Ovarian Cancer

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Practice Essentials

Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the United States. Malignant ovarian lesions include primary lesions arising from normal structures within the ovary and secondary lesions from cancers arising elsewhere in the body. Primary lesions include epithelial ovarian carcinoma (70% of all ovarian malignancies). Current research suggests that the majority of these originate from the fallopian tubes.  

Stromal tumors of the ovary include germ-cell tumors, sex-cord stromal tumors, and other more rare types. Metastases to the ovaries are relatively frequent; common sources are tumors in the endometrium, breast, colon, stomach, and cervix. See the image below.



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An enlarged ovary with a papillary serous carcinoma on the surface.

Signs and symptoms

Early ovarian cancer causes minimal, nonspecific, or no symptoms. The patient may feel an abdominal mass. Most cases are diagnosed in an advanced stage.

Epithelial ovarian cancer presents with a wide variety of vague and nonspecific symptoms, including the following:

Symptoms independently associated with the presence of ovarian cancer include pelvic and abdominal pain, increased abdominal size and bloating, and difficulty eating or feeling full.[1] Symptoms associated with later-stage disease include gastrointestinal symptoms such as nausea and vomiting, constipation, and diarrhea.[2] Presentation with swelling of a leg due to venous thrombosis is not uncommon. Paraneoplastic syndromes due to tumor-mediated factors lead to various presentations.

See Presentation for more detail.

Diagnosis

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.

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

Screening

The US Preventive Services Task Force (USPSTF) recommends against screening (with serum CA-125 level or transvaginal ultrasonography) for ovarian cancer in the general population.[3] The US Food & Drug Administration (FDA) recommends against the use of tests marketed for ovarian cancer screening.[4] The National Cancer Institute (NCI) cites evidence of lack of mortality benefit with screening, and potential harms relating to false-positive test results.[5]

Laboratory testing

No tumor marker (eg, CA-125, beta-human chorionic gonadotropin, alpha-fetoprotein, lactate dehydrogenase) is completely specific; therefore, use diagnostic immunohistochemistry testing in conjunction with morphologic and clinical findings. Also, obtain a urinalysis to exclude other possible causes of abdominal/pelvic pain, such as urinary tract infections or kidney stones.

Imaging studies

Routine imaging is not required in all patients in whom ovarian cancer is highly suggested. In cases in which the diagnosis is uncertain, consider the following imaging studies:

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

Procedures

Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended, as it may delay diagnosis and treatment of ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, the patient should undergo laparoscopic evaluation or  laparotomy, based on the presentation,  for diagnosis and staging. An FNA or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass.

See Workup for more detail.

Management

Standard treatment for women with ovarian cancer involves aggressive debulking surgery and chemotherapy. The aim of cytoreductive surgery is to confirm the diagnosis, define the extent of disease, and resect all visible tumor.  Neoadjuvant chemotherapy is increasingly used. 

Surgery

The type of procedure depends on whether or not disease is visible outside the ovaries. When no disease is visible outside the ovaries, or no lesion greater than 2 cm is present outside of the pelvis, the patient requires formal surgical staging, including peritoneal cytology, multiple peritoneal biopsies, omentectomy, pelvic and para-aortic lymph node sampling, and biopsies of the diaphragmatic peritoneum.

If visible disease is noted, aggressive surgical debulking, with the intent to remove all visible disease should be undertaken. If the surgeon determines that optimal debulking is not possible, then neoadjuvant chemotherapy should be considered. For patients with stage IV disease, surgery should be individualized on the basis of presentation.

Surgical procedures that may be performed in women with ovarian cancer are as follows:

Chemotherapy

Postoperative chemotherapy is indicated in all patients with ovarian cancer, except those who have surgical-pathologic stage I disease with low-risk characteristics. Standard postoperative chemotherapy for ovarian cancer is combination therapy with a platinum compound and a taxane (eg, carboplatin and paclitaxel). Additional agents for recurrent disease include the following:

Adjunctive medications include the following:

See Treatment and Medication for more detail.

For patient education information, see the Ovarian Cancer Health Center.

Background

Malignant lesions of the ovaries include primary lesions arising from normal structures within the ovary and secondary lesions from cancers arising elsewhere in the body. Primary lesions include epithelial ovarian carcinoma (70% of all ovarian malignancies), germ-cell tumors, sex-cord stromal tumors, and other more rare types. Metastases to the ovaries are relatively frequent, with the most common being from the endometrium, breast, colon, stomach, and cervix.

Although many histologic types of ovarian tumors have been described, more than 90% of ovarian malignancies are epithelial tumors. Many of these actually originate in the fallopian tubes. (See Pathophysiology.)

The precise cause of ovarian cancer is unknown. However, several risk and contributing factors (including both reproductive and genetic factors) have been identified. (See Etiology.)

Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the United States. Around the world, more than 200,000 women are estimated to develop ovarian cancer every year and about 100,000 die from the disease. The lifetime risk of a woman developing epithelial ovarian cancer is 1 in 70. (See Epidemiology.)

Early disease causes minimal, nonspecific, or no symptoms. Therefore, most cases are diagnosed in an advanced stage. Prognosis in ovarian cancer is closely related to the stage at diagnosis; thus, overall, prognosis for these patients remains poor. (See Presentation and Prognosis.)

Standard treatment involves aggressive debulking surgery followed by chemotherapy. The incorporation of neoadjuvant chemotherapy has recently increased, with multiple studies indicating that in some situations it offers an improvement in morbidity and possibly survival.(See Treatment and Medication.)

Pathophysiology

Historically, most theories of the pathophysiology of ovarian cancer included 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. However, new evidence indicates that the majority of these tumors actually originate in the fimbria of the fallopian tube. Detailed pathologic studies have pushed much of the thinking about the origin of these tumors in this direction.[9]  

Ovarian cancer typically spreads to the peritoneal surfaces and omentum. Spread can occur by local extension, lymphatic invasion, intraperitoneal implantation, hematogenous dissemination, or 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.

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 tumors represent the most common histology (90%) of ovarian tumors. Other histologies include the following:

Epithelial ovarian cancer

Epithelial ovarian cancer is thought to arise from epithelium covering the fimbria of the fallopian tubes, or the ovaries, both of which are 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.

Four main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the cervix, uterus, and fallopian tube, as follows:

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.



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An enlarged ovary with a papillary serous carcinoma on the surface.

Epithelial ovarian cancer most often spreads initially within the peritoneal cavity (see the image 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 as follows:



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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. The 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.

Increasing evidence suggests that a high proportion of high-grade serous carcinoma originates from distal fallopian tube epithelium or the tuboperitoneal junction rather than the ovarian surface epithelium. Serous intraepithelial or early invasive carcinoma has been found in up to 10% of fallopian tubes from BRCA mutation carriers who had undergone prophylactic bilateral salpingo-oophorectomies. Clinical, molecular, and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for high-grade serous ovarian carcinoma.[9, 10]

Those findings have prompted the suggestion that prevention of ovarian cancer in selected women at high risk could be better accomplished with salpingectomy. A study comparing standard risk-reducing salpingo-oophorectomy with the combination of early risk-reducing salpingectomy and delayed oophorectomy in BRCA carriers is currently recruiting participants.[11]

Tumors of low malignant potential

Tumors of low malignant potential (LMP), or borderline tumors, are a distinct variety of epithelial ovarian cancer that behave in a much less aggressive fashion and have a very favorable prognosis. These tumors cause great anxiety to patients, and the concept of LMP sometimes is difficult to explain. They comprise approximately 20% of malignant ovarian tumors. The mean age of diagnosis is younger than for invasive epithelial ovarian cancer, at approximately 48 years, and no large peak of incidence is observed.

These tumors are staged identically to epithelial ovarian cancer, using the FIGO (Fédération Internationale de Gynécologie et d'Obstétrique; International Federation of Obstetrics and Gynecology) system. In contrast to epithelial ovarian cancer, however, most LMP tumors are stage I at presentation, with a distribution as follows:

LMP tumors can cause a range of symptoms similar to epithelial ovarian cancer, including increasing abdominal girth, an abdominal mass, abdominal pain, abnormal uterine bleeding, urinary symptoms, and gastrointestinal symptoms. They may be asymptomatic and found on routine physical examination or ultrasound scan.

For more information, see Borderline Ovarian Cancer.

Malignant germ cell tumors

Malignant germ cell tumors (GCTs), which include dysgerminoma, endodermal sinus tumor, malignant teratoma, embryonal carcinoma, and choriocarcinoma, are thought to derive from primitive germ cells in the embryonic gonad. GCT of the ovary is much rarer than GCT of the testis in males, and much of the development of the management approach has been based on experience with male GCT.

Common characteristics of these tumors include rapid growth, a predilection for lymphatic spread, frequent mixtures of tumor types, and a predominantly unilateral pattern of ovarian involvement (except for dysgerminoma). GCT is much more common in young women but occasionally occurs in infants and older women.

Many GCTs produce tumor markers that can be measured in the blood and then used to monitor response to treatment and for follow-up care. Endodermal sinus tumors secrete alpha-fetoprotein and choriocarcinoma, and dysgerminomas occasionally secrete beta human chorionic gonadotropin (bHCG). Dysgerminoma may secrete lactate dehydrogenase and placental alkaline phosphatase.

No factors have been established related to etiology, apart from an increased incidence associated with dysgenetic gonads.

Although these tumors may be asymptomatic and present as a palpable mass, many patients present with abdominal pain. The mass may lead to acute pain due to torsion, rupture, or hemorrhage, or, patients may have abdominal distension, vaginal bleeding, or fever.

Most are stage I and confined to the ovary at the time of diagnosis.

Dysgerminoma

This is the most common malignant GCT and represents 3-5% of all ovarian malignancies. Ninety percent occur in people younger than 30 years, and 75% occur in the second and third decades, with a median age of 22 years.

Dysgerminomas are bilateral in 10-35% of cases. Five percent occur in phenotypic females with abnormal gonads. They may have a 46XY karyotype with pure gonadal dysgenesis or androgen insensitivity syndrome, or, they may have a 45X, 46XY karyotype with mixed gonadal dysgenesis. Dysgerminomas may be large and usually are solid, with a smooth external surface and a fleshy pink-tan color inside. The majority are confined to the ovary at diagnosis, but approximately 25% of otherwise stage I dysgerminomas have lymph node metastasis.

For more information, see Ovarian Dysgerminomas.

Cystic teratoma

Teratomas are germ cell tumors commonly composed of multiple cell types derived from one or more of the 3 germ layers. Inconsistent nomenclature often confuses discussions of various subtypes of teratomas. The word is derived from the Greek teras, meaning monster, which Virchow coined in the first edition of his book on tumors published in 1863.[12] Teratomas range from benign, well-differentiated (mature) cystic lesions to those that are solid and malignant (immature). Additionally, teratomas may be monodermal and highly specialized. Rarely, within some mature teratomas certain elements (most commonly squamous components) undergo malignant transformation.

In 1831, Leblanc coined the term dermoid cyst in the veterinary literature when he removed a lesion that resembled skin at the base of a horse's skull, which he called a “kyste dermoid.”[13] Both dermoid and teratoma, terms now more than a century old, remain in general use and often are used interchangeably with various preferences among subspecialties. The earliest implications were that dermoids comprised elements similar to skin and its appendages, whereas teratomas had no such limits. Dermoids now are recognized as often being trigeminal and containing practically any type of tissue.

For those who continue to make a distinction, dermoids are tumors that maintain rather orderly arrangements, with well-differentiated ectodermal and mesodermal tissues surrounding endodermal components. Teratomas, specifically solid teratomas, are essentially devoid of organization; thus, the presence of some degree of organization, a high degree of cellular differentiation, and cystic structure differentiates dermoids from teratomas (see the images below).[12]



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Mature cystic teratoma of the ovary exhibiting multiple tissue types.



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Mature cystic teratoma of the ovary with hair, sebaceous material, and thyroid tissue.

For more information, see Teratoma, Cystic.

Immature teratoma

This is the second most common GCT. It occurs mostly in females aged 10-20 years but may occur after menopause. The tumor spreads most commonly to peritoneal surfaces.

Other germ cell tumors

Endodermal sinus tumor occurs at a mean age of 18 years, and one third occur before puberty. Embryonal carcinoma and choriocarcinoma are extremely rare.

Sex-cord stromal tumors

These include tumors arising from the sex cords; granulosa cells; Sertoli cells; and the specialized stroma of the genital ridge, theca, and Leydig cells. They comprise fewer than 5% of all ovarian 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. Benign tumors in the group include thecoma and fibroma. Granulosa cell tumors and pure Sertoli cell tumors commonly secrete estrogen, while Leydig cell tumors and combined Sertoli-Leydig tumors often secrete androgens.

Granulosa cell tumor

This is the most common malignant sex-cord stromal tumor. Ninety percent of granulosa cell tumors are stage I at the time of diagnosis. This tumor account for approximately 2% of all ovarian tumors and can be divided into adult (95%) and juvenile (5%) types based on histologic findings. Juvenile granulosa cell tumor is a variant of granulosa cell tumor that is rarely malignant. It most often presents in young girls with isosexual precocious puberty. The tumor is usually unilateral and confined to the ovary and can be managed with surgery alone.

Granulosa cell tumor can occur at any age, with a mean age of the early 50s. Because of the secretion of estrogen, the presenting features depend on the patient's age. Prepubertal girls typically present with precocious sexual development, women of reproductive age have heavy or irregular periods, and postmenopausal women may have postmenopausal bleeding. At all ages, the tumor may present with acute abdominal pain due to rupture or hemorrhage.

The tumors vary in size and may be solid or partially cystic (see the image below).



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Granulosa cell tumor excised from a woman aged 44 years. Note the yellowish tumor that has eroded through, onto the surface of the ovary.

The cut surface may be gray-white or yellow, depending on lipid content. Necrosis and hemorrhage often are present, with cystic compartments filled with fluid or clotted blood (see the image below).



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This photo shows a granulosa cell tumor, with the cut surface showing classic features of a hemorrhagic cyst and yellowish solid component.

The microscopic features are granulosa cells in a wide variety of patterns, and characteristic Call-Exner bodies may be present.

For more information, see Granulosa-Theca Cell Tumors.

Sertoli-Leydig cell tumor

These tumors are rare. They are a form of low-grade malignancy that typically produces androgens and rarely estrogens.

Other rare tumors

Small-cell carcinoma is a rare type of carcinoma that occurs in females aged 2-46 years. It often is associated with hypercalcemia.

The most common form of sarcoma in the ovary is the mixed mesodermal sarcoma or carcinosarcoma.

Metastatic tumors of the ovary arise from direct extension and spread within the bloodstream or lymphatic system or within the peritoneal cavity. Sites of origin include the endometrium; cervix; and nongynecologic sites such as breast, colon, and stomach. The classic Krukenberg tumor refers to bilateral enlargement of the ovaries from metastases from a signet-ring carcinoma of the stomach.

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 ovarian cancer in women with and without symptoms.[14] 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 significantly.

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.[15]

Evidence from the Cancer Genome Atlas Network showed that serous ovarian tumors and breast basal-like tumors shared a number of molecular characteristics, such as the types and frequencies of genomic mutations, suggesting that ovarian and breast cancer may have a related etiology and potentially similar responsiveness to some of the same therapies.[16]

At least two 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.[17]

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.[18] This allele was also associated with breast cancer.

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.[19] 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 one extra ovarian cancer for approximately 8300 women taking hormone therapy each year.

Other factors

There is fair evidence that increased adult height and body mass index (BMI) are associated with a modestly increased risk of ovarian cancer.[20] A Danish study found that size in childhood may also affect risk, with increased risks of ovarian cancer overall in girls who were overweight or tall at 7 and 13 years, compared with average-sized girls at both ages.[21]

Endometriosis ihas beenlinked to an increased risk of ovarian cancer.[22] The association is stronger with nonserous histologic subtypes, specifically endometrioid and clear cell carcinomas.[20]

The use of talcum powder on the vulva and perineum may be associated with increased risk of epithelial ovarian cancer.[23] High lactose consumption has been associated with increased risk of ovarian cancer, but evidence linking lactose and specific dairy products with ovarian cancer remains contradictory.[24, 25]

According to the findings of a longitudinal study, women who experienced six or more symptoms of post-traumatic stress disorder (PTSD) at some point in life had a twofold greater risk of developing ovarian cancer compared with women who never had any PTSD symptoms (age-adjusted hazard ratio [HR]=2.10, 95% confidence interval [CI]=1.12, 3.95). Analyzing data from nearly 55,000 participants in the Nurses' Health Study II, Roberts et al reported that having higher levels of PTSD symptoms can be associated with increased risks of ovarian cancer even decades after a traumatic event. The study also showed that women who experienced 6-7 symptoms associated with PTSD were at a significantly higher risk of developing the high-grade serous histotype of ovarian cancer, the most aggressive form of ovarian cancer.[26]

Epidemiology

In the United States, the incidence of ovarian cancer is 11.2 per 100,000 women per year, based on 2013-2014 cases.[27] The incidence of ovarian cancer has decreased by about 1% per year since at least the mid-1970s among women younger than age 65, but only since the early 1990s in older women.[28] Ovarian cancer is more common in whites than in blacks (11.7 versus 9.1 cases per 100,000 women per year, respectively).[27]

Epithelial ovarian cancer can occur in girls as young as 15 years, but the mean age at diagnosis is 63 years, and most cases are diagnosed in women 55-64 years of age.[27] In the United States, the estimated lifetime risk is 1.25%.[5]

The American Cancer Society estimates that 21,750 new cases of ovarian cancer will be diagnosed in 2020 and 13,980 women will die from the disease.[28] Although ovarian cancer is the 17th most common cancer in women, it is the fifth most common cause of cancer death in women, accounting for 5% of cancer deaths—more than any other gynecologic cancer.[28, 27]

From 2008 to 2017, the death rate from ovarian cancer decreased by an average of 2.2% each year. Median age at death is 70 years.[27]

International statistics

Internationally, ovarian cancer is the eighth most common cancer in women and the 18th most common cancer overall, with almost 300,000 new cases and almost 200,000 deaths in 2018.[29, 30] Age-standardized rates per 100,000 ranged from 9.5 in Japan to 16.6 in Serbia.[29]

Prognosis

Although the 5-year survival rate for ovarian cancer has improved significantly in the past 30 years, the prognosis for ovarian cancer remains poor overall, with a 48.6% 5-year relative survival rate.[27] The prognosis of ovarian cancer is closely related to the stage at diagnosis,[31, 32] as determined according to the staging system developed by the International Federation of Gynecology and Obstetrics (FIGO). (See Workup/Staging.) Approximately 20%, 5%, 58%, and 17% of women present with stage I, II, III, and IV, respectively.

The 5-year survival rates (rounded to the nearest whole number) for epithelial ovarian carcinoma by FIGO stage are as follows:

Bakhru et al found poorer survival among patients with ovarian cancer and diabetes. Although the underlying reason for this association is unknown, further studies are needed.[33]

Among women with high-grade serous ovarian cancer, BRCA2 mutation but not BRCA1 deficiency was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.[34]

A study by Bolton et al found improved 5-year overall survival among carriers of BRCA1 or BRCA2, with BRCA1 having the best prognosis.[35]

Prognosis of Tumors of Low Malignant Potential

Overall survival rate at 5 years according to FIGO is shown below. Others have reported better survival rates with 5-year, 10-year, 15-year, and 20-year survival for patients with serous LMP as 97%, 95%, 92%, and 89%, respectively.

Five-year-survival rate for LMP tumors by FIGO stage (survival percentages rounded to nearest whole number) are as follows:

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 as 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.[1] 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.[2] 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 only 8% of patients overall but in 43% of those with ovarian cancer.[36]

Physical Examination

Physical findings are uncommon in patients with early disease. Patients with more advanced disease may present with any of the following:

Approach Considerations

The 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.

Current guidelines from the Society of Gynecologic Oncology and the American Society of Clinical Oncology recommend that the primary clinical evaluation for ovarian cancer include a computed tomography (CT) scan of the abdomen and pelvis with oral and intravenous contrast, and chest imaging (CT preferred) to evaluate the extent of disease and the feasibility of surgical resection.[42] National Comprehensive Cancer Network guidelines recommend ultrasound and/or abdominal/pelvic CT or magnetic resonance imaging (MRI), as clinically indicated, and chest CT or x-ray, as clinically indicated. Positron emission tomography (PET)/CT scan or MRI may be indicated for indeterminate lesions, if the results will alter management.[43]

MRI can increase the specificity of imaging evaluation in cases where the ultrasound appearance of the lesion is indeterminate.[8] 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.[44]

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 (CA-125) level.[45] Tumor markers such as CA-125 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 gastrointestinal (GI) symptoms, a GI tract workup may be indicated, including one of the following:

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, surgical evaluation for diagnosis and staging can be performed. An FNA, percutaneous biopsy, or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass, or in patients who will be treated with neoadjuvant chemotherapy. .

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 CA-125 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.[3]

A randomized trial in a US population found that simultaneous screening with ultrasonography and CA-125 did not reduce ovarian cancer mortality, and evaluation of false-positive results was associated with complications.[46]

The US Food & Drug Administration (FDA) recommends against the use of tests marketed for ovarian cancer screening.[4] The National Cancer Institute (NCI) cites evidence of lack of mortality benefit with screening, and potential harms relating to false-positive test results.[5]

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 in 202,638 women; 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.

Primary analysis of data from the United Kingdom Collaborative Trial of Ovarian Cancer Screening found no significant difference in ovarian cancer mortality in women who underwent annual multimodal screening (MMS) with serum CA-125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound, or no screening. When prevalent cases were excluded, however, a significant mortality reduction with MMS was noted, with evidence of a mortality reduction in years 7-14. The authors conclude that "further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening."[47]

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.[48]

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.[49]

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 CA-125, in addition to diagnostic imaging, is useful in the diagnosis of ovarian cancer.

CA-125 is a glycoprotein antigen detected by using mouse monoclonal antibody OC125 raised from an ovarian cancer cell line. CA-125 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 CA-125 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 CA-125 has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA-125 in serum has generally reflected persistence of disease at second-look surveillance procedures. However, CA-125 levels can return to within normal limits and residual disease can be found at laparoscopy or laparotomy.

CA-125 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. CA-125 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.[37]

A study by Hirai et al found that stage IA ovarian cancers in women with normal CA125 levels are usually smaller, have slightly different histopathologic type distribution, and have less solid components than cancers with elevated CA-125 levels.[50]

A study by Buys et al found that among women in the general US population, screening simultaneously with CA-125 and transvaginal ultrasonography did not reduce ovarian cancer mortality compared with usual care. False-positive results occurred in 9.6% of women, resulting in 6.2% undergoing surgery.[51]

Tests that use multiple markers have been devised. The OVA1 test includes five markers: transthyretin, apolipoprotein A1, transferrin, beta-2 macroglobulin, and CA-125. The Ovasure test includes six markers: leptin, prolactin, osteopontin, insulinlike growth factor II, macrophage inhibitory factor, and CA-125. The National Comprehensive Cancer Network (NCCN) does not endorse either of those for ovarian cancer screening.[43]

Other markers that have been investigated include 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.[52] 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.[53]

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.[54]

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.

Imaging in Ovarian Cancer

Imaging studies used in ovarian cancer include ultrasonography, chest radiography, computed tomography (CT), 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 or CT is performed routinely, as it is useful in helping exclude pleural effusions or 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.

In many cases, CT is complementary to surgical staging. CT can identify possible sites of unsuspected disease such as the pelvic peritoneum, paraaortic nodes, diaphragm, and chest.[55]

For more information, see Malignant Ovarian Tumor Imaging.

GI Tract Workup

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

Carcinoembryonic antigen (CEA) levels may also be measured.

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 surgical evaluation for diagnosis and staging.

FNA, percutaneous biopsy, or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass, and in patients who will be treated with neoadjuvant chemotherapy

Mammography

The preoperative workup also should include mammography for women older than 40 years who have not had a recent mammogram. 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, often bilaterally. Mammography can help rule out the possibility of a nongynecologic primary neoplasm in the breast.

Workup of Tumors of Low Malignant Potential

All histologic subtypes of endothelial ovarian cancer have serous, mucinous, endometrioid, clear cell, and Brenner low malignant potential (LMP) variants, with the essential feature being that no invasion occurs. Mucinous and serous types are most common (see the image 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.



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Inside of a large, smooth-surfaced tumor replacing the ovary. Final histologic studies indicated the tumor was a mucinous carcinoma of low malignant p....

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.

Workup of Malignant Germ Cell Tumors

If a malignant germ cell tumor (GCT) is suspected at presentation, blood should be examined for tumor markers, including beta human human chorionic gonadotropin (beta-hCG), 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.

Patients with immature teratomas will not have elevated levels of tumor markers unless the tumor contains elements of other GCTs. The cardinal histologic feature is immature elements, mostly of neural tissue.

Staging

Ovarian cancer is typically staged by means of the system formulated and updated by the International Federation of Obstetrics and Gynecology (FIGO),[56] as listed below.

Stage I

In stage I, growth is limited to the ovaries. Substages are as follows:

Stage II

In stage II, tumor involves one or both ovaries, with pelvic extension (below the pelvic brim) or primary peritoneal cancer. Substages are as follows:

Stage III

In stage III, tumor involves one or both ovaries, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis, and/or metastasis to the retroperitoneal lymph nodes. Substages are as follows:

Stage IV

Stage IV comprises distant metastasis, excluding peritoneal metastasis. Substages are as follows:

Other recommendations

Additional major recommendations from FIGO include the following:

Approach Considerations

Surgery is often the initial treatment of choice for ovarian cancer, provided patients are medically fit. Patients who are not candidates for optimal debulking should be considered for neoadjuvant chemotherapy followed by interval debulking surgery and further chemotherapy.  Patients who are not fit for surgery may be given chemotherapy and considered for surgery later, or treated primarily with chemotherapy.

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.

Surgery should be used in conjunction with chemotherapy with a taxane and a platinum compound (eg, paclitaxel plus carboplatin). For more information on chemotherapy regimens, see Ovarian Cancer Treatment Protocols.

In women who present with peritoneal 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 can be treated with cytoreductive surgery and platinum-based chemotherapy.

For more information on screening, prevention, diagnosis, and treatment, see Guidelines.

Choosing Appropriate Surgery

The appropriate surgical approach varies, depending on whether disease is visible outside the ovaries. For patients with no disease visible outside the ovaries, adequate surgical staging is essential 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 thorax can be considered for cytoreductive surgery if medically fit.

If the patient does not desire future fertility, perform a total abdominal hysterectomy and excise the opposite ovary. Appendectomy can be performed if a 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 surgical approach should be individualized and may involve laparotomy or use of a minimally invasive approach. Regardless of approach, staging requires several key components. 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:

Cytoreductive Surgery

Cytoreductive surgery 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 National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines, in newly diagnosed invasive epithelial ovarian cancer that involves the pelvis and upper abdomen, 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.[43] The NCCN notes that one or more of the following procedures may be considered for optimal surgical cytoreduction:

Patients with advanced ovarian cancer are classified in three groups as follows, based on the postoperative residual tumor:

Interval Debulking

Interval debulking can be performed in patients whose cancer was 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 three cycles of postoperative chemotherapy. Approximately 60% of patients are then able to undergo optimal resection. Surgical treatment is followed by three more cycles of chemotherapy.

A prospective, randomized, clinical trial conducted in Europe demonstrated that this approach improves the outcome of patients with advanced ovarian cancer.[57] However, this was not confirmed in a study conducted in the United States.[58] 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.[59]

Laparoscopic Surgery

According to guidelines developed by the American College of Obstetricians and Gynecologists, laparoscopy may be used for diagnostic purposes in a patient at low risk for ovarian cancer and to remove cystic masses, provided that all the following criteria are met[37] :

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 during a single anesthetic session, 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 NCCN ovarian cancer guidelines state that minimally invasive surgery may be used by an experienced surgeon in selected patients to achieve surgical staging and debulking. In addition, the NCCN considers that minimally invasive surgery may be useful when evaluating whether maximum cytoreduction can be achieved in patients with newly diagnosed or recurrent ovarian cancer.[43]

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.[60]

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, and endometrioid 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 CA-125 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.

Higher-risk early-stage disease includes all histologic subtypes with stage IA and stage IB grade 3 or IC any grade These patients are usually treated with front-line chemotherapy with a taxane/platinum combination for a minimum of three courses. They should consider participating in clinical trials. Patients with IA and IB, grade 2 disease may also be candidates for chemotherapy. All patients with stage II cancer and greater should receive front-line chemotherapy or consider participation in clinical trials.

The NCCN recommends three to six cycles of intravenous taxane/carboplatin adjuvant chemotherapy for high-risk stage IA, IB, or IC epithelial ovarian cancer.[43] For stage II-IV disease, the recommended options include intraperitoneal chemotherapy, in patients with < 1 cm optimally debulked stage II and III disease; or intravenous taxane/carboplatin for six cycles. In addition, completion surgery, as indicated by tumor response and potential resectability, may be used in selected patients.[43]

Carboplatin is 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. In patients who have received extensive prior chemotherapy or radiation, treatment should start at 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.[61] Docetaxel in combination with carboplatin has been shown to provide equivalent survival rates with less neurotoxicity but greater neutropenia.

Either cisplatin or carboplatin may be combined with paclitaxel. 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 adding other drugs to this regimen has proved disappointing, investigators have studied the use of a dose-dense regimen, in which paclitaxel is given on days 1, 8, and 15 and carboplatin on day 1.[62, 63] The dose-dense regimen has resulted in longer median progression-free survival and higher overall survival. Early discontinuance may be more common with the dose-dense regimen, and increased toxicity has been reported.

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 an 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.[64]

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.[65] 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.

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.[66]

A phase III study by Pignata et al found that, compared with standard therapy using carboplatin plus paclitaxel, treatment with carboplatin plus pegylated liposomal doxorubicin produced a similar response rate but a different pattern of toxicity—less neurotoxicity and alopecia but more hematologic adverse effects. These authors conclude that carboplatin plus pegylated liposomal doxorubicin could be an alternative regimen.[67]

Monitoring during chemotherapy

The NCCN recommends the following for monitoring during primary chemotherapy[43] :

Ovarian function and future pregnancy

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.

Pazopanib

Adding pazopanib, a kinase inhibitor, to the standard postsurgical chemotherapy regimen has shown promise for progression-free survival in advanced ovarian cancer. In a study of 940 women with advanced ovarian cancer (epithelial ovarian, fallopian tube, or primary peritoneal cancers) who had not shown evidence of postsurgical progression after five or more cycles of platinum-taxane chemotherapy, progression-free survival in these patients was increased with the addition of pazopanib to standard treatment.[68]

Most of the women in the study had stage III/IV disease (91%) at initial diagnosis and no residual disease after surgery (58%).[68] At a median follow-up of 24 months, patients treated with 800 mg of pazopanib once daily had a prolonged progression-free survival, as compared with those receiving placebo. However, the pazopanib group also had a higher incidence of adverse events and serious adverse events, of which the most common were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia.[68] Four fatal adverse events occurred, three in the pazopanib group and one in the placebo group.

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. Results from randomized clinical trials suggest that in patients with optimally debulked disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous administration.[69, 70] Meta-analyses have confirmed that intraperitoneal chemotherapy is associated with improved survival, but also with more toxicity.[71, 72]

A retrospective analysis of Gynecologic Oncology Group protocols 114 and 172 found that in patients with advanced ovarian cancer, median survival with intraperitoneal therapy was 61.8 months, compared with 51.4 months for intravenous therapy. Intraperitoneal therapy was associated with a 23% decreased risk of death, and with improved survival in patients with gross residual (≤1 cm) disease. Risk of death decreased by 12% for each cycle of intraperitoneal chemotherapy completed.[69] Thus, intraperitoneal chemotherapy should be strongly considered for the treatment of front-line disease following surgery where 5 mm or less of residual disease exists, and perhaps for more advanced cancers.

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.[73] Patients receiving adjuvant intraperitoneal chemotherapy are more likely to have recurrences outside the abdominal cavity, according to a study by Tanner et al.[74]

Intraperitoneal chemotherapy may cause more adverse 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. Modifications to improve the tolerability of intraperitoneal chemotherapy that are being examined include reduction of the total 3-hour amount of cisplatin given.[75]

Neoadjuvant chemotherapy

According to NCCN guidelines, neoadjuvant chemotherapy may be considered for patients with bulky stage III-IV disease ovarian cancer or those who are poor candidates for surgery; however, the NCCN recommends that the assessment of such patients be performed by a gynecologic oncologist. The NCCN notes that upfront debulking surgery remains the treatment of choice in the United States. [43]

Neoadjuvant chemotherapy for ovarian cancer has been controversial. Although a 2006 meta-analysis concluded that neoadjuvant chemotherapy was associated with worse prognosis,[76]  a 2010 study found that in women with stage III and IV ovarian cancer, neoadjuvant chemotherapy followed by interval surgery provided equivalent outcomes to standard primary surgery followed by chemotherapy.[77]  

Melamed et al reported that in regions of the United States (eg, New England) that rapidly increased the use of neoadjuvant chemotherapy for stage IIIC or IV epithelial ovarian cancer from 2011 to 2012, all-cause mortality through 3 years post-diagnosis dropped significantly in this patient population (hazard ratio [HR], 0.81). In contrast, regions where use of neoadjuvant chemotherapy remained unchanged (eg, the south Atlantic) saw no improvement in mortality (HR, 1.02).[78]

Neoadjuvant chemotherapy comprises two or more cycles of conventional chemotherapy. If the patient has a good response, interval debulking surgery may be performed followed by further chemotherapy.

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.[79]

A meta-analysis indicated that continuing chemotherapy improved progression-free survival and overall survival, especially if complete response was reached after primary therapy.[80]

Niraparib (Zejula) is a poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) enzyme inhibitor that was approved by the FDA in March 2017 for maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in women who are in complete or partial response to platinum-based chemotherapy. Niraparib is active both in patients with and those without BRCA mutations. See Management of Recurrent Disease, below.

Rucaparib (Rubraca) is also a PARP inhibitor. It was initially approved by the FDA as monotherapy for patients with ovarian cancer with a deleterious BRCA mutation following prior treatment with two or more chemotherapies. In April 2018, the FDA approved rucaparib for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA status. 

Maintenance treatment approval was based on findings from the phase 3 ARIEL3 study, which enrolled 564 patients and randomly assigned them to either 600 mg of rucaparib twice daily or placebo. Progression-free survival was 10.8 months in the intention-to-treat population compared with 5.4 months in the placebo group. In the nested BRCA-mutant cohort, the median progression-free survival in patients with a BRCA-mutant carcinoma was 16.6 months for patients receiving rucaparib compared with 5.4 months for the placebo group.[81]

Maintenance treatment with the PARP inhibitor olaparib resulted in a marked increase in progression-free survival in patients with advanced ovarian cancer who carry a BRCA mutation and have completed successful first-line chemotherapy. A phase III randomized trial in 391 patients found that after a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo.[82, 83]

Bevacizumab

The FDA has approved bevacizumab (Avastin) for patients with  stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by single-agent bevacizumab, after initial surgical resection.[84]  

In the OCEANS phase III study, women who received the combination of bevacizumab with chemotherapy had a 52% risk reduction for recurrence in disease progression (hazard ratio 0.48, P< 0.0001) 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.[85]

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.[85] However, on final analysis, median overall survival was not significantly different in patients who received bevacizumab and those who received placebo (33.6 versus 32.9 months, respectively; hazard ratio=0.95; log-rank p=0.65).[86]

A second phase III trial found adding bevacizumab to chemotherapy showed an overall survival difference of 5 months compared with paclitaxel plus carboplatin chemotherapy alone (median OS: 42.6 months vs. 37.3 months; Hazard Ratio (HR)=0.84, 95% CI: 0.69-1.01 and HR=0.82, 95% CI: 0.68-0.996). The GOG-0213 study showed that women lived a median of 3.4 months longer without disease progression with the addition of bevacizumab to chemotherapy compared with chemotherapy alone (median PFS: 13.8 months vs. 10.4 months; HR=0.61, 95% CI: 0.51-0.72).[87]

Consolidation chemotherapy

Ovarian cancer has a very high response rate to front-line treatment; despite this, most patients develop recurrent cancer. Many groups 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.[79] 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 plus hyperthermic chemotherapy, which combines three separately useful modalities: surgical debulking, intraperitoneal chemotherapy, and heat. See the videos below.



View Video

Dr. Oliver Zivanovic, MD, PhD, discusses the role of hyperthermic intraperitoneal chemotherapy in ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.



View Video

Dr. Oliver Zivanovic, MD, PhD, demonstrates hyperthermic intraperitoneal chemotherapy for ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.

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.

In younger women with endometrioid subtypes, ERT is a concern because these tumors theoretically are estrogen sensitive. If estrogen is used in such patients, a progestin should also be considered.

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 patients found to have disease after 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 during the study.[70]

Efforts are now under way 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. In many instances it may be possible to perform this evaluation adequately using the laparoscope.

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.

Cancer antigen 125

National Comprehensive Cancer Network (NCCN) guidelines recommend that if the cancer antigen 125 (CA-125) level was initially elevated, follow-up should include measurement of CA-125 or other tumor markers.[43] The finding of an elevated serum CA-125 level in the absence of clinical or radiographic disease is relatively common in patients with epithelial ovarian cancer following initial treatment. Management in these cases is controversial.The NCCN notes that recommended options include the following[43] :

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 express 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 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.[88]

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.[89]

Management of Recurrent Disease

In most patients who present with advanced epithelial ovarian cancer, the disease recurs, and the prognosis for these patients is poor. Treatment of recurrent disease may involve surgery, chemotherapy, and radiation. If a localized mass is present, surgery may play a role prior to the initiation of further chemotherapy. Participation in clinical trials should be considered. 

Recurrent ovarian cancer is classified into two 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.[90, 91]  The probability of response increases with the duration of the disease-free interval. For platinum-sensitive recurrent disease, National Comprehensive Cancer Network (NCCN) guidelines recommend any of the following as preferred regimens[43] :

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.[92]  In a phase III randomized study, topotecan and cisplatin followed by carboplatin and paclitaxel were more toxic and without improved efficacy.[80]

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.[93]  

Single-agent therapy is usually given for recurrent disease, although bevacizumab may be added in some cases.[43]  Agents that may elicit a response in patients whose disease is resistant to platinum-based therapies include the following:

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 with conventional 5-day schedules.[94]  

A study by Haldar et al found that epithelial growth factor inhibitors, including pertuzumab, may add activity to standard chemotherapy in women with platinum-resistant ovarian cancer.[95]

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 selection of chemotherapy agents with the greatest potential for activity and avoidance of those associated with extreme resistance.

Single agents available for targeted therapy include PARP inhibitors.

PARP inhibitors

Poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) enzymes are involved in normal cellular homeostasis (eg, DNA transcription, cell cycle regulation, DNA repair). PARP enzyme inhibitors result in disruption of cellular homeostasis and cell death. The following PARP inhibitors are approved by the US Food and Drug Administration (FDA) for use in ovarian cancer:

Olaparib

Olaparib is an inhibitor of PARP1, PARP2, and PARP3. Olaparib capsules and tablets are approved as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with three or more prior lines of chemotherapy. Additionally, the tablets are approved for maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. The tablets and capsules are not interchangeable on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation, and therefore, should not be substituted with one another.

Approval of olaparib tablets for maintenance therapy for women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer was based on two randomized, placebo-controlled, double-blind, multicenter trials, SOLO-2 and Study 19. In the SOLO-2 clinical trial, 295 patients with recurrent germline BRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned to receive olaparib tablets 300 mg orally twice daily or placebo. A statistically significant improvement in progression-free survival (PFS) in the olaparib arm was observed that showed an improvement of 24.7 months (P < 0.0001) compared with placebo, thus reducing the risk for disease progression by nearly 75%.[96]

In the Study 19 (n=265) trial, patients were randomly assigned to receive olaparib capsules 400 mg orally twice daily or placebo. This cohort differed from that of the SOLO-2 trial in that patients did not have to harbor BRCA mutations. Results also showed a statistically significant improvement in investigator-assessed PFS in the olaparib arm as compared with placebo (P < 0.0001). The estimated median PFS was 8.4 months for the olaparib group and 4.8 months for the placebo group.[97]

Another phase II clinical trial involved 298 patients with ovarian cancer associated with germline BRCA1/2 mutations, all of whom received olaparib. The overall response rate was 31.1% and stabilization of disease > 8 weeks was seen in 40% of patients.[98]

Olaparib 400 mg PO BID continuously was compared with pegylated liposomal doxorubicin (PLD) 50 mg/m2 IV every 4 weeks. Median PFS was 8.8 months for olaparib compared with 7.1 months for PLD. Overall response rate was 31% for olaparib and 18% for PLD.[99]

Rucaparib

The PARP inhibitor rucaparib gained accelerated approval by the FDA in December 2016. It is indicated for monotherapy of women with deleterious BRCA mutations (germline and/or somatic) associated with advanced ovarian cancer who have been treated with ≥2 prior lines of chemotherapy.

Approval was based results from 106 women enrolled in 2 single-arm clinical trials, Study 10 and ARIEL2 (Assessment of Rucaparib In Ovarian CancEr TriaL2). Patients in these trials had an overall response rate of 54% (complete, 9%; partial, 45%) and a median duration of response of 9.2 months, according to the FDA press materials. The drug's prescribing information also indicates that the overall response rate as assessed by an independent radiology review was 42%, with a median duration of response of 6.7 months, while the investigator-assessed response rate was 66%.[100, 101, 102]

Continued approval of rucaparib for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The ARIEL3 maintenance confirmatory study has completed enrollment and the ARIEL4 treatment confirmatory study is open for enrollment at the time of this update.

Niraparib

Niraparib was approved by the FDA in March 2017 for maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in women who are in complete or partial response to platinum-based chemotherapy. Unlike other PARP inhibitors (eg, olaparib, rucaparib), niraparib is active both in patients with and those without BRCA mutations

.Approval of niraparib was based on results from the placebo-controlled NOVA phase 3 trial (n=553), which showed a significant improvement in PFS with niraparib. In the germline BRCA mutation (gBRCA) cohort, PFS with niraparib versus placebo was 21.0 vs 5.5 months, respectively. PFS was 12.9  vs 3.8 months in the non-gBRCA patients who had tumors with homologous recombination deficiency (HRD), and 9.3  vs 3.9 months in the overall non-gBRCA cohort (P< 0.001 for all 3 comparisons).[103]

The combination of niraparib and pembrolizumab showed promising antitumor activity in an open-label, single-arm phases 1 and 2 study in a 62 patients with recurrent ovarian carcinoma with resistance to or ineligibility for retreatment with a platinum-based chemotherapy regimen.  The objective response rate was was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 patients (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, and 28 (47%) with stable disease; 20 (33%) experienced progressive disease.[104]

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. 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. A somatostatin analog to decrease gastrointestinal secretions can be 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 complication 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, in patients undergoing surgical relief of bowel obstruction or other intervention. However, long-term parenteral nutritional support is seldom appropriate 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 phosphate. 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.

Experimental Medications

Folate receptor alpha (FRα), which is expressed by the majority of ovarian cancers but not by normal ovarian tissue, is emerging as a therapeutic target in ovarian cancer, and particularly in platinum-resistant cases.[105] Mirvetuximab soravtansine is an antibody-drug conjugate consisting of an anti-FRα antibody linked to a potent antimitotic agent. The phase III FORWARD I trial is comparing the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with FRα-positive, platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer.[106]

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, gonadotropin-releasing hormone (GnRH) agonists, and megestrol (Megace) have all been reported in a small number of patients with progressive disease not responsive to chemotherapy.[107]

Several 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. [108]  Patients with recurrent disease have 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.

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.[109]

Management of 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.

Management of Tumors of Low Malignant Potential (Borderline Tumors)

The accepted initial treatment for tumors of low malignant potential (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 sufficient 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 one 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.

For more information, see Borderline Ovarian Cancer

Treatment of 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.[110]

Endodermal sinus cell tumors secrete alpha-fetoprotein. Following standard surgery, all patients should be treated with BEP. Other chemotherapy regimens may be necessary.

Treatment of 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%.

Treatment of 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.

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

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 (eg, solid or mixed solid and cystic tumors, ascites) 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, lactate dehydrogenase (LDH), AFP, beta-hCG, and inhibin levels. Appropriate referral should be made if any of these are significantly elevated.

Patients with primarily gastrointestinal (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 (EOC) is significantly reduced by the following:

Evidence suggests that taking oral contraception 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.[111] The American College of Obstetricians and Gynecologists recommends offering bilateral salpingo-oophorectomy to women with BRCA1 or BRCA2 mutations after completion of childbearing (level B recommendation).[112]  On the basis of their study in 5,783 women with a BRCA1 or BRCA2 mutation, Kinch et al concluded that in BRCA1 mutation carriers, oophorectomy at age 35 years can be recommended.[113]

Surgical prophylaxis decreases the risk by at least 80%.[113] Salpingo-oophorectomy does not prevent all cases of related cancer, 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 EOC from developing, a small risk still exists for developing carcinoma of the peritoneum, a disease that behaves similarly to EOC.

BRCA1 and BRCA2 mutations are common among women with invasive ovarian cancer; thus, women diagnosed with invasive, nonmucinous ovarian cancer are candidates for genetic testing.[114]

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.[115]

Guidelines Summary

Guidelines Contributor: Jori S Carter, MD, MS, Assistant Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Screening

The U.S. Preventive Services Task Force (USPSTF) has concluded that annual screening of asymptomatic women with transvaginal ultrasonography and testing for a serum tumor marker, cancer antigen (CA)–125, does not reduce ovarian cancer deaths, but can lead to major surgical interventions in women who do not have cancer. With the harms of screening outweighing the benefits, USPSTF recommends against routine screening in asymptomatic women without a known high-risk hereditary cancer syndrome.[3]

The consensus among major medical organizations is in agreement with the USPSTF that screening for ovarian cancer in the general population is not recommended. However, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) recommend that women at high risk be offered an evaluation that includes transvaginal ultrasonography, CA-125 testing, and a thorough pelvic examination.[116]

Risk Assessment and Genetic Counseling

The following organizations have issued guidelines for genetic risk assessment of women with BRCA1 and BRCA2 mutations, Lynch syndrome (hereditary nonpolyposis colon cancer), or a family history of ovarian cancer:

U.S. Preventive Services Task Force

In 2019, the USPSTF issued updated guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The recommendation is that primary care providers screen women who have a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations, using one of several available brief familial risk tools, including the following[117] :

Women with a positive screening result should receive genetic counseling, with further BRCA testing if warranted. Women without a family history associated with an increased risk for mutations should not receive routine risk assessment, genetic counseling, or BRCA testing.

National Comprehensive Cancer Network

The NCCN provides specific criteria for genetic counseling and testing of BRCA, as well as additional genetic mutations associated with ovarian cancer risk: CDH1, STK11/LKB1, and Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) genes. Separate criteria for genetic evaluation is given for individuals affected with breast or ovarian cancer and unaffected individuals with a family history suggestive of genetic risk.[118]

The criteria for affected individuals include having at least one of the following risk factors:

The criteria for unaffected individuals include a family history of at least one of the following:

Women who meet the assessment criteria should receive genetic counseling, with further BRCA testing if warranted. Multi-gene testing may be considered in women who have tested negative (indeterminate) for a single syndrome, but whose personal or family history remains suggestive of an inherited susceptibility.

American Society of Clinical Oncology

In 2015, ASCO updated its general guidelines for genetic testing for cancer susceptibility. Genetic testing is recommended when the patient has a personal or family history suggestive of genetic cancer susceptibility, the test can be adequately interpreted, and the results will aid in diagnosis or medical management of the patient or family member. ASCO also recommends genetic testing only when pretest and posttest counseling are included.[119]

European Society of Medical Oncology

Guidelines from ESMO, updated in 2016, note that testing criteria differ between countries based on the population prevalence of the mutation and include not only specific criteria very similar to that of NCCN, but also more general criteria such as having a 10-20% probability of finding a mutation based on predictive models, or the assumption of a potential benefit in the medical or surgical management of the individual or close family members.[120]

Overall, ESMO recommends that all patients referred for BRCA testing first complete informed consent and genetic counseling and that those who are mutation carriers be encouraged to advise close family members to obtain genetic counseling.[120]

American College of Obstetricians and Gynecologists

Guidelines issued by ACOG in 2009 recommend genetic risk assessment for women who have more than a 20% to 25% risk for an inherited predisposition to breast and ovarian cancer.[121]

Society of Gynecologic Oncologists

In 2014, the Society of Gynecologic Oncologists updated its clinical practice statement on genetic testing for ovarian cancer to recommend that all women diagnosed with ovarian cancer receive genetic counseling and be offered genetic testing regardless of family history.[122]

Surgical Intervention for Ovarian Cancer Prevention

The NCCN recommends bilateral salpingo-oophorectomy (RRSO) for risk reduction in women with BRCA1 or BRCA2 mutations, ideally at the age of 35-40 years and upon completion of childbearing or at an individualized age based on earliest age of ovarian cancer diagnosed in the family.[118] Both the USPSTF and ACOG also support offering salpingo-oophorectomy for risk reduction to women with BRCA1 or BRCA2 mutations.[117, 121] ESMO guidelines concur and suggest that the surgery take place after age 35 and childbearing is completed.[120]

The NCCN guidelines also note that women considering RRSO should be made aware of the increased risk of osteoporosis and cardiovascular disease associated with premature menopause, as well as the potential effects of possible cognitive changes, accelerated bone loss, and vasomotor symptoms on quality of life.[118]

SGO guidelines are in agreement that women who have BRCA mutations should be offered RRSO, after completion of childbearing, as the best strategy for reducing their risk of developing ovarian cancer. The guidelines further recommend that for those women who choose not to undergo RRSO because of the health risks and impact on quality of life associated with premature menopause, physicians may offer the option of salpingectomy after childbearing is completed, followed by oophorectomy in the future. However, women who delay oophorectomy will remain at risk for developing ovarian cancer. Additionally, they will not benefit from the 50% reduction in breast cancer provided through premenopausal oophorectomy.[123]

The SGO advises that pathologic processing of RRSO specimens from high-risk women should include micro-sectioning of the ovaries and tubes, with special attention to the fimbriae.[123]

For women at average risk of ovarian cancer, risk-reducing salpingectomy should also be considered at the time of abdominal or pelvic surgery or hysterectomy or in lieu of tubal ligation. The pathologic specimen processing in low risk-women should include representative sections of the tube, any suspicious lesions, and entire sectioning of the fimbriae.[123]

Diagnostic Evaluation

The American College of Obstetricians and Gynecologists has established referral guidelines for a patient with a newly diagnosed pelvic mass. Women who meet the criteria below would benefit from preoperative consultation with a gynecologic oncologist.[116]

For premenopausal women, referral criteria are as follows:

For menopausal women, referral criteria are as follows:

The National Comprehensive Cancer Network (NCCN) guidelines make a category 1 recommendation that in all patients undergoing surgical evaluation for ovarian cancer, the procedure should be performed by an experienced gynecologic oncologist.[43]

Guidelines from the SGO and American Society of Clinical Oncology (ASCO) contain a strong recommendation, similar to that of the NCCN, that all women with suspected stage IIIC or IV invasive epithelial ovarian cancer be evaluated by a gynecologic oncologist to determine whether they are candidates for primary cytoreductive surgery.[42]

Staging

Two major staging systems are commonly used in ovarian cancer, as follows:

For details on these systems, see Ovarian Cancer Staging

Primary Treatment

According to the National Comprehensive Cancer Network (NCCN) guidelines, surgery is the primary treatment for ovarian cancer, followed in most patients by systemic chemotherapy. The aim of surgery is to confirm the diagnosis, define the extent of disease, and resect all visible tumor.[43]

Additional recommendations are as follows:[43]

Chemotherapy

In 2016, the Society of Gynecologic Oncology (SGO) and American Society of Clinical Oncology (ASCO) released guidelines for neoadjuvant chemotherapy (NACT) in newly diagnosed patients with advanced ovarian cancer. The SGO/ASCO guidelines include the following recommendations[42] :

National Comprehensive Cancer Network (NCCN) guidelines recommend that patients wishing to preserve fertility be referred to a fertility specialist prior to initiation of therapy.[43] For primary chemotherapy, NCCN recommendations are as follows[43] :

For a first recurrence, the NCCN prefers combination platinum-based chemotherapy. Agents for platinum-resistant disease include the following:

Agents for targeted therapy include bevacizumab, rucaparib, and olaparib. Hormonal therapy agents may include aromatase inhibitors, leuprolide, megestrol, or tamoxifen.

For details on chemotherapy regimens, see Ovarian Cancer Treatment Protocols

Surveillance

The Society of Gynecologic Oncologists 2011 guidelines for post-treatment surveillance include the following[126] :

The National Comprehensive Cancer Network recommendations are similar and include the following[43] :

Medication Summary

Standard postoperative chemotherapy is combination therapy with platinum and paclitaxel. Carboplatin plus paclitaxel is the preferred initial regimen. Randomized studies have proved that cisplatin plus paclitaxel produces equivalent survival rates, but the combination of carboplatin and paclitaxel is preferred because of its more tolerable toxicity profile. 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-day 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.[62] 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.

Cisplatin (Platinol)

Clinical Context:  Indicated in established combination therapy in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic procedures. It also is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received cisplatin therapy. For cisplatin, intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed mechanisms of action.

Carboplatin

Clinical Context:  For carboplatin, intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed mechanisms of action.

Paclitaxel (Taxol)

Clinical Context:  Indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel is indicated in combination with cisplatin. The mechanism of action of paclitaxel is tubulin polymerization and microtubule stabilization.

Liposomal doxorubicin (Doxil)

Clinical Context:  Liposomal doxorubicin interferes with synthesis of nucleic acid by intercalating with DNA nucleotide pairs and topoisomerase II inhibition. Indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

Class Summary

Cisplatin, carboplatin, and paclitaxel are chemotherapy agents approved for the initial treatment of ovarian cancer. Intrastrand cross-linking of DNA and inhibition of DNA precursors are among proposed mechanisms of action for cisplatin. The mechanism of action for paclitaxel is tubulin polymerization and microtubule stabilization. A study by Hetland et al found that class III beta-tubulin expression in prechemotherapy effusions is associated with poor response and shorter survival; thus, it may be a successful therapeutic target in ovarian cancer.[127]

Results from randomized studies have shown that platinum-containing regimens are superior to those that do not contain platinum. In addition, the combination of platinum and paclitaxel is superior to a regimen that does not include paclitaxel.

Etoposide

Clinical Context:  Etoposide is a glycosidic derivative of podophyllotoxin that exerts its cytotoxic effect through stabilization of the normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks.

Topotecan (Hycamtin)

Clinical Context:  Topotecan binds to the topoisomerase I‑DNA complex and prevents religation of single-strand breaks.  Indicated as monotherapy for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy.

Gemcitabine (Gemzar)

Clinical Context:  Gemcitabine is a cytidine analog that is metabolized intracellularly to an active nucleotide. It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. It is indicated for advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy and is used in combination with carboplatin. It is cell-cycle specific for the S phase.

Docetaxel (Taxotere)

Clinical Context:  Docetaxel is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division, leading to cell death.

Vinorelbine (Navelbine)

Clinical Context:  Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin polymerization during G2 phase of cell division, thereby inhibiting mitosis.

Ifosfamide

Clinical Context:  Ifosfamide inhibits DNA and protein synthesis and, thus, cell proliferation, by causing DNA cross-linking and denaturation of double helix.

Fluorouracil (Adrucil)

Clinical Context:  Fluorouracil (5-FU) is a cycle-specific agent that has activity as single agent and, for many years, has been combined with biochemical modulator leucovorin. 5-FU inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability.

Melphalan (Alkeran)

Clinical Context:  Melphalan inhibits mitosis by cross-linking DNA strands. Tablets are indicated for the palliation of nonresectable epithelial ovarian carcinoma.

Altretamine (Hexalen)

Clinical Context:  The mechanism of action of altretamine is unclear; reactive intermediates covalently bind to microsomal proteins and DNA, possibly causing DNA damage. Altretamine inhibits DNA and RNA synthesis by inhibiting the incorporation of radioactive thymidine and uridine into DNA and RNA. Indicated as palliative treatment of patients with persistent or recurrent ovarian cancer.

Bevacizumab (Avastin)

Clinical Context:  Bevacizumab is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) receptors. Blocking the angiogenic VEGF receptor, in turn inhibits tumor angiogenesis, starving tumor of blood and nutrients. It is indicated in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent epithelial ovarian cancer in patients who received no more than 2 prior chemotherapy regimens. It is also indicated for women with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine chemotherapy, followed by bevacizumab alone.

Class Summary

Antineoplastic agents inhibit cell growth and proliferation. Several antineoplastic 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).

Olaparib (Lynparza)

Clinical Context:  Olaparib is an inhibitor of PARP enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis (eg, DNA transcription, cell cycle regulation, DNA repair). Available as either tablets or capsules. The tablets and capsules are not interchangeable on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation, and therefore, should not be substituted with one another. The capsules and tablets are indicated as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with 3 or more prior lines of chemotherapy. Additionally, the tablets are approved for maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. Discontinue bevacizumab before initiating maintenance therapy.

Rucaparib (Rubraca)

Clinical Context:  By inhibiting PARP, rucaparib may cause increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis, and cell death. Increased cytotoxicity due to rucaparib was observed in tumor cell lines deficient in BRCA1/2 and other DNA repair genes. Indicated for monotherapy of women with deleterious BRCA mutation (germline and/or somatic) associated with advanced ovarian cancer who have been treated with ≥2 prior lines of chemotherapy. Also, indicated for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. 

Niraparib (Zejula)

Clinical Context:  Niraparib is a highly selective for PARP-1 and PARP-2. PARP-1 and PARP-2 are involved in detecting DNA damage and promote repair. Inhibiting PARP enzymatic activity results in DNA damage, apoptosis and cell death. PARP inhibitor that is active both in patients with and those without BRCA mutations. Indicated for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Discontinue bevacizumab before initiating maintenance therapy.

Class Summary

Inhibition of poly (ADP-ribose) polymerase (PARP) enzymes result in disruption of cellular homeostasis and cell death.

Mesna (Mesnex)

Clinical Context:  Mesna detoxifies metabolites of ifosfamide and cyclophosphamide. Usage is somewhat controversial, but it is commonly accepted that the total dose should be at least 60% of the total dose of the alkylating agent.

Class Summary

Mesna is indicated in the prevention of hemorrhagic cystitis in patients being treated with ifosfamide and cyclophosphamide.

Ondansetron (Zofran)

Clinical Context:  Ondansetron is a selective 5-HT3 receptor antagonist that blocks serotonin both peripherally and centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.

Granisetron (Kytril)

Clinical Context:  Granisetron is also a 5-HT3-receptor antagonist. It is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin.

Palonosetron (Aloxi)

Clinical Context:  Palonosetron is a selective 5-HT3 receptor antagonist with long half-life (40 h). It is indicated for the prevention and treatment of chemotherapy-induced nausea and vomiting. Palonosetron blocks 5-HT-3 receptors peripherally and centrally in the chemoreceptor trigger zone.

Dexamethasone (Decadron)

Clinical Context:  Dexamethasone is used as an antiemetic in low doses during chemotherapy. It is usually employed in multiagent antiemetic regimens with 5HT-3 receptor antagonists.

Class Summary

Antiemetics are used for the prevention and treatment of nausea and vomiting associated with chemotherapy.

How common is ovarian cancer?What are the signs and symptoms of ovarian cancer?How is the diagnosis of ovarian cancer confirmed?What are the guidelines on ovarian cancer screening in the general population?Which lab tests are performed in the diagnosis of ovarian cancer?Which imaging studies are performed in the workup of ovarian cancer?When is a GI tract workup indicated in the evaluation of ovarian cancer?When are FNA or biopsy indicated in the workup of ovarian cancer?How is ovarian cancer treated?Which surgical procedures are used in the treatment of ovarian cancer?Which chemotherapy agents are used in the treatment of ovarian cancer?What is ovarian cancer?What is the pathophysiology of ovarian cancer?What is the pathophysiology of epithelial ovarian cancer?What is the pathophysiology of epithelial ovarian tumors of low malignant potential (LMP)?What is the pathophysiology of malignant germ cell tumors (GCTs) of the ovary?What is the pathophysiology of dysgerminoma of the ovary?What is the pathophysiology of cystic teratoma of the ovary?What is the pathophysiology of ovarian immature teratoma?What are the rare germ cell tumors (GCTs) of the ovary?What is the pathophysiology of sex-cord stromal ovarian tumors?What is the pathophysiology of granulosa cell tumor ovarian tumors?What is the pathophysiology of Sertoli-Leydig cell ovarian tumors?What are the types of carcinoma and sarcoma of the ovary?What is the pathophysiology of metastatic tumors of the ovary?What causes ovarian cancer?What are the reproductive risk factors for ovarian cancer?What are the genetic risk factors for ovarian cancer?What is the role of hormone therapy in the etiology of ovarian cancer?What are the environmental risk factors for ovarian cancer?Is post-traumatic stress disorder (PTSD) a risk factor for ovarian cancer?What is the prevalence of ovarian cancer in the US?What is the mortality rate of ovarian cancer in the US?What is the global prevalence of ovarian cancer?What is the prognosis of ovarian cancer?What is the prognosis of ovarian tumors of low malignant potential (LMP)?Which clinical history findings are characteristic of ovarian cancer?Which physical findings are characteristic of ovarian cancer?How are ovarian cysts differentiated from ovarian cancer?How are benign adnexal masses differentiated from ovarian cancer?Which conditions are included in the differential diagnoses of ovarian cancer?What are the differential diagnoses for Ovarian Cancer?How is ovarian cancer diagnosed?How does screening and early detection of ovarian cancer affect mortality rates?What is the role of tumor markers in the diagnosis of ovarian cancer?What is the role of imaging in the workup of ovarian cancer?How are GI symptoms assessed in the workup of ovarian cancer?What is the role of biopsy in the workup of ovarian cancer?What is the role of mammography in the workup of ovarian cancer?How are ovarian tumors of low malignant potential (LMP) diagnosed?How are malignant ovarian germ cell tumors (GCTs) diagnosed?How is ovarian cancer staged?How is stage I ovarian cancer defined?How is stage II ovarian cancer defined?How is stage III ovarian cancer defined?How is stage IV ovarian cancer defined?What are the FIGO recommendations for ovarian cancer staging?What is the role of surgery in the treatment of ovarian cancer?Which factors are used to determine the appropriate surgical approach to the treatment of ovarian cancer?When is surgical staging indicated for ovarian cancer?What are the components of surgical staging for ovarian cancer?What is the role of cytoreductive surgery in the treatment of ovarian cancer?How is risk classified in advanced ovarian cancer?What is the role of interval debulking in the treatment of ovarian cancer?What is the role of laparoscopy in the diagnosis and treatment of ovarian cancer?When is a secondary cytoreductive surgery indicated in the treatment of ovarian cancer?What is the role of chemotherapy in the treatment of ovarian cancer?How are patients monitored during chemotherapy for ovarian cancer?How does chemotherapy affect future fertility and pregnancy outcomes?What is the role of pazopanib in the treatment of ovarian cancer?What is the role of intraperitoneal chemotherapy in the treatment of ovarian cancer?What is the role of neoadjuvant chemotherapy in the treatment of ovarian cancer?What are the most effective maintenance therapies for ovarian cancer?What is the role of bevacizumab (Avastin) in the treatment of ovarian cancer?What is the role of consolidation therapy in the treatment of ovarian cancer?What is the role of hyperthermic intraperitoneal chemotherapy in the treatment of ovarian cancer?What is the role of radiation therapy in the treatment of ovarian cancer?What is the role of ERT in the treatment of ovarian cancer?What is the role of second-look laparotomy in the treatment of ovarian cancer?How is response to therapy assessed in ovarian cancer?What is the role of the cancer antigen 125 (CA-125) level in response to therapy assessment for ovarian cancer?What is the role of squamous cell carcinoma antigen testing in response to therapy assessment for ovarian cancer?What is the role of carcinoembryonic antigen testing in response to therapy assessment for ovarian cancer?What is the role of AFP testing in response to therapy assessment for ovarian cancer?What is the role of lysophosphatidic acid in in response to therapy assessment for ovarian cancer?What is the role of MIB-1 testing in response to therapy assessment for ovarian cancer?What is the role of LT (CAM) testing in response to therapy assessment for ovarian cancer?How is recurrent ovarian cancer treated?What is the role of PARP inhibitors in the treatment of ovarian cancer?What is the role of olaparib (Lynparza) in the treatment of ovarian cancer?What is the role of rucaparib (Rubraca) in the treatment of ovarian cancer?What is the role of niraparib (Zejula) in the treatment of ovarian cancer?What is included in palliative care for ovarian cancer?How is bowel obstruction treated in ovarian cancer?How is ascites treated in ovarian cancer?How is anorexia treated in ovarian cancer?How is constipation treated in ovarian cancer?How is anemia treated in ovarian cancer?What is the role of hormone therapy in the treatment of ovarian cancer?What is the role of aromatase inhibitors (AIs) in the treatment of ovarian cancer?What is the role of targeted therapies in the treatment of ovarian cancer?How are ovarian cysts treated?How are ovarian tumors of low malignant potential (LMP) treated?How are malignant ovarian germ cell tumors (GCTs) treated?How are ovarian sex-cord stromal tumors treated?How are ovarian carcinomas and sarcomas treated?What is included in the long-term monitoring of ovarian cancer?Which specialist consultations are beneficial to patients with ovarian cancer?How is ovarian cancer prevented?What are ovarian cancer screening guidelines?Which organizations have released guidelines on genetic risk assessment for ovarian cancer?What are the USPSTF guidelines on genetic risk assessment for ovarian cancer?What are the NCCN guidelines on genetic risk assessment for ovarian cancer?What are the ASCO guidelines on genetic risk assessment for ovarian cancer?What are the ESMO guidelines on genetic risk assessment for ovarian cancer?What are the ACOG guidelines on genetic risk assessment for ovarian cancer?What are the SGO guidelines on genetic risk assessment for ovarian cancer?What are the NCCN guidelines on ovarian cancer prevention?What are the SGO guidelines on ovarian cancer prevention?What are the ACOG criteria for ovarian cancer workup?What are the guidelines on ovarian cancer workup?Which staging systems are used for ovarian cancer?What are the NCCN guidelines on primary treatment of ovarian cancer?What are the SGO/ASCO guidelines on neoadjuvant chemotherapy (NACT) for ovarian cancer?What are the NCCN guidelines on chemotherapy for ovarian cancer?What are the SGO guidelines on ovarian cancer surveillance?What are the NCCN guidelines on ovarian cancer surveillance?Which medications are used in the treatment of ovarian cancer?Which medications in the drug class Antiemetics are used in the treatment of Ovarian Cancer?Which medications in the drug class Cytoprotective Agents are used in the treatment of Ovarian Cancer?Which medications in the drug class PARP Inhibitors are used in the treatment of Ovarian Cancer?Which medications in the drug class Antineoplastic Agents are used in the treatment of Ovarian Cancer?Which medications in the drug class Chemotherapy agents are used in the treatment of Ovarian Cancer?

Author

Andrew E Green, MD, Consulting Staff, Northeast Georgia Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Agustin A Garcia, MD, Associate Professor of Medicine, University of Southern California Keck School of Medicine

Disclosure: Nothing to disclose.

Samina Ahmed, MD, Fellow, Division of Oncology, Department of Medicine, University of Southern California, Keck School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Yukio Sonoda, MD, Associate Professor, Weill Cornell Medical College; Associate Attending Surgeon, Gynecology Service, Department of Surgery, Memorial Hospital for Cancer and Allied Diseases; Associate Member, Memorial Sloan-Kettering Cancer Center

Disclosure: Nothing to disclose.

Acknowledgements

Robert P Edwards, MD Professor, Department of Obstetrics, Gynecology, and Reproductive Science, University of Pittsburgh; Vice-Chair, Clinical Affairs, Director, Ovarian Cancer Center of Excellence, Magee-Womens Hospital of University of Pittsburgh

Robert P Edwards, MD is a member of the following medical societies: American Association for Cancer Research, American College of Obstetricians and Gynecologists, American College of Surgeons, American Medical Association, and Society for Gynecologic Investigation

Disclosure: Nothing to disclose.

C William Helm, MB, BCh, MA, FRCS(Edin), FRCS Professor, Division of Gynecologic Oncology, Saint Louis University School of Medicine

C William Helm, MB, BCh, MA, FRCS(Edin), FRCS is a member of the following medical societies: American College of Obstetricians and Gynecologists, European Society of Gynaecologic Oncology, and International Gynecologic Cancer Society

Disclosure: ThermaSolutions, Inc Grant/research funds Research Registry of patients treated with hyperthemic intraperitoneal chemotherapy; Sanofi-Aventis, Inc Grant/research funds Support for and investigator initiated research study of HIPEC for consolidation in ovarian cancer; ThermaSolutions, Inc Honoraria Speaking and teaching; UpToDate Royalty Online Text Book Chapters; Genzyme, Inc Honoraria Speaking and teaching

Warner K Huh, MD Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Senior Scientist, Comprehensive Cancer Center, University of Alabama School of Medicine

Warner K Huh, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American College of Surgeons, American Society of Clinical Oncology, Massachusetts Medical Society, and Society of Gynecologist Oncologists

Disclosure: MERCK Consulting fee Consulting; ROCHE PHARMA/DIAGNOSTICS Consulting fee Consulting; INTUITIVE SURGICAL Proctor Fee Consulting; Qiagen Consulting fee Consulting

Karen Loeb Lifford, MD Director of General Gynecology, Associate Program Director, Department of Obstetrics and Gynecology, Instructor, Brigham and Women's Hospital, Harvard Medical School

Karen Loeb Lifford, MD is a member of the following medical societies: Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Michel E Rivlin, MD Professor, Department of Obstetrics and Gynecology, University of Mississippi School of Medicine

Michel E Rivlin, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Mississippi State Medical Association, and Royal College of Surgeons of Edinburgh

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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An enlarged ovary with a papillary serous carcinoma on the surface.

An enlarged ovary with a papillary serous carcinoma on the surface.

Metastases from epithelial ovarian carcinoma involving the omentum.

Mature cystic teratoma of the ovary exhibiting multiple tissue types.

Mature cystic teratoma of the ovary with hair, sebaceous material, and thyroid tissue.

Granulosa cell tumor excised from a woman aged 44 years. Note the yellowish tumor that has eroded through, onto the surface of the ovary.

This photo shows a granulosa cell tumor, with the cut surface showing classic features of a hemorrhagic cyst and yellowish solid component.

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.

Dr. Oliver Zivanovic, MD, PhD, discusses the role of hyperthermic intraperitoneal chemotherapy in ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.

Dr. Oliver Zivanovic, MD, PhD, demonstrates hyperthermic intraperitoneal chemotherapy for ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.

An enlarged ovary with a papillary serous carcinoma on the surface.

Metastases from epithelial ovarian carcinoma involving the omentum.

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.

Granulosa cell tumor excised from a woman aged 44 years. Note the yellowish tumor that has eroded through, onto the surface of the ovary.

This photo shows a granulosa cell tumor, with the cut surface showing classic features of a hemorrhagic cyst and yellowish solid component.

Mature cystic teratoma of the ovary exhibiting multiple tissue types.

Mature cystic teratoma of the ovary with hair, sebaceous material, and thyroid tissue.

Dr. Oliver Zivanovic, MD, PhD, discusses the role of hyperthermic intraperitoneal chemotherapy in ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.

Dr. Oliver Zivanovic, MD, PhD, demonstrates hyperthermic intraperitoneal chemotherapy for ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.