopausal and premenarchal patients with adnexal masses should have

the benefit of a consultation with an oncologist because the risk of malignancy is greater. In

reproductive-aged patients, the vast majority of adnexal masses are benign. Patients with

radiologic or sonographic findings suggestive of malignancy (solid or mixed solid and cystic

tumors, ascites, etc) and patients with endocrinologic symptoms and an adnexal mass should

have the benefit of a preoperative consultation with a gynecologic oncologist. Patients with a

question of malignancy preoperatively can also be evaluated with serum tumor markers

including CA125, CA19-9, LDH, AFP, beta-hCG, and inhibin levels. Appropriate referral should

be made if any of these are significantly elevated.

Patients with primarily GI complaints may benefit from a consultation with a gastroenterologist

to rule out a primary GI source prior to surgical exploration. Endoscopy can be performed during

this preoperative evaluation if indicated.

Deterrence and Prevention

The risk of developing epithelial ovarian cancer is significantly reduced by bearing children,

using the combined oral contraceptive pill, undergoing tubal ligation, and undergoing bilateral

oophorectomy.

Evidence suggests that taking the oral contraceptive pill for at least 5 years reduces the relative

risk of developing EOC to 50% of the risk for a woman who has never taken it.

Prophylactic bilateral salpingo-oophorectomy is indicated in high-risk women.[62] The American

College of Obstetricians and Gynecologists recommends offering salpingo-oophorectomy to

women with BRCA1 or BRCA2 mutations by age 40 years or when childbearing is complete

(level A recommendation).[69] Surgical prophylaxis decreases the risk by at least 90%. Not all

cases of ovarian cancer are prevented, as women are still at risk for developing primary

peritoneal carcinomas.

The epithelial lining of the ovaries is embryologically identical with the lining of the peritoneal

cavity, and similar cancers can develop from the peritoneum. Thus, while oophorectomy

prevents a pure epithelial ovarian cancer from developing, a small risk still exists for developing

carcinoma of the peritoneum, a disease that behaves similarly to epithelial ovarian cancer.

BRAC1 and BRAC2 mutations are common among women with invasive ovarian cancer; thus,

women diagnosed with invasive, nonmucinous ovarian cancer are candidates for genetic testing.[70]

For patients who are known carriers of BRCA1 or BRCA2 mutations, bilateral oophorectomy

may be performed as soon as childbearing is complete, and probably before the patient is aged

35 years. This reduces the chance of developing EOC, but it does not prevent carcinoma of the

peritoneum.

For women with BRCA1 and BRCA2 mutations who opt to not undergo early oophorectomy, the

task force of the Cancer Genetics Studies Consortium recommends transvaginal ultrasound,

timed to avoid the middle of the menstrual cycle, together with serum CA125 levels performed

every 6-12 months in women aged 25-35 years. Use of the oral contraceptive pill is associated

with lower risk of EOC in these women.

Long-term Monitoring

Follow-up should occur at 2- to 3-month intervals for the first 2 years for patients not undergoing

chemotherapy. Then, this can be spaced out to every 4-6 months for the next 3 years, then yearly

thereafter. A history should be obtained and pelvic examination should be performed at each

visit. Also, serum determination of tumor markers (ie, inhibin levels) should be performed if

these were elevated preoperatively or immediately postoperatively.

If any evidence of recurrence arises during follow-up, imaging studies, usually an

abdominopelvic CT scan should be performed to look for recurrent tumors. Most recurrences are

confined to the abdomen and pelvis. Other imaging studies may be ordered as dictated by

physical examination findings.