AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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 patients are diagnosed in an advanced stage. Overall, prognosis for these patients remains poor. Standard treatment involves aggressive debulking surgery followed by chemotherapy. Many histological types of ovarian tumors are described. However, more than 90% of malignant tumors 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. On the other hand, early hematogenous spread is clinically unusual, although it is not infrequent in patients with advanced disease.

Frequency

United States

Approximately 22,430 new cases of ovarian cancer are diagnosed annually. Estimates indicate that 1 in 70 women will develop ovarian cancer in her lifetime. Ovarian cancer accounts for 3.3% of all new cases of cancer.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

History

• The signs and symptoms of ovarian cancer are nonspecific. Most patients present with symptoms of several months' duration.
• Symptoms include the following:
• • Abdominal/pelvic pain
  • Vaginal bleeding
  • Bloating
  • Abdominal distension
  • Irregular menses
  • Change in bowel habit

Physical

• Physical findings are uncommon in patients with early disease.
• Patients with more advanced disease present with the following:
• • Ovarian or pelvic mass
  • Ascites
  • Pleural effusion
  • 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
• • Parity is an important risk factor. Women who have been pregnant have a 50% decreased risk for developing ovarian cancer compared to nulliparous women. Multiple pregnancies offer an increasingly protective effect.
  • Oral contraceptive use decreases the risk of ovarian cancer.
  • These factors support the theory that risk for ovarian cancer is related to ovulation and that conditions that suppress this ovulatory cycle play a protective role.
  • 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
• • 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 to a 4-5% risk when 1 first-degree family member is affected, rising to 7% when 2 relatives are affected.
  • A history of breast cancer increases a woman's risk of developing ovarian cancer.
• Hereditary ovarian cancer
• • Families in which multiple members have ovarian cancer (alone or associated with other tumors) are defined as having hereditary ovarian cancer.
  • 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Other Problems to be Considered

Gastric adenocarcinoma
Malignant gastric tumors
Appendiceal tumors

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Lab Studies

• If ovarian cancer due to a pelvic or ovarian mass is suggested, minimize preoperative testing and expedite a diagnostic and staging laparotomy.
• Routine preoperative tests include CBC count, 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.

Other Tests

• In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be indicated, including one of the following:
• • Upper and/or lower endoscopy
  • Barium enema
  • Upper GI series

Procedures

• Biopsy
• • A fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended. In most cases, taking this approach instead of performing a surgical staging laparotomy may only serve to delay appropriate diagnosis and treatment of ovarian cancer.
  • If a clinical suggestion of ovarian cancer is present, the patient should undergo a diagnostic and surgical procedure.
  • 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 (1) low malignant or borderline ovarian tumors, (2) sex cord stromal tumors, (3) germ cell tumors, (4) primary peritoneal carcinoma, and (5) metastatic tumors of the ovary.

Staging

FIGO staging for ovarian cancer is as follows:

• Stage I - Growth limited to the ovaries
• • Stage Ia - Growth limited to 1 ovary, no ascites, no tumor on external surface, capsule intact
  • Stage Ib - Growth limited to both ovaries, no ascites, no tumor on external surface, capsule intact
  • 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
• • Stage IIa - Extension and/or metastases to the uterus or tubes
  • Stage IIb - Extension to other pelvic tissues
  • 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 equal stage III
• • Stage IIIa - Tumor grossly limited to pelvis, negative lymph nodes but histological proof of microscopic disease on abdominal peritoneal surfaces
  • Stage IIIb - Confirmed implants outside of pelvis in the abdominal peritoneal surface; no implant exceeds 2 cm in diameter and lymph nodes are negative
  • 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 equals stage IV

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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 (stage I and II) or advanced disease (stage III and IV).

• Patients with limited disease are classified as having low or high risk for recurrence as follows:
• • Low risk for recurrence includes the following:
    • Grade 1 or 2 disease
    • No tumor on external surface of the ovary
    • Negative peritoneal cytology
    • No ascites
    • Tumor growth confined to the ovaries
  • High risk for recurrence includes 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
• For postoperative treatment, chemotherapy is indicated in all patients with ovarian cancer except those patients with surgical-pathological stage I disease with low-risk characteristics.
• For female patients with carcinomatosis of an unknown primary tumor, consider the following:
• • Frequently, female patients present with carcinomatosis without an obvious pelvic mass. In many patients, an extensive search for a GI tumor fails to identify the primary tumor.
  • Consider treating these patients as having a presumed ovarian carcinoma or primary peritoneal carcinoma. Treat with cytoreductive surgery followed by platinum-based chemotherapy.

Surgical Care

The standard care for ovarian cancer includes a primary staging and cytoreductive or debulking surgical exploration.

• Surgical staging
• • If the disease appears to be confined to the pelvis, comprehensive surgical staging is indicated.
  • The staging procedure should include (1) peritoneal cytology, (2) multiple peritoneal biopsies, (3) omentectomy, and (4) pelvic and para-aortic lymph node sampling.
• Cytoreductive surgery
• • This should be performed by a gynecological 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.
• Prognosis of patients after cytoreductive surgery: Patients with advanced ovarian cancer are classified in 3 groups as follows, based on the postoperative residual tumor:
• • Good risk - Microscopic disease outside the pelvis (stage IIIa) or macroscopic disease less than 2 cm outside the pelvis (stage IIIb)
  • Intermediate risk - Macroscopic disease less than 2 cm outside the pelvis only after surgery
  • Poor risk - Macroscopic disease more than 2 cm after surgery or disease outside the peritoneal cavity
• Interval debulking
• • This can be performed in patients who were not adequately debulked at the time of initial surgery.
  • Patients receive 3 cycles of postoperative chemotherapy. Approximately 60% of patients are then able to undergo optimal resection. Surgical treatment is followed by 3 more cycles of chemotherapy.
  • A European prospective, randomized, clinical trial demonstrated that this approach improves the outcome of patients with advanced ovarian cancer. However, this was not confirmed in a study conducted in the United States. A major difference between both studies was the extent of the initial debulking procedure. In the latter study, initial optimal debulking was attempted in all patients.
  • Interval debulking surgery may be considered in those patients in whom an initial debulking surgery was not attempted.

Consultations

• Consult a gynecologic oncologist if ovarian cancer is suspected.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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, then paclitaxel should be administered as a 24-hour infusion to decrease the risk of neurotoxicity. Another alternative is to combine carboplatin with docetaxel.

Intraperitoneal chemotherapy: Results from 3 randomized clinical trials suggest that in patients with optimally debulked disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous administration. Three recent meta-analyses confirm that intraperitoneal administration of chemotherapy is associated with an improvement in survival.^{1, 2, 3} 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.

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 then be re-evaluated 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% of them relapse and ultimately die from the disease. Therefore, strategies to decrease the risk of recurrence have been investigated. A phase III randomized trial reported an improvement in disease-free survival (DFS) when patients were treated with 12 cycles of maintenance paclitaxel.

Second-line chemotherapy: Most patients with ovarian cancer have a recurrence. Based on the disease-free interval after completing chemotherapy, patients can be classified in 2 categories: (1) platinum-sensitive (relapse >6 mo after initial chemotherapy) and (2) platinum-resistant. Patients with platinum-sensitive disease may exhibit a good response if rechallenged with a platinum-based regiment. 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, also exhibits modest activity but has a favorable toxicity profile.

Drug Category: 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.

Drug Name	Carboplatin (Paraplatin)
Description	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.
Adult Dose	Target AUC of 4-7.5 IV q3-4wk recommended
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
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

Drug Name	Paclitaxel (Taxol)
Description	Mechanism of action is tubulin polymerization and microtubule stabilization.
Adult Dose	175 mg/m2 as 3-h IV infusion q3wk; alternatively, 135 mg/m2 as 24-h IV infusion q3wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; severe cardiac disease
Interactions	Coadministration with cisplatin may further increase myelosuppression
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

Drug Name	Liposomal doxorubicin (Doxil)
Description	Interferes with synthesis of nucleic acid by intercalating with DNA nucleotide pairs and topoisomerase II inhibition.
Adult Dose	40-50 mg/m2 IV q4wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression; impaired liver function
Interactions	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
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

Drug Category: Antineoplastic Agents

These agents inhibit cell growth and proliferation.

Drug Name	Gemcitabine (Gemzar)
Description	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	May cause myelosuppression (particularly thrombocytopenia); toxicities include flu like syndrome, LFT abnormality, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic uremic syndrome; clearance reduced in women and elderly individuals

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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, particularly women with a genetic predisposition for ovarian cancer (ie, BRCA carriers). 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. However, the use of transvaginal ultrasonography and CA-125 tumor marker is recommended in high-risk women.

Prognosis

• The 5-year survival rates are as follows:
  
  
  • Stage I - 73%
  • Stage II - 45%
  • Stage III - 21%
  • 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.

ACKNOWLEDGMENTS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Omid Hamid and Anthony El-Khoueiry to the development and writing of this article.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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Article Last Updated: Dec 13, 2007