RISK FACTORS Family history; multiple geneticfactors. Environmental factors as yet undefined Professional occupations and jobs requiring administrative roles are associated with an Increased incidence of ovarian cancer
Genetics:
β’ For a woman who has a first-degree relative with a history of ovarian cancer, her risk for disease increases
from 1.4% to 5%. With 2 or more such relatives lifetime risk is 7%. In families with hereditary ovarian cancer
syndrome (site-specific familial ovarian cancer syndrome, breast-ovarian cancer syndrome, and Lynch
syndrome II) risk rises to 40-50%. Transmission is autosomal dominant. These syndromes are associated with a variety of mutations in BRCA-1 and BRCA-2, and commercial screens for these genes are available. The
clinical utility of such screening is under study. Patients with germ-line mutations of BRCA-1 appear to have
better survival rates compared to patients who do not. The over-expression of certain oncogenes (her-2/neu,
K-ras, c-myc) and of a mutant form of the tumor suppression factor p53 are associated with poor outcome.
β’ A history of breast cancer impacts risk for ovarian cancer significantly. In women diagnosed with breast
cancer prior to the age of 40, the risk for ovarian cancer increases 60%. If this same woman has a family history of either breast or ovarian cancer in a fi rst-degree relative, then her risk for ovarian cancer increases 17-fold more than a woman without breast cancer. Consequently, women with onset of breast cancer prior to the age of 40 should be monitored closely for the possibility of ovarian cancer.
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
MEDICAL TREATMENT :
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.
DRUG TREATMENT : 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 randomized clinical trials suggest that in patients with optimally debulked disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous administration. However, this approach is also associated with more toxicity.
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 reevaluated for surgical cytoreduction.
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 agent. The probability of response increases with the duration of the disease-free interval. 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 very 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
- CARBOPLATIN
- PACLITAXEL
- LIPOSOMAL DOXORUBICIN
- TOPOTECAN
PATIENT MONITORING
β’ A logarithmic or sevenfold fall in CA-125 suggests a good response, but normal values correlate poorly <50%) with absence of disease. Persistent elevations reflect a poor response to therapy.
β’ A rise in CA-125 usually requires a change in therapy, while an inadequate drop after 3 courses of chemotherapy may require a change.
β’ In germ cell cancers, serum markers should fall to normal range. Normal levels correlate closely with absence
of disease.
PREVENTION/AVOIDANCE
For epithelial cancer, frequency of ovulation appears to be important. Ovulation causes the surface epithelium
to be in a state of flux and this may promote the genetic changes necessary for uncontrolled growth and malignant transformation. Consistent with this, the following factors are protective:
. Use of oral contraceptives
. Multiparity
. Late menarche
. Early menopause
. Premenopausal women without contraindications should be encouraged to use OCPs. The progestin
component of OCPs may protect against ovarian cancer by regulating apoptosis of the ovarian epithelium.
. In contrast, a recent prospective cohort study in 211,581 women evaluated the effect of HRT on ovarian
cancer risk. The annual age-adjusted ovarian cancer death rates for every 100,000 women are 64.4 after 10
yrs of continuous HRT use, 38.3 in former users who used HRT for 10 or more years, and 26.4 in women who never used HRT. This data should be considered when counseling women about the relative risks.
. Clomiphene use in infertile women may increase the incidence of ovarian neoplasia, but newer studies are
refuting this
. In the New York University Womens Health Study, aspirin use was associated with a reduction in epithelial ovarian cancer, possibly by inhibiting precarcinogenic inflammatory changes
. Acetaminophen use may be protective by lowering luteinizing hormone levels
. Women with strong family histories of ovarian cancer (2 or more first-degree relatives) should be counseled
concerning cancer risk . Patients with hereditary ovarian cancer syndromes should be counseled about prophylactic oophorectomy after child-bearing is completed or by age 35. Even after oophorectomy, there is a small risk of developing intra-abdominal carcinomatosis histologically identical to ovarian carcinoma.
. Screening - there are no adequate screening measures for the early detection of ovarian cancer in asymptomatic women. The routine use of CA-125 and transvaginal ultrasound for screening is currently discouraged. Annual pelvic examinations are recommended, particularly in postmenopausal women. An adnexal mass in a premenarchal female or a palpable adnexa in a postmenopausal female warrants immediate further evaluation. Women with a family history of a hereditary ovarian cancer syndrome should undergo pelvic examinations, CA-125 quantitation, and transvaginal ultrasonography every 6-12 months.
. A completely novel methodology for screening utilizing proteomic patterns in women is currently under development. Detailed low molecular weight serum protein profiling has been shown to distinguish malignant and benign ovarian tumors with high sensitivity and specificity in a small group of women. Larger studies will help to define the role of this methodology in future ovarian screening efforts.
POSSIBLE COMPLICATIONS
. Pleural effusion
. Pseudomyxoma peritonei
. Ascites
. Radiotherapy and chemotherapy adverse reactions
. Bowel obstruction
. Malnutrition
. Electrolyte disturbances
. Fistula formation
EXPECTED COURSE/PROGNOSIS
Five year survival rates for ovarian cancer based on FIGO data
Stage Survival rate
----------------------------------------------------
I a 84%, b 79%, c 73%
II a 65%, b 54%, c 51%
III a 52%, b 29%, c 18%
IV 14%
---------------------------------------------------------
β’ In germ cell and stromal tumors, outcome related to histologic cell type in addition to clinical stage and histologic grade.
β’ In epithelial cell cancers, prognosis is determined by stage, histologic grade, and the amount of residual
disease rather than the histologic cell type.