Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of ovarian epithelial cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Genetic characteristics and risk factors.
• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: Separate PDQ summaries on Genetics of Breast and Ovarian Cancer; Ovarian Cancer Screening; and Ovarian Cancer Prevention are also available. Information on ovarian cancer in children is available in the PDQ summary on Unusual Cancers of Childhood.

Note: Estimated new cases and deaths from ovarian cancer in the United States in 2008:^[1]

• New cases: 21,650.
• Deaths: 15,520.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women older than 65 years.^[2] Approximately 5% to 10% of ovarian cancers are familial and three distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers.^[3] The most important risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. The highest risk appears in women with two or more first-degree relatives with ovarian cancer.^[4] The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.

In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21.^[5][6][7] BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.^[8] The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over the general population.^[9][10] Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared with BRCA1-mutation–negative women.^[11][12][Level of evidence: 3iiiA] The majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, these women may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.

For women at increased risk, prophylactic oophorectomy may be considered after the age of 35 if childbearing is complete. In a family-based study among women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, two of them (0.8%) developed subsequent papillary serous peritoneal carcinoma, and six of them (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a higher than 90% reduction in the risk of ovarian cancer (relative risk [RR] = 0.04; 95% confidence interval [CI], 0.01–0.16), with an average follow-up of 9 years;^[13] however, family-based studies may be associated with biases resulting from case selection and other factors that may influence the estimate of benefit.^[14] (Refer to the Evidence of Benefit section in the PDQ summary on Ovarian Cancer Prevention for more information.) After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer.^[15] The prognostic information presented below deals only with epithelial carcinomas. Stromal and germ cell tumors are relatively uncommon and comprise less than 10% of cases. (Refer to the PDQ summaries on Ovarian Germ Cell Tumor Treatment and Ovarian Low Malignant Potential Tumor Treatment for more information.)

Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported to be as much as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.^[16] In this study, the pelvic nodes were involved as often as the para-aortic nodes. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Also, transdiaphragmatic spread to the pleura is common.

Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include:^{[17][18][19][20][21]}

• Younger age.
• Good performance status.
• Cell type other than mucinous and clear cell.
• Lower stage.
• Well-differentiated tumor.
• Smaller disease volume prior to any surgical debulking.
• Absence of ascites.
• Smaller residual tumor following primary cytoreductive surgery.

For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites.^[22] DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients.^[23] Patients with clear cell histology appear to have a worse prognosis.^[24] Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.^[25]

Although the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease.^[26] For patients whose elevated CA 125 normalizes with chemotherapy, more than one subsequent elevated CA 125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.^[27][28]

Most patients with ovarian cancer have widespread disease at presentation. This may be partly explained by relatively early spread (and implantation) of high grade papillary serous cancers to the rest of the peritoneal cavity.^[29] Conversely, symptoms such as abdominal pain and swelling, gastrointestinal symptoms, and pelvic pain, often go unrecognized, leading to delays in diagnosis.^[30][31][32] As a result of these confounding factors, yearly mortality in ovarian cancer is approximately 65% of the incidence rate. Long-term follow-up of suboptimally debulked stage III and stage IV patients showed a 5-year survival rate of less than 10% with platinum-based combination therapy prior to the current generation of trials including taxanes.^[17] By contrast, optimally debulked stage III patients treated with a combination of intravenous taxane and intraperitoneal platinum plus taxane achieved a median survival of 66 months in a Gynecologic Oncology Group trial .^[33] Numerous clinical trials are in progress to refine existing therapy and test the value of different approaches to postoperative drug and radiation therapy. Patients with any stage of ovarian cancer are appropriate candidates for clinical trials.^[34][35] Information about ongoing clinical trials is available from the NCI Web site.

References

Cellular Classification

The following is a list of ovarian epithelial cancer histologic classifications.

• Serous cystomas:
  • Serous benign cystadenomas.
  • Serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
  • Serous cystadenocarcinomas.
• Mucinous cystomas:
  • Mucinous benign cystadenomas.
  • Mucinous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
  • Mucinous cystadenocarcinomas.
• Endometrioid tumors (similar to adenocarcinomas in the endometrium):
  • Endometrioid benign cysts.
  • Endometrioid tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
  • Endometrioid adenocarcinomas.
• Clear cell (mesonephroid) tumors:
  • Benign clear cell tumors.
  • Clear cell tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
  • Clear cell cystadenocarcinomas.
• Unclassified tumors that cannot be allotted to one of the above groups.
• No histology.
• Other malignant tumors (malignant tumors other than those of the common epithelial types are not to be included with the categories listed above).

(Refer to the PDQ summary on Ovarian Low Malignant Potential Tumor Treatment for more information.)

Stage Information

In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires laparotomy. The role of surgery in patients with stage IV disease and extra-abdominal disease is yet to be established. If disease appears to be limited to the ovaries or pelvis, it is essential at laparotomy to examine and biopsy or to obtain cytologic brushings of the diaphragm, both paracolic gutters, the pelvic peritoneum, para-aortic and pelvic nodes, and infracolic omentum, and to obtain peritoneal washings.^[1]

The serum CA 125 level is valuable in the follow-up and restaging of patients who have elevated CA 125 levels at the time of diagnosis.^[2][3][4] While an elevated CA 125 level indicates a high probability of epithelial ovarian cancer, a negative CA 125 level cannot be used to exclude the presence of residual disease.^[5] CA 125 levels can also be elevated in other malignancies and benign gynecologic problems such as endometriosis, and CA 125 levels should be used with a histologic diagnosis of epithelial ovarian cancer.^[6][7]

The Federation Internationale de Gynecologie et d’Obstetrique and the American Joint Committee on Cancer have designated staging.^[8][9]

Stage I

Stage I ovarian cancer is limited to the ovaries.

• Stage IA: Tumor limited to one ovary; capsule intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
• Stage IB: Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
• Stage IC: Tumor limited to one or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings.^[8]

*The term, malignant ascites, is not classified. The presence of ascites does not affect staging unless malignant cells are present.

Stage II

Stage II ovarian cancer is tumor involving one or both ovaries with pelvic extension and/or implants.

• Stage IIA: Extension and/or implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.
• Stage IIB: Extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
• Stage IIC: Pelvic extension and/or implants (stage IIA or stage IIB) with malignant cells in ascites or peritoneal washings.

Different criteria for allotting cases to stage IC and stage IIC have an impact on diagnosis. To assess this impact, of value would be to know if rupture of the capsule was (1) spontaneous or (2) caused by the surgeon; and, if the source of malignant cells detected was (1) peritoneal washings or (2) ascites.

Stage III

Stage III ovarian cancer is tumor involving one or both ovaries with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically verified malignant extension to small bowel or omentum.

• Stage IIIA: Microscopic peritoneal metastasis beyond pelvis (no macroscopic tumor).
• Stage IIIB: Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension.
• Stage IIIC: Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis.

Stage IV

Stage IV ovarian cancer is tumor involving one or both ovaries with distant metastasis. If pleural effusion is present, positive cytologic test results must exist to designate a case to stage IV. Parenchymal liver metastasis equals stage IV.

Stage I and Stage II Ovarian Epithelial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options:

1. If the tumor is well differentiated or moderately well differentiated, total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy is adequate for patients with stage IA and stage IB disease. The undersurface of the diaphragm should be visualized and biopsied; pelvic and abdominal peritoneal biopsies and pelvic and para-aortic lymph node biopsies are required and peritoneal washings should be obtained routinely.^[1] In selected patients who desire childbearing and have grade I tumors, unilateral salpingo-oophorectomy may be associated with a low risk of recurrence.^[2]
2. If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and death from ovarian cancer is as much as 30%.^[3][4][5][6] Clinical trials evaluating the following treatment approaches have been performed:
   • Intraperitoneal P-32 or radiation therapy.^[1][7][8]
   • Systemic chemotherapy based on platinums alone or in combination with alkylating agents.^{[1][7][9][10][11]}
   • Systemic chemotherapy based on platinums with paclitaxel.

In two large European trials, European Organisation for Research and Treatment of Cancer–Adjuvant ChemoTherapy in Ovarian Neoplasm (EORTC–ACTION) and International Collaborative Ovarian Neoplasm (ICON1), patients with stage IA and stage IB (grades II and III), all stage IC and stage II, and all stage I and stage IIA clear-cell carcinoma were randomly assigned to adjuvant chemotherapy or observation. Data were reported individually and in pooled form.^[12][13][14]

The EORTC–ACTION trial required four cycles or more of carboplatin or cisplatin-based chemotherapy as treatment. Although surgical staging criteria were monitored, inadequate staging was not an exclusion criterion. Recurrence-free survival (RFS) was improved in the adjuvant chemotherapy arm (hazard ratio [HR] = 0.63; P = .02), but overall survival (OS) was not affected (HR = 0.69; 95% confidence interval [CI], 0.44–1.08; P = .10). OS was improved by chemotherapy in the subset of patients with inadequate surgical staging.

The ICON1 trial randomized patients to six cycles of single-agent carboplatin or cisplatin or platinum-based chemotherapy (usually cyclophosphamide, doxorubicin, and cisplatin) versus observation and had similar entry criteria to the EORTC–ACTION trial, but the ICON1 trial did not monitor whether adequate surgical staging was performed. Both RFS and OS were significantly improved: 5-year survival figures were 79% with adjuvant chemotherapy versus 70% without adjuvant chemotherapy.

The pooled data from both studies indicate significant improvement in RFS (HR = 0.64; 95% CI, 0.50–0.82; P = .001) and OS (HR = 0.67; 95% CI, 0.50–0.90; P = .008). These pooled data provide for an OS at 5 years of 82% with chemotherapy and 74% with observation, with a 95% CI in the difference of 2% to 12%. An accompanying editorial emphasizes that the focus of subsequent trials must be to identify patients who do not require additional therapy among the early ovarian cancer subset.^[15][Level of evidence: 1iA]. Optimal staging is one way to better identify these patients. Except for the most favorable subset (patients with stage IA well-differentiated disease), Gynecologic Oncology Group (GOG) trials, and the evidence above, which is based on double-blinded, randomized controlled trials with total mortality endpoints, support treatment with cisplatin, carboplatin, and paclitaxel (in the United States).

In future trials, the Ovarian Committee of the GOG has opted to include patients with stage II disease in advanced ovarian cancer trials and not to include further study of patients with stage I disease at this time. Information about ongoing clinical trials is available from the NCI Web site.

References

Stage III and Stage IV Ovarian Epithelial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options for patients with all stages of ovarian epithelial cancer have consisted of surgery followed by chemotherapy.

Surgery

Treatment Options for Patients With Optimally Cytoreduced Stage III Disease

Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease

Recurrent or Persistent Ovarian Epithelial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Surgery

Treatment Options With Group 1 Drugs

Treatment Options With Group 2 Drugs

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Changes to This Summary (03/05/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Updated statistics with estimated new cases and deaths for 2008 (cited American Cancer Society).