Introduction
Background
Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the United States. Early disease causes minimal, nonspecific, or no symptoms. Therefore, most cases are diagnosed in an advanced stage. Overall, prognosis for these patients remains poor. Standard treatment involves aggressive debulking surgery followed by chemotherapy. Although many histologic types of ovarian tumors have been described, more than 90% of ovarian malignancies are epithelial tumors. Therefore, the remainder of this article focuses on these tumors. For specific information on malignant lesions of the ovaries, see Malignant Lesions of the Ovaries.
Pathophysiology
Ovarian carcinoma can spread by local extension, lymphatic invasion, intraperitoneal implantation, hematogenous dissemination, and transdiaphragmatic passage. Intraperitoneal dissemination is the most common and recognized characteristic of ovarian cancer. Malignant cells can implant anywhere in the peritoneal cavity but are more likely to implant in sites of stasis along the peritoneal fluid circulation. As discussed later, these mechanisms of dissemination represent the rationale to conduct surgical staging, debulking surgery, and intraperitoneal administration of chemotherapy. In contrast, hematogenous spread is clinically unusual early on in the disease process, although it is not infrequent in patients with advanced disease.
Frequency
United States
The American Cancer Society estimated that there would be 21,550 new cases of ovarian cancer in 2009 and 14,600 deaths from the disease.1 Estimates indicate that 1 in 70 women will develop ovarian cancer in her lifetime. The ovaries are the ninth most common site of cancer in women, accounting for approximately 3% of all new cases, but ovarian cancer causes 5% of cancer deaths—more than any other cancer of the female reproductive system. However, during 2001–2005, the incidence of ovarian cancer declined at a rate of 2.4% annually, and the death rate from ovarian cancer has been stable since 1998.1
Mortality/Morbidity
* Overall, the prognosis of ovarian cancer remains poor, with a 45% 5-year survival rate. Approximately 15,280 women die every year in the United States from ovarian cancer.
* The prognosis of ovarian cancer is closely related to the stage at diagnosis.
* Ovarian cancer is staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Approximately 20%, 5%, 58%, and 17% of women present with stage I, II, III, and IV, respectively. Despite this, the 5-year survival rate for ovarian cancer has improved significantly in the last 30 years. The overall survival rate in 1975-1977 was 36%, compared to 45% in 1995-2002.
Sex
* Ovarian cancer affects females.
Age
* The disease is uncommon in patients younger than 40 years, after which incidence increases.
* Most cases are diagnosed in the seventh decade of life.
Clinical
History
* The signs and symptoms of ovarian cancer are nonspecific. Most patients present with symptoms of several months' duration.
* Symptoms include the following:
o Abdominal/pelvic pain
o Vaginal bleeding
o Bloating
o Abdominal distention
o Irregular menses
o Change in bowel habits
* A prospective case-control study of 1,709 women visiting primary care clinics found that the combination of bloating, increased abdominal size, and urinary symptoms was found in 43% of those with ovarian cancer but in only 8% of those presenting to primary care clinics.2
Physical
* Physical findings are uncommon in patients with early disease.
* Patients with more advanced disease present with the following:
o Ovarian or pelvic mass
o Ascites
o Pleural effusion
o Abdominal mass or bowel obstruction
Causes
Traditionally, ovarian cancer has been suggested to originate from cells in the serosa of the ovary. However, some authors suggest a different cell of origin. The precise cause of ovarian cancer is unknown, but several risk and contributing factors have been identified.
* Reproductive factors
o Parity is an important risk factor. 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.
o Oral contraceptive use decreases the risk of ovarian cancer.
o These factors support the theory that risk for ovarian cancer is related to ovulation and that conditions that suppress the ovulatory cycle play a protective role.
o Ovarian cancer may develop from an abnormal repair process of the surface of the ovary, which is ruptured and repaired during each ovulatory cycle. Therefore, the probability of ovarian cancer may be related to the number of ovulatory cycles.
* Genetic factors
o Family history plays an important role in the risk of developing ovarian cancer.
o 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.
o A history of breast cancer increases a woman's risk of developing ovarian cancer.
* Hereditary ovarian cancer
o Families in which multiple members have ovarian cancer (alone or associated with other tumors) are defined as having hereditary ovarian cancer.
o Fewer than 5% of all ovarian cancers have a hereditary predisposition. At least 2 syndromes are clearly identified, as follows:
+ Breast/ovarian cancer syndrome: This 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.
+ Lynch II syndrome or hereditary nonpolyposis colorectal cancer: These families 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.Differential Diagnoses
Adnexal Tumors
Ovarian Cysts
Ascites
Pancreatic Cancer
Borderline Ovarian Cancer
Peritoneal Cancer
Irritable Bowel Syndrome
Rectal Cancer
Other Problems to Be Considered
Gastric adenocarcinoma
Malignant gastric tumors
Appendiceal tumors
Workup
Laboratory Studies
* If ovarian cancer is suspected on the basis of a pelvic or ovarian mass, minimize preoperative testing and expedite laparotomy for diagnosis and staging.
* Routine preoperative tests include CBC, chemistry panel (including liver function tests), and a cancer antigen 125 assay (CA-125). Remember that CA-125 may be within normal limits in 50% of women with early ovarian cancer.
Imaging Studies
* Routine imaging is not required in all patients in whom ovarian cancer is highly suggested.
* If diagnostic uncertainty is present, a pelvic ultrasound or CT scan of the abdomen and pelvis is warranted.
* Chest radiographs are common and considered routine.
* CT scan of the chest is seldom indicated.
* MRI can increase the specificity of imaging evaluation in cases where the ultrasound appearance of the lesion is indeterminate.3 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.4
* 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 CA-125 level.5
Other Tests
* In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be indicated, including one of the following:
o Upper and/or lower endoscopy
o Barium enema
o Upper GI series
Procedures
* Biopsy
o Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended. In most cases, this approach may only serve to delay diagnosis and treatment of ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, the patient should undergo a laparotomy for diagnosis and staging.
o An FNA or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass.
Histologic Findings
Epithelial tumors represent the most common histology (90%) of ovarian tumors. Other histologies include the following:
* Low malignant or borderline ovarian tumors
* Sex cord stromal tumors
* Germ cell tumors
* Primary peritoneal carcinoma
* Metastatic tumors of the ovary.
Staging
FIGO staging for ovarian cancer is as follows:
* Stage I - Growth limited to the ovaries
o Stage Ia - Growth limited to 1 ovary, no ascites, no tumor on external surface, capsule intact
o Stage Ib - Growth limited to both ovaries, no ascites, no tumor on external surface, capsule intact
o Stage Ic - Tumor either stage Ia or Ib but with tumor on surface of one or both ovaries, ruptured capsule, ascites with malignant cells or positive peritoneal washings
* Stage II - Growth involving one or both ovaries, with pelvic extension
o Stage IIa - Extension and/or metastasis to the uterus or fallopian tubes
o Stage IIb - Extension to other pelvic tissues
o Stage IIc - Stage IIa or IIb but with tumor on surface of one or both ovaries, ruptured capsule, ascites with malignant cells or positive peritoneal washings
* Stage III - Tumor involving one or both ovaries, with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastases constitute stage III disease
o Stage IIIa - Tumor grossly limited to pelvis, negative lymph nodes but histological proof of microscopic disease on abdominal peritoneal surfaces
o Stage IIIb - Confirmed implants outside of pelvis in the abdominal peritoneal surface; no implant exceeds 2 cm in diameter and lymph nodes are negative
o Stage IIIc - Abdominal implants larger than 2 cm in diameter and/or positive lymph nodes
* Stage IV - Distant metastases; pleural effusion must have a positive cytology to be classified as stage IV; parenchymal liver metastases constitute stage IV diseaseTreatment
Medical Care
The standard treatment for ovarian cancer starts with staging and cytoreductive surgery. Based on the surgical staging, patients are classified as having limited disease (stages I and II) or advanced disease (stages III and IV).
* Patients with limited disease are classified as having low or high risk for recurrence as follows:
o Low risk for recurrence is indicated by the following:
+ Grade 1 or 2 disease
+ No tumor on external surface of the ovary
+ Negative peritoneal cytology
+ No ascites
+ Tumor growth confined to the ovaries
o High risk for recurrence is indicated by the following:
+ Grade 3 disease
+ Preoperative rupture of the capsule
+ Tumor on the external surface of the ovary
+ Positive peritoneal cytology
+ Ascites
+ Tumor growth outside of the ovary
+ Clear cell tumors
+ Surgical stage II
* Postoperative chemotherapy is indicated in all patients with ovarian cancer except those who have surgical-pathologic stage I disease with low-risk characteristics.
o 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.6
* For female patients with carcinomatosis of an unknown primary tumor, consider the following:
o In women who present with GI carcinomatosis but without an obvious pelvic mass, an extensive search often fails to identify a primary tumor. These patients can be presumed to have ovarian carcinoma or primary peritoneal carcinoma and treated with cytoreductive surgery followed by platinum-based chemotherapy.
Surgical Care
The standard care for ovarian cancer includes surgical exploration for primary staging and for cytoreduction or debulking.
* Surgical staging
o If the disease appears to be confined to the pelvis, comprehensive surgical staging is indicated.
o The staging procedure should include the following:
+ Peritoneal cytology
+ Multiple peritoneal biopsies
+ Omentectomy
+ Pelvic and para-aortic lymph node sampling.
* Cytoreductive surgery
o This should be performed by a gynecologic oncologist at the time of initial laparotomy.
o The volume of residual disease at the completion of surgery represents one of the most powerful prognostic factors.
* Prognosis after cytoreductive surgery: Patients with advanced ovarian cancer are classified in 3 groups as follows, based on the postoperative residual tumor:
o Good risk - Microscopic disease outside the pelvis (stage IIIa) or macroscopic disease less than 2 cm outside the pelvis (stage IIIb)
o Intermediate risk - Macroscopic disease less than 2 cm outside the pelvis only after surgery
o Poor risk - Macroscopic disease more than 2 cm after surgery or disease outside the peritoneal cavity
* Interval debulking
o This can be performed in patients who were not adequately debulked at the time of initial surgery.
o Patients receive 3 cycles of postoperative chemotherapy. Approximately 60% of patients are then able to undergo optimal resection. Surgical treatment is followed by 3 more cycles of chemotherapy.
o A European prospective, randomized, clinical trial demonstrated that this approach improves the outcome of patients with advanced ovarian cancer.7 However, this was not confirmed in a study conducted in the United States.8 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.9
o Interval debulking surgery may also be considered in those patients in whom an initial debulking surgery was not attempted.
* Secondary surgery
o 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.10
Consultations
* Consult a gynecologic oncologist if ovarian cancer is suspected.
Medication
Chemotherapy regimens
Standard postoperative chemotherapy is combination therapy with platinum and paclitaxel. Cisplatin and paclitaxel or carboplatin and paclitaxel are accepted alternatives. Randomized studies have proven that both regimens result in equivalent survival rates. However, because of a more tolerable toxicity profile, the combination of carboplatin and paclitaxel is preferred. If patients are treated with cisplatin, paclitaxel should be administered as a 24-hour infusion to decrease the risk of neurotoxicity. Another alternative is to combine carboplatin with docetaxel.
The combination of paclitaxel and carboplatin is customarily given every 3 weeks (day 1 of a 21-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 1.11 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.
Intraperitoneal chemotherapy
Results from randomized clinical trials suggest that in patients with optimally debulked disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous administration.12 Recent meta-analyses confirm that intraperitoneal administration of chemotherapy is associated with an improvement in survival.13,14 However, this approach is also associated with more toxicity. The National Cancer Institute released a clinical announcement supporting the use of intraperitoneal chemotherapy in optimally debulked ovarian cancer.15
Neoadjuvant chemotherapy
Patients with advanced ovarian cancer who are not candidates for surgical cytoreduction may be treated initially with 2-3 cycles of conventional chemotherapy and can then be reevaluated for surgical cytoreduction. However, optimal initial cytoreduction remains the standard of care for most patients.
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.16
Second-line chemotherapy
Recurrent ovarian cancer is classified into 2 categories, depending on the length of time the patient remained disease-free after completing chemotherapy: (1) relapse that occurs more than 6 months after initial chemotherapy is considered platinum-sensitive; (2) earlier relapse is considered platinum-resistant. Patients with platinum-sensitive disease may exhibit a good response if rechallenged with a platinum-based regimen.17,18 The probability of response increases with the duration of the disease-free interval.
Results from clinical trials suggest that combination chemotherapy offers an improvement in response rate, progression-free survival, and overall survival. Several chemotherapy agents elicit a response in patients whose disease is resistant to platinum-based therapies. These include liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, docetaxel, and vinorelbine. Other agents that may be used are ifosfamide, 5-fluorouracil with leucovorin, and altretamine (Hexalen). Tamoxifen, an oral antiestrogen, exhibits modest activity but has a favorable toxicity profile.
Chemotherapy agents
Cisplatin, carboplatin, and paclitaxel are chemotherapy agents approved for the initial treatment of ovarian cancer. 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.
Cisplatin (Platinol)
Intrastrand cross-linking of DNA and inhibition of DNA precursors are among proposed mechanisms of action.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
60-100 mg/m2 IV q3wk
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Increases toxicity of bleomycin and ethacrynic acid
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity, preexisting renal insufficiency, myelosuppression, and hearing impairment
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Can cause potassium- and magnesium-wasting nephropathy (IV hydration is used to decrease risk); frequency and severity of peripheral neuropathy are increased if cisplatin is combined with short infusions of paclitaxel; highly emetogenic (aggressive antiemetic prophylaxis with a selective serotonin antagonist and steroids recommended); produces modest myelosuppression
Carboplatin (Paraplatin)
Analog of cisplatin. Has same efficacy as cisplatin but with better toxicity profile.
Dose is based on the following formula: total dose (mg) = (target AUC) X (GFR = 25) where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Target AUC of 4-7.5 IV q3-4wk recommended
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; bone marrow suppression
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Produces significantly less nephrotoxicity, peripheral neuropathy, nausea, and vomiting compared to cisplatin; IV hydration not required; produces more myelosuppression than cisplatin
Paclitaxel (Taxol)
Mechanism of action is tubulin polymerization and microtubule stabilization.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
175 mg/m2 as 3-h IV infusion q3wk; alternatively, 135 mg/m2 as 24-h IV infusion q3wk
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration with cisplatin may further increase myelosuppression
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; severe cardiac disease
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Patients should be premedicated with steroids and H1 and H2 blockers to decrease risk of hypersensitivity reactions; other adverse effects include myelosuppression, alopecia, peripheral neuropathy, myalgias/arthralgias, and cardiac arrhythmia
Liposomal doxorubicin (Doxil)
Interferes with synthesis of nucleic acid by intercalating with DNA nucleotide pairs and topoisomerase II inhibition.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
40-50 mg/m2 IV q4wk
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression; impaired liver function
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function; adverse effects include infusion reactions, mucositis, and skin toxicity (palmar-plantar erythrodysesthesia); nausea and vomiting are mild; alopecia and cardiac toxicity are uncommon
Antineoplastic Agents
These agents inhibit cell growth and proliferation.
Topotecan (Hycamtin)
Inhibits topoisomerase I, inhibiting DNA replication. Patients who have received prior chemotherapy should be given a lower dose initially.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1.5 mg/m2/d IV for 5 d q4wk
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Concomitant administration with other antineoplastics may result in prolonged neutropenia and thrombocytopenia in addition to increased morbidity/mortality
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; bone marrow suppression and renal function impairment
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Adverse effects include myelosuppression, dermatitis, nausea, and vomiting; monitor bone marrow function
Gemcitabine (Gemzar)
Cytidine analog. Metabolized intracellularly to active nucleotide. Inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Cell-cycle specific for S phase. Indicated for advanced ovarian cancer (that has relapsed at least 6-months after completion of platinum-based therapy. Used in combination with carboplatin.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1000 mg/m2 IV infused over 30 min on days 1 and 8 of each 21-day cycle; administer carboplatin on day 1 after gemcitabine
Pediatric
Not establishedFollow-up
Deterrence/Prevention
* Pregnancy and the use of oral contraceptives significantly decrease the risk of ovarian cancer.
* Prophylactic bilateral salpingo-oophorectomy is indicated in high-risk women.19 The American College of Obstetricians and Gynecologists recommends offering salpingo-oophorectomy to women with BRCA1 or BRCA2 mutations by age 40 years or when childbearing is complete (level A recommendation).20 Surgical prophylaxis decreases the risk by at least 90%. Not all cases of ovarian cancer are prevented, as women are still at risk for developing primary peritoneal carcinomas.
* 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 ultrasound 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.21
* Screening with transvaginal ultrasonography and CA-125 tumor marker measurement is recommended in high-risk women.
Prognosis
* The 5-year survival rates are as follows:
o Stage I - 73%
o Stage II - 45%
o Stage III - 21%
o Stage IV - Less than 5%
Patient Education
For excellent patient education resources, visit eMedicine’s Cancer and Tumors Center and Women's Health Center. Also, see eMedicine’s patient education articles Ovarian Cancer and Ovarian Cysts.
