WOMEN'S HEALTH
March 22, 2008

Epithelial Ovarian Cancer

Renata Urban, M.D., and Jonathan S. Berek, M.D., M.M.S.
By the time most women seek treatment for epithelial ovarian cancer, the disease has already reached an advanced stage.
Dr. Urban is a Resident and Dr. Berek is Professor and Chair, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA.


Ovarian cancer is the most lethal of all cancers that affect only women. Because it is so rarely discovered before it has reached an advanced stage, it is both difficult to treat and difficult to deal with for patients and their families. Detecting early-stage ovarian cancer has proven to be a challenge that modern technology, even high-tech screening methods, have not been able to meet. The vast majority of ovarian tumors begin in the ovarian epithelium, a type of tissue that forms the surface of the ovaries.

One meta-analysis, however, showed that a period of infertility lasting greater than five years was associated with an increased risk of ovarian cancer.

By the time most women seek treatment for epithelial ovarian cancer, the disease has already reached an advanced stage, despite the fact that they usually have no more than mild, vague symptoms. Upon diagnosis, the usual next step is surgery to remove all visible tumors, followed by chemotherapy. If the disease is particularly advanced, it may be treated with either intravenous (delivered into the blood through an IV) or intraperitoneal (placed directly inside the abdomen) chemotherapy.

Who Gets Epithelial Ovarian Cancer?

The Odds
A contemporary American woman's lifetime risk of developing ovarian cancer is approximately 1 in 70. In 2008, an estimated 21,650 women will be diagnosed with ovarian cancer and 15,520 will die from the disease.

Risk Factors
Menopause
Most epithelial ovarian tumors occur in women who are between 56 and 60 and have experienced the physical and hormonal changes of menopause. Nearly 30% of ovarian masses in women who are past menopause are malignant (cancerous), while only 7% are malignant in women of reproductive age.

Patterns of Fertility
Ovarian cancer is also related to fertility. Early sexual maturity and late menopause both increase a woman's statistical risk of ovarian cancer.

Fertility Drugs, but Not Birth Control
Some have speculated that fertility drugs increase the risk of ovarian cancer, though several studies have found otherwise. One meta-analysis, however, showed that a period of infertility lasting greater than five years was associated with an increased risk of ovarian cancer.
Taking birth control pills helps protect women against the development of ovarian cancer, with the benefit lasting as long as 15 years after the pill is discontinued.

Obesity
Obesity is another risk factor for ovarian cancer.

Germline Mutations
Nearly 90% of ovarian tumors are sporadic; that is, they have no genetic cause; however, in 5-10% of ovarian malignancies there are genetic mutations. Two of these genetic mutations, called BRCA-1 and BRCA-2, are more common in women of Ashkenazi Jewish descent. Women who carry the BRCA-1 mutation have been estimated to have a lifetime risk for ovarian cancer of between 28-44%, and for women with a BRCA-2 mutation, the risk has been estimated as high as 27%. In women with a mutation in either the BRCA-1 or BRCA-2 gene, the use of oral contraceptives seems to have a protective effect. Furthermore, a recent study of 1,828 women with a BRCA-1 or BRCA-2 mutation found that having a preventive bilateral salpingooophorectomy -- a surgical operation that removes the Fallopian tubes and ovaries -- reduced cancer risk by 80%.

Symptoms and Diagnosis
Most women with ovarian cancer experience some symptoms; unfortunately, as mentioned above, these symptoms tend to be mild and vague. A 2000 survey of 1,725 women with ovarian cancer revealed that 95% of women had symptoms before being diagnosed; interestingly, 89% of those with early stage disease reported symptoms. These symptoms include bloating, urinary symptoms and increased abdominal size. Urinary frequency or constipation may be caused by compression of the bladder or rectum by an ovarian tumor.

In the advanced stage of the disease, typical symptoms include abdominal distension, nausea, anorexia or a premature feeling of fullness when eating. One of the most important signs of ovarian cancer is the presence of an unusual mass near the pelvis. A mass that is solid, irregularly shaped or fixed in the pelvis is suspicious for cancer. An upper abdominal mass or ascites (excess fluid in the abdomen) is an almost certain sign of ovarian cancer. Unfortunately, these can be hard to detect in a physical exam, especially with obese women.

In a women with a mass in the adnexa, (the area including the ovaries and Fallopian tubes), an ultrasound is usually performed before surgery. Various tests are used to determine if an adnexal mass is benign or malignant.

Recently, proteomics -- the study of an organism's full complement of proteins -- has been suggested as a way to screen for ovarian cancer, but studies have been inconclusive.

Before doctors operate on a woman suspected of having ovarian cancer, they must first eliminate a number of other disorders and diseases, including other cancers that might have metastasized into the ovary. Any woman with evidence of intestinal obstruction should undergo a colonoscopy. If there are any symptoms of disease in the upper gastrointestinal tract, an endoscopy should be done.

Women with breast masses should have bilateral mammography performed, because breast cancer can rarely metastatize to the ovaries. If there is fluid buildup in the abdomen, but no pelvic mass, a CT scan or MRI of the abdomen and pelvic area should be done to look for other kinds of tumors.

Surgery and Ovarian Cancer
Epithelial ovarian malignancies are classified by stages, according to the 2002 revised American Joint Committee on Cancer (AJCC) and the International Federation of Gynecologic and Obstetrics (FIGO) system, which is shown below (Table 1). This is fairly technical; if you or a loved one is being treated for ovarian cancer and you have questions about these stagings, you should discuss them with your physician. The majority of patients (58-63%) who are diagnosed with ovarian cancer have stage III-IV disease.

Table 1.
FIGO Staging.
Stage I
Growth limited to the ovaries.

Stage IA
Growth limited to one ovary, no ascites, or abnormal intraabdominal fluid, containing malignant cells. No tumor on the external ovarian surface, ovarian capsule intact.

Stage IB
Growth involving both ovaries, no ascites containing malignant cells, no tumor on the external surface, capsule intact.

Stage IC
Tumor either stage IA or IB but with tumor on the surface on one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells.

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

Stage IIA
Extension and/or metastases to the uterus and/or tubes.

Stage IIB
Extension to other pelvic tissues.

Stage 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 lymph nodes. Superficial liver metastases equals stage III. Tumor is limited to the true pelvis, but with histology proves malignant extension to small bowel or omentum.

Stage IIIA
Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.

Stage IIIB
Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes negative.

Stage IIIC
Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes.

Stage IV
Growth involving one or both ovaries with distant metastasis.


Surgery for ovarian cancer is normally done as follows:
  1. Performance of a laparotomy, or surgical incision in the abdomen
  2. Removal of free fluid to be analyzed for the presence of cancerous cells; if no free fluid is present, washing should be obtained by placing saline solution in the pelvic cul-de-sacs and gutters
  3. Total hysterectomy and bilateral salpingooophorectomy (removal of all ovaries and Fallopian tubes)
  4. Exploration of all intraabdominal and peritoneal surfaces, with biopsies of suspicious lesions
  5. Assessment of the pelvic and paraaortic lymph nodes with removal of lymph nodes that might be cancerous.
  6. Physical examination of the diaphragm, liver and spleen
  7. Removal of the omentum, which is a piece of tissue that hangs below the stomach.
  8. Appendectomy.
In young women with early stage disease, a more conservative approach may be undertaken that spares an unaffected ovary and uterus. However, the uterus and ovary will need to be removed once childbearing is completed.
Treatment
The technique for surgical staging centers on removal of all malignant cells. This principle is based on studies that have shown an improved outcome for patients with less than 1 cm of disease after surgical staging.Thorough surgical staging is crucial to the management of patients with ovarian cancer, as postoperative therapy and prognosis will depend on the surgical stage. In a study of 100 patients who were initially thought to have early stage disease, a second surgical procedure revealed that 31% had advanced stage disease.

After surgery, most women with epithelial ovarian cancer will be given chemotherapy (carboplatin and paclitaxel).

Table 2.
Combination Chemotherapy for Advanced Epithelial Ovarian Cancer: Recommended Regimens.

Drugs Dose (mg/m2)* Route Interval (weeks) Treatments (cycles)
Standard Regimens
Intraperitoneal Chemotherapy
Paclitaxel 135 IV 3, day 1 6
Cisplatin 50Ð100 IP day 2
Paclitaxel 60 IP day 8
Intraperitoneal Chemotherapy
Paclitaxel 175 IV 3 6-8
Carboplatin AUC* = 5-6 IV
Paclitaxel 135 IV 3 6-8
Cisplatin 75 IV
Alternative Drugs**
Docetaxel 75 IV 3
Doxorubicin, liposomal 35-50 IV 3-4
Topotecan 1.0-1.25 IV 1
4.0 IV 3 (daily 3 3-5 days)
Etoposide 50 PO 3, days 14-21
* Except for carboplatin dosing, where AUC -- area under the curve -- dose calculated by using Calvert formula

** Drugs that can be substituted for paclitaxel if hypersensitivity to that drug occurs; the number of treatments ad

An old technique known as intraperitoneal chemotherapy seems to be making a comeback; this involves placing an anticancer drug directly inside the abdomen. Given that ovarian malignancies have a propensity to spread throughout the abdominal cavity, this technique may achieve a much higher concentration of anti-cancer drugs near the tumor cells than conventional chemotherapy. In 1996, intraperitoneal cisplatin was shown in more than 500 patients with Stage III disease to be associated with improved survival and lower toxicity, compared with intravenous cisplatin. A subsequent study demonstrated a significant improvement in progression-free survival in women receiving intravenous carboplatin and paclitaxel as well as intraperitoneal cisplatin; however, the improvement in overall survival was not statistically significant. The most recent trials of intraperitoneal agents demonstrated an improvement in overall survival in women who received intraperitoneal cisplatin and both intravenous and intraperitoneal paclitaxel, compared with those who received the same drugs intravenously only.

A down-side of intraperitoneal chemotherapy are the complications associated with intraperitoneal catheters, including infection and obstruction. Intraperitoneal chemotherapy is currently considered first-line chemotherapy for women with stage III ovarian cancer who have had complete surgical removal of the tumor.

Conclusion
In summary, because it is rarely diagnosed until well advanced, ovarian cancer remains the deadliest of the gynecologic malignancies. Epithelial ovarian cancer is the most common type of ovarian cancer. The best current therapy is surgery followed by conventional intravenous chemotherapy or, in some women, intraperitoneal chemotherapy.
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