In the US, ovarian cancer is the 2nd most common gynecologic cancer (affecting about 1/70 women). It is the 5th leading cause of cancer-related deaths in women and, in the US, will cause an estimated 21,750 new cases and 13,940 deaths in 2020. Incidence is higher in developed countries.
Etiology of Ovarian Cancer
Ovarian cancer affects mainly perimenopausal and postmenopausal women.
Risk of ovarian cancer is increased by
A history of ovarian cancer in a 1st-degree relative
Nulliparity
Delayed childbearing
Early menarche
Delayed menopause
A personal or family history of endometrial, breast, or colon cancer
Risk is decreased by
Oral contraceptive use
Germline alterations in breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes are identified in 14 to 18% of patients with high-grade serous ovarian cancer; 3% have somatic BRCA mutations (BRCAm) or inactivation due to methylation (1 Etiology references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ). Deficiency of homologous recombination (which is involved in the repair of DNA damage and replication [2]) is detected in about half of patients with high-grade serous ovarian cancer (2 Etiology references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ).
Mutations in the autosomal dominant BRCA gene are associated with a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is increased less. Incidence of these mutations is higher in Ashkenazi Jews than in the general population. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and/or ovarian cancer.
XY gonadal dysgenesis predisposes to ovarian germ cell cancer.
Etiology references
1. Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature 474 (7353):609–615, 2011. doi: 10.1038/nature10166
2. Li X, Heyer WD: Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18 (1):99–113, 2008. doi: 10.1038/cr.2008.1
Pathology of Ovarian Cancer
Ovarian cancers are histologically diverse (see table Types of Ovarian Cancer Types of Ovarian Cancers 
).
High-grade serous epithelial ovarian carcinoma, fallopian tube Fallopian Tube Cancer Fallopian tube cancer is usually adenocarcinoma, manifesting as an adnexal mass or with vague symptoms. Diagnosis, staging, and primary treatment are surgical. High-grade serous epithelial ovarian... read more , and peritoneal carcinomas share clinical behavior and treatment.
Most (90%) ovarian cancers develop from epithelial cells; the rest (germ cell tumors, sex-cord stromal tumors) develop from other ovarian cell types.
Epithelial ovarian carcinoma may be divided into five subtypes:
High--grade serous
Low-grade serous
Endometrioid
Clear cell
Mucinous
High-grade serous ovarian carcinoma is the most common subtype (> 70%) of epithelial carcinomas.
At presentation, nearly 27% of patients with stage I epithelial ovarian cancers have mucinous histology, but < 10% with stage III or IV do.
Germ cell cancers usually occur in women < 30.
Ovarian cancer spreads by
Direct extension
Exfoliation of cells into the peritoneal cavity (peritoneal seeding)
Lymphatic dissemination to the pelvis and around the aorta
Less often, hematogenously to the liver or lungs
Symptoms and Signs of Ovarian Cancer
Early ovarian cancer is usually asymptomatic; an adnexal mass, often solid, irregular, and fixed, may be discovered incidentally. Pelvic and rectovaginal examinations typically detect diffuse nodularity. A few women present with severe abdominal pain secondary to torsion of the ovarian mass Adnexal Torsion Adnexal torsion is twisting of the ovary and sometimes the fallopian tube, interrupting the arterial supply and causing ischemia. Adnexal torsion is uncommon, occurring most often during reproductive... read more .
Most women with advanced cancer present with nonspecific symptoms (eg, dyspepsia, bloating, early satiety, gas pains, backache). Later, pelvic pain, anemia, cachexia, and abdominal swelling due to ovarian enlargement or ascites usually occur.
Germ cell or stromal tumors may have functional effects (eg, hyperthyroidism, feminization, virilization).
Diagnosis of Ovarian Cancer
Ultrasonography (for suspected early cancers) or CT or MRI (for suspected advanced cancers)
Tumor markers (eg, cancer antigen [CA] 125)
Surgical staging
Ovarian cancer is suspected in women with the following:
Unexplained adnexal masses
Unexplained abdominal bloating
Changes in bowel habits
Unintended weight loss
Unexplained abdominal pain
An ovarian mass is more likely to be cancer in older women. Benign functional cysts Benign Ovarian Masses Benign ovarian masses include functional cysts and tumors; most are asymptomatic. Treatment varies depending on the patient's reproductive status. There are 2 types of functional cysts:... read more can simulate functional germ cell or stromal tumors in young women.
A pelvic mass plus ascites usually indicates ovarian cancer but sometimes indicates Meigs syndrome (a benign fibroma with ascites and right hydrothorax).
Imaging
If early cancer is suspected, ultrasonography is done first; the following findings suggest cancer:
A solid component
Surface excrescences
Size > 6 cm
Irregular shape
Low vascular resistance detected by transvaginal Doppler flow studies
If advanced cancer is suspected (eg, based on ascites, abdominal distention, or nodularity or fixation detected during physical examination), CT or MRI is usually done before surgery to determine extent of the cancer.
Tumor markers
Tumor markers, including the beta subunit of human chorionic gonadotropin (beta-hCG), lactic dehydrogenase (LDH), alpha-fetoprotein, inhibin, and CA 125, are typically measured in young patients, who are at higher risk of nonepithelial tumors (eg, germ cell tumors, stromal tumors). In perimenopausal and postmenopausal patients, only CA 125 is measured because most ovarian cancers in this age group are epithelial tumors. CA 125 is elevated in 80% of advanced epithelial ovarian cancers but may be mildly elevated in endometriosis, pelvic inflammatory disease, pregnancy, fibroids, peritoneal inflammation, or nonovarian peritoneal cancer.
A mixed solid and cystic pelvic mass in postmenopausal women, especially if CA 125 is elevated, suggests ovarian cancer.
Biopsy
A biopsy is not routinely recommended unless a patient is not a surgical candidate. In those rare cases, samples are obtained by needle biopsy for masses or by needle aspiration for ascitic fluid.
For masses that appear benign on ultrasonography, histologic analysis is not required, and ultrasonography is repeated after 6 weeks. Such benign-appearing masses include benign cystic teratomas (dermoid cysts), follicular cysts, and endometriomas.
Staging
Suspected or confirmed ovarian cancer is staged surgically (see table FIGO Surgical Staging of Ovarian, Fallopian Tube, and Peritoneal Cancer FIGO Surgical Staging of Ovarian, Fallopian Tube, and Peritoneal Cancer ).
If early-stage cancer is suspected, staging may be done by laparoscopy or robotic-assisted laparoscopic surgery. Otherwise, an abdominal midline incision that allows adequate access to the upper abdomen is required. All peritoneal surfaces, hemidiaphragms, and abdominal and pelvic viscera are inspected and palpated. Washings from the pelvis, abdominal gutters, and diaphragmatic recesses are obtained, and multiple biopsies of the peritoneum in the central and lateral pelvis and in the abdomen are done. For early-stage cancer, the infracolic omentum is removed, and pelvic and para-aortic lymph nodes are sampled.
Cancers are also graded histologically from 1 (least aggressive) to 3 (most aggressive). The most recent classification distinguishes epithelial ovarian cancers as low-grade (grade 1) or high-grade (grade 2 or 3).
Screening
There is no screening test for ovarian cancer. However, women with a known hereditary risk, such as those with BRCA mutations, should be followed closely.
Although data from large trials indicate that CA 125 has a high specificity (up to 99.9% in one study), sensitivity is only moderate (71% in one study), and positive predictive value is low; thus, CA 125 is not recommended as a screening test for asymptomatic, average-risk women. Screening asymptomatic women using both ultrasonography and serum CA 125 measurements can detect some cases of ovarian cancer but has not been shown to improve outcome, even for high-risk subgroups (including women with BRCA mutations).
Evaluation for a hereditary cancer syndrome should be considered in all women diagnosed with ovarian, fallopian tube, or peritoneal cancer, and they should have a genetic risk evaluation. Most breast and ovarian cancers are sporadic; only about 6% of breast cancer and 15% of ovarian cancer cases are caused by mutations in BRCA genes. A germline or somatic BRCA1 or BRCA2 mutation may affect treatment and maintenance therapy. A detailed personal and family history of other cancers should be obtained to identify women who are more likely to have a hereditary cancer syndrome (eg, one involving BRCA1 or BRCA2 mutations, hereditary nonpolyposis colorectal cancer [Lynch syndrome]).
Women should be screened for abnormalities in the BRCA gene if their family history includes any of the following:
Diagnosis of ovarian cancer in a 1st-degree relative before age 40
Diagnosis of breast and ovarian cancer in only one 1st-degree relative if one of the cancers was diagnosed before age 50
Two cases of ovarian cancer among 1st- and 2nd-degree relatives of the same lineage
Two cases of breast cancer and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage
One case of breast and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage if breast cancer was diagnosed before age 40 or if ovarian cancer was diagnosed before age 50
Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if both cases were diagnosed before age 50
Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if one was diagnosed before age 40
Also, if Ashkenazi Jewish women have one family member with breast cancer diagnosed before age 50 or with ovarian cancer, screening for abnormalities in the BRCA gene should be considered.
Prognosis for Ovarian Cancer
The 5-year survival rates with treatment are
Stage I: 85 to 95%
Stage II: 70 to 78%
Stage III: 40 to 60%
Stage IV: 15 to 20%
Prognosis is worse when tumor grade is higher or when surgery cannot remove all visibly involved tissue; in such cases, prognosis is best when the involved tissue can be reduced to < 1 cm in diameter or ideally to a microscopic residual amount (cytoreductive surgery).
With stages III and IV, recurrence rate is about 70%.
Treatment of Ovarian Cancer
Usually hysterectomy and bilateral salpingo-oophorectomy
Cytoreductive surgery
Usually postoperative chemotherapy, often with carboplatin and paclitaxel
(See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer.)
Hysterectomy and bilateral salpingo-oophorectomy are usually indicated except for stage I nonepithelial or low-grade unilateral epithelial ovarian cancers in young patients; fertility can be preserved by not removing the unaffected ovary and uterus.
Primary surgical cytoreduction followed by systemic chemotherapy is the preferred initial treatment for patients with stage III or IV ovarian cancer. Patients not considered candidates for surgical resection because of the location and volume of the cancer, or because of comorbidities are treated with neoadjuvant chemotherapy.
In patients with extensive spread, surgery is not indicated or can be deferred if they have one or more of the following:
Multiple liver metastases
Lymphadenopathy in the porta hepatis
Suprarenal para-aortic lymph nodes
Diffuse mesenteric disease
Evidence of pleural or parenchymal lung disease
These patients are treated with neoadjuvant chemotherapy (eg, with carboplatin plus paclitaxel). Surgery can sometimes be done after initial chemotherapy.
When hysterectomy and bilateral salpingo-oophorectomy are done, all visibly involved tissue is surgically removed if possible (cytoreduction). Cytoreduction is associated with increased survival time; the volume of residual disease remaining after cytoreduction correlates inversely with survival time. Cytoreduction may be
Complete: Cytoreduction to no grossly visible disease
Optimal: Cytoreduction with residual disease that is ≤ 1 cm in maximum tumor diameter, as defined by the Gynecologic Oncology Group
Suboptimal: Cytoreduction with any visible tumor nodules > 1 cm remaining
Cytoreductive surgery for ovarian cancer usually includes
Supracolic omentectomy, sometimes with rectosigmoid resection (usually with primary reanastomosis)
Radical peritoneal stripping
Resection of diaphragmatic peritoneum or splenectomy
Predicting feasibility of cytoreduction
Because cytoreduction is associated with increased survival, being able to predict when cytoreduction to no gross residual disease can be done is important, but doing so is difficult; there are no uniform criteria.
Optimal cytoreduction is less likely if patients have the following:
Poor performance status
Age > 60 years
American Society of Anesthesiologists physical status 3 or 4
Medical comorbidities
Poor nutritional status
Extra-abdominal disease
Large tumor bulk
Involvement of large bowel
Metastases to retroperitoneal lymph nodes above the renal vessels > 1 cm in largest dimension
Parenchymal liver involvement
A preoperative CA 125 > 500 U/mL
Algorithms based on results of preoperative imaging (eg, CT, MRI, positron emission tomography [PET]/CT) to assess optimal cytoreduction have not been reliably reproducible.
Diagnostic laparoscopy before laparotomy could spare patients an unnecessary laparotomy resulting in suboptimal cytoreduction. Laparoscopy enables clinicians to do a tissue biopsy, make a definitive diagnosis, and analyze the biopsy sample. Thus, patients who are not candidates for cytoreduction can begin chemotherapy treatment earlier. Laparoscopic findings indicating that optimal cytoreduction is unlikely include
Omental cake
Extensive peritoneal or diaphragmatic carcinomatosis
Mesenteric retraction
Bowel and stomach infiltration
Spleen and/or liver superficial metastasis
The Fagotti score, based on 7 laparoscopic findings, can help predict the likelihood of optimal cytoreduction in patients with advanced ovarian cancer (see table Calculating the Fagotti Score to Predict the Likelihood of Optimal Cytoreduction ). This scoring system assigns a value of 0 or 2 depending on whether disease is present in certain locations. If patients score ≥ 10, optimal cytoreduction is very unlikely. If they score < 10, they are considered candidates for cytoreductive surgery (1 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ).
Postoperative treatment
Postoperative treatment of ovarian cancer depends on the stage and grade (see table Postoperative Treatment of Ovarian Cancer by Stage and Type Postoperative Treatment of Ovarian Cancer by Stage and Type ).
For patients with stage IA or IB ovarian tumors (confined to the ovary) and/or grade 1 tumors, prognosis is excellent (survival 90%) after surgery alone. For patients with stage IC, II, grade 3, or clear cell histology, adjuvant chemotherapy treatment (eg, with carboplatin and paclitaxel) is recommended.
For stage III or IV, primary surgical cytoreduction followed by systemic chemotherapy is the standard treatment.
For certain patients at higher risk of recurrence (eg, those who have pleural effusions or ascites and do not have a BRCA mutation), adding bevacizumab to chemotherapy and continuing it as maintenance therapy is an option.
PARP (polyadenosine diphosphate-ribose polymerase) enzymes are essential to the repair of single-strand breaks in DNA. Inhibition of PARP enzymes leads to persistent single-strand breaks, which cause accumulation of double-strand breaks during DNA replication and ultimately lead to tumor cell death.
In several clinical trials, a PARP inhibitor (PARPi) after chemotherapy improved progression-free survival in women who have serous or high-grade endometrioid ovarian cancer and who completed first-line chemotherapy, even if they did not have a BRCA1 or BRA2 mutation (2 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more , 3 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more , 4 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more , 5 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ).
Two placebo-controlled phase III trials evaluated maintenance therapy with a PARPi in patients that responded to first-line platinum therapy. The SOLO1 study evaluated maintenance therapy with olaparib in patients with somatic and germline BRCAm (5 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ), and the PRIMA/ENGOT-Ov26 study evaluated niraparib in patients with newly diagnosed advanced ovarian cancer (not restricted to BRCAm carriers [3 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ]).
The VELIA trial included patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. This three-arm placebo-controlled phase III trial compared standard chemotherapy alone, standard chemotherapy plus veliparib, and standard chemotherapy plus veliparib followed by maintenance therapy with veliparib (2 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ). Progression-free survival was longest with veliparib chemotherapy plus veliparib maintenance.
Even if chemotherapy results in a complete clinical response (ie, normal physical examination, normal serum CA 125, negative CT scan of the abdomen and pelvis), about 50% of patients with stage III or IV cancer have residual tumor. Of patients with persistent elevation of CA 125, 90 to 95% have residual tumor.
Recurrent disease
Recurrence of ovarian cancer can be detected serologically with tumor markers (eg, CA 125) and/or by radiologic signs of progression. Treatment of recurrence depends on the time between the completion of platinum-based treatment and detection of recurrence (platinum-free interval [PFI]):
Patients with a PFI of ≥ 6 months are considered to have platinum-sensitive disease.
Patients with a PFI of < 6 months are considered to have platinum-resistant disease.
If cancer recurs or progresses after effective chemotherapy, chemotherapy is restarted. Useful drugs may include liposomal doxorubicin, docetaxel, paclitaxel, gemcitabine, bevacizumab, and a combination of cyclophosphamide plus bevacizumab or of gemcitabine plus cisplatin. Targeted therapy with biologic agents is under study.
If platinum-sensitive ovarian cancer recurs, a PARP inhibitor—olaparib, niraparib, or rucaparib—is used for maintenance therapy (6 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more , 7 Treatment references Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more ).
Treatment references
1. Petrillo M, Vizzielli G, Fanfani F, et al: Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: Proof of a concept. Gynecol Oncol. 139 (1):5–9, 2015. doi:10.1016/j.ygyno.2015.07.095. Epub 2015 Jul 18.
2. Coleman RL, Fleming GF, Brady MF, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med 381 (25):2403–2415, 2019. doi: 10.1056/NEJMoa1909707. Epub 2019 Sep 28.
3. González-Martín A, Pothuri B, Vergote I, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 381 (25):2391–2402, 2019. doi: 10.1056/NEJMoa1910962. Epub 2019 Sep 28.
4. Ray-Coquard I, Pautier P, Pignata S, et al: Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381 (25):2416–2428, 2019. doi: 10.1056/NEJMoa1911361
5. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379 (26):2495–2505, 2018. doi: 10.1056/NEJMoa1810858. Epub 2018 Oct 21.
6. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366 (15):1382–1392, 2012. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.
7. Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18 (9):1274–1284, 2017. doi: 10.1016/S1470-2045(17)30469-2. Epub 2017 Jul 25.
Prevention of Ovarian Cancer
For patients with BRCA1 or BRCA2 gene mutations, risk of ovarian and, to a lesser degree, breast cancer is reduced if prophylactic bilateral salpingo-oophorectomy is done after childbearing is completed. Cancer risk appears to be lower with this approach than with surveillance. Patients with BRCA1 or BRCA2 gene mutations should be referred to a gynecologic oncologist for counseling.
Key Points
Ovarian cancer affects mostly postmenopausal and perimenopausal women; nulliparity, delayed childbearing, early menarche, delayed menopause, and certain genetic markers increase risk.
Early symptoms (eg, dyspepsia, bloating, early satiety, gas pains, backache) are nonspecific.
If cancer is suspected, do ultrasonography first (sometimes followed by CT or MRI), measure tumor markers (eg, CA 125), and surgically stage tumors.
Screening asymptomatic women with ultrasonography and/or CA 125 is not useful unless risk of BRCA mutations is high.
Diagnostic laparoscopy before laparotomy could spare some patients an unnecessary laparotomy that results in suboptimal cytoreduction.
Typically, treatment is hysterectomy, bilateral salpingo-oophorectomy, and cytoreductive surgery followed by chemotherapy (eg, carboplatin, paclitaxel, and bevacizumab).
More Information
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
National Cancer Institute: Ovarian, Fallopian Tube, and Primary Peritoneal Cancer: This web site provides links to information about causes, genetics, prevention, and treatment of ovarian, fallopian tube, and primary peritoneal cancer, as well as links to information about screening, statistics, and supportive and palliative care.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
carboplatin |
No US brand name |
paclitaxel |
TAXOL |
bevacizumab |
AVASTIN |
olaparib |
LYNPARZA |
niraparib |
ZEJULA |
docetaxel |
TAXOTERE |
gemcitabine |
GEMZAR |
cyclophosphamide |
No US brand name |
cisplatin |
No US brand name |
