Ovarian Cancer

One in 70 women will develop ovarian cancer during their lifetime. There are approximately 25,000 new cases of ovarian cancer and 14,000 deaths annually. Epithelial ovarian cancer comprises 90% of all ovarian cancers. This translates into 22,500 cases of epithelial ovarian cancer annually. The median age of onset is 61 years.

Risk Factors

The risk of ovarian cancer increases with age and peaks at about 70 years. Patients of low parity, decreased fertility, and delayed child-bearing appear to be at greater risk for ovarian cancer. There also appears to be autosomal dominant inherited forms which account for only 3-5% of all cases of ovarian cancer. They tend to occur at younger ages (approximately 10 years before non-heritable ovarian cancer). A dysfunctional BRCA 1/2 gene plays a major role in these syndromes. There are three recognized hereditary forms which include the following:

1. Site Specific Familial Ovarian Cancer
2. Breast-Ovarian Familial Cancer Syndrome
3. Lynch II Syndrome (Non-polyposis colon cancer, endometrial cancer, breast cancer and ovarian cancer clusters in first and second degree relatives).

Note: Use of oral contraceptives appears to have a protective effect which may last up to 10 years.

PathologyThere are 8 different major histologic groups of epithelial ovarian cancer:

Histologic Types % of Ovarian Tumors % Bilateral
Serous 46 73
Mucinous 36 47
Endometrioid 8 33
Clear Cell 3 13
Transitional 2 -
Mixed 3 -
Undifferentiated <2 53
Unclassified <1 -

Routes of Spread

1. Transcoelemic (most common)- Exfoliated cells tend to assume the circulatory path of the peritoneal fluid and implant along this path.
2. Lymphatic dissemination
3. Hematogenous dissemination (uncommon)

Clinical Features

The interval from onset of disease to diagnosis is often prolonged secondary to lack of specific diagnostic symptoms in early stage disease therefore diagnosis is often not made until patients have disseminated disease. It is estimated that more than half (60%) of patients with ovarian cancer are stage III or stage IV at time of diagnosis. Clinical signs and symptoms often seen in these patients are abdominal fullness, early satiety, dyspepsia, urinary frequency, and constipation. In some cases, an adnexal mass is noted on routine pelvic exam or a palpable ovary in a postmenopausal asymptomatic patient.

Note: Five percent of patients explored for presumed ovarian cancer have another primary which has metastasized to the ovary. The most common sources of metastatic lesions are the breast, GI tract, and pelvic organs.

Pretreatment Work-Up

1. Careful physical exam
2. Routine blood tests
3. Serum tumor markers: CA-125 is elevated in approximately 80-85% of cases of epithelial ovarian cancer. Unfortunately, the predictive power of pre-operative CA-125 is quite low.
4. Chest X-Ray
5. Imaging studies are often helpful but most often will not change the planned staging procedure. Computerized Axial Tomography (CT) may help determine the extent of disease and a Barium Enema (BE) will offer information on the status of the colon. Other imaging studies which are helpful in certain clinical situations include Intravenous Pyelography (IVP).

Staging

Stage I: Growth limited to the ovaries.

Ia- Growth limited to one ovary; no ascites; no tumor on the external surface; capsule intact.
IIB- Growth limited to both ovaries; no ascites; no tumor on external surface; capsules intact.
IC- Tumor either stage Ia or IIB, but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal cytology.

Stage II: Growth involving one or both ovaries with pelvic extension.

IIA- Extension and/or metastases to the uterus and/or tubes.
IIB- Extension to other pelvic tissue.
IIC- Tumor either stage IIA or IIB, but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured or with ascites present containing malignant cells or with 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 equals stage III. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum.

IIIA- Tumor grossly limited to the true pelvis with negative nodes but histologically confirmed microscopic seeding of abdominal peritoneal surfaces.
IIIB- Tumor involving one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2cm in diameter. Nodes are negative.
IIIc- Abdominal implants greater than 2cm in diameter and/or positive retroperitoneal or inguinal nodes.

Stage IV: Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to stage IV. Parenchymal liver metastases equals stage IV.

Treatment

Surgery:

The initial step in treatment of epithelial ovarian cancer involves surgical exploration and appropriate staging procedures which include the following:

1. Abdominal Cytology
2. Careful exploration of all abdominal structures and surfaces.
3. Abdominal Hysterectomy and Bilateral Salpingoophorectomy (TAH/BSO). There are some exceptions to this when fertility is a concern and there is early stage disease.
4. Infracolic omentectomy, +/- appendectomy.
5. Selective pelvic and aortic lymph node sampling.

Primary cytoreduction is a key component of more advanced cases and survival is directly correlated to the amount of residual tumor remaining. Optimal tumor reduction surgery is loosely defined as the largest residual tumor diameter being less than or equal to 2cm. If residual is greater, the cytoreduction is deemed sub-optimal.

Note: There are certain exceptions to the initial treatment step, whereby primary chemotherapy may be employed followed by interval debulking procedures in certain subsets of patients with advanced disease, bulky disease or those patients not appropriately primarily cytoreduced. The impact on survival in this approach, however, is unproven in those patients with advanced and bulky disease.

Adjuvant Chemotherapy:

Stage Ia , Grade 1 Tumors: Adjuvant chemotherapy is not necessary in this subset of patients. If fertility is an issue in those patients who have had a thorough staging procedure, the uterus and contra-lateral ovary may be conserved.

Stages Ia (Grades 2 and 3), IC, II, III, IV: Current treatment consists of Taxol and Carboplatin based regimens.

Prognostic Factors

1. Histopathologic factors:

Histologic type
Histologic grade
DNA ploidy

2. Clinical Factors:

Surgico-pathologic stage
Extent of residual disease remaining following primary cytoreduction
Volume of ascites
Patient age
Performance status

Survival

1. Overall – 40-60%

2. Residual Disease (All Stages) Five Year Survival:

Microscopic 40-75%
Macroscopic (Optimal) 30-50%
Macroscopic (Suboptimal) 5-30%

3. Performance Status: As expected patients with poorer performance status (Karnofsky’s <70) prior to treatment have significantly shorter survival.

Recommended Follow-Up

Follow-up for the first 2 years is every 3 months, every 6 months for years 3, 4 and 5 and yearly thereafter. Pelvic exam and CA-125 at each visit and PAP smear on an annual basis. Routine performance of imaging studies (CT scans, Chest X-ray, etc) should be individualized.