PROGRESS REPORT ON OVARIAN CANCER

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Until recently, the clinical picture of ovarian cancer has been bleak. Often growing undetected until tiny tumors dot the abdominal cavity and cancer cells invade other organs, ovarian cancer commonly has progressed or returned despite extensive surgery and the most effective known chemotherapy.

Now there are optimistic signs about this disease, the fifth leading cause of cancer death among American women. New drugs are available to treat advanced cancer, and testing is underway on a variety of innovative treatment approaches for all stages of disease. For women who develop invasive ovarian cancer, the overall five-year survival rate has risen more than 25% in the past 20 years, and for cancer diagnosed early, the five-year survival rate is greater than 90%. Best of all, the rate of invasive ovarian cancer has fallen significantly in the past few years, and scientists believe this trend will continue.

Diagnosing Ovarian Cancer
Despite ovarian cancer's reputation as the "silent killer," in recent surveys, more than 90% of patients with ovarian cancer (whether early or advanced) reported they experienced symptoms long before diagnosis. However, so many symptoms are nonspecific and mimic those of common non-gynecological conditions, such as irritable bowel syndrome, that ovarian cancer is often not suspected until late. Experts suggest that physicians consider the possibility of ovarian cancer in a woman if certain symptoms persist and do not respond to standard treatment: abdominal swelling; digestive disturbances, including gas, bloating, chronic stomach pain, or indigestion; pelvic pressure; a constant need to urinate or defecate; persistent or worsening changes in bowel or bladder patterns; pain in the pelvis, lower back, or legs; vaginal bleeding that is not part of a normal menses; unexplained weight loss; fatigue; or shortness of breath.

The first step in diagnosing ovarian cancer is a thorough medical history and pelvic exam to feel the ovaries. If the physician suspects an ovarian abnormality, he or she may request an ultrasound, usually using a probe placed in the vagina to gain the clearest image. Ultrasound can determine if the ovaries are enlarged or misshapen and help differentiate a tumor from normal tissue or a fluid-filled cyst. Other imaging techniques, including computed tomography or magnetic resonance imaging, may be used to pinpoint pelvic tumors. However, no imaging method provides enough information to definitively diagnose a malignant tumor.

If cancer is suspected, the physician may obtain a blood test to measure CA-125. This protein is produced by ovarian cancer cells and is elevated in more than 80% of women with advanced ovarian cancers and 50% of those with early-stage cancers. However, it's an imperfect diagnostic tool. CA-125 also may be elevated during ovulation, and in the presence of another type of cancer or benign conditions such as endometriosis or fibroids.

A definitive diagnosis is made only during surgery to inspect the ovaries and other organs of the abdomen. Of the women who have surgery for suspected ovarian cancer, less than 20% are diagnosed with the disease.

Occasionally, the ovaries will be evaluated during laparoscopy (done with a lighted tube inserted into the pelvis through a small incision). But if cancer is strongly suspected, or determined during laparoscopy, surgery is performed through an incision down the middle of the abdomen (laparotomy).

During surgery, the abdominal organs - including the diaphragm, bowel, and peritoneum (the sac lining the abdomen) - are carefully examined for areas of tumor. Lymph nodes, fluid samples, and tissue biopsies are removed to test for cancer cells. Ovarian cancer is ranked as early or stage I if it is confined to the ovary, stage II if other pelvic organs are involved, stage III if cancer has spread to other abdominal organs (but not the liver), and stage IV if it has spread to the liver or organs outside the abdominal cavity. The cancer is considered advanced at stages II-IV.

Because surgery is critical to diagnosis and appropriate treatment of ovarian cancer, a gynecological oncologist should operate or consult during the operation.

Treating Ovarian Cancer
The surgeon will remove as much cancerous tissue as possible, along with both ovaries, the uterus, fallopian tubes, and omentum (a fatty layer of tissue that supports the abdominal organs). Sometimes, a woman with very early cancer can have successful fertility-sparing treatment if only her affected ovary is removed.

Following surgery, most women receive a six-treatment course of chemotherapy using paclitaxel (Taxol) with intravenous platinum. The most commonly used platinum is carboplatin (Paraplatin), which has fewer side effects, but sometimes cisplatin (Platinol) is used. Occasionally, chemotherapy is delivered directly into the peritoneal cavity. Effective chemotherapy usually makes CA-125 return to normal levels. If CA-125 remains high or rises during therapy, it suggests recurrence. If the tumor returns within six months of therapy, the cancer cells may be resistant to the drug treatment.

After treatment, a woman is monitored by her physician every few months for the first two years and less frequently thereafter. At the visits, she should have a thorough physical and pelvic exam along with a CA-125 test. Transvaginal ultrasound and other imaging techniques may be used.

Last summer, the FDA approved Doxil (doxorubicin HCl liposome injection, previously used to treat Kaposi's sarcoma) for advanced disease that is resistant to standard chemotherapy. For women who responded well to initial chemotherapy, only to have their tumors recur later, the drug topotecan (Hycamtin) recently has shown good results and fewer side effects than retreatment with a platinum drug. Other common drugs used in resistant or recurrent disease - including etoposide (VePesid), docetaxel (Taxotere), and gemcitabine (Gemzar) - are borrowed from the treatment of other cancers.

Toward Screening and Better Diagnosis
Although early ovarian cancer is just as curable as early-stage breast or cervical cancer, there is no screening test like a mammogram or Pap smear to detect it before symptoms appear. However, better early detection is an active area of research.

Thus far, tests that aid diagnosis have not been useful in screening. Because CA-125 misses half of early cancers and can be elevated by many benign conditions, the National Cancer Institute does not endorse using CA-125 to screen women at ordinary risk. Experts suggest it is reasonable to use CA-125 along with ultrasound, however, to monitor women at high risk of the disease (e.g., a woman with two or more relatives with ovarian, breast, or colon cancer). Large studies are in progress to see whether screening with ultrasound and CA-125 can reduce ovarian cancer deaths in older women.

Other researchers seek ways to use CA-125 more effectively. In one pilot study, scientists found that a rapidly rising CA-125 level (instead of an elevation on any single test) could help detect 80% of early cancers.

Multicenter studies are underway to determine whether plasma levels of lysophosphatidic acid (LPA), a growth factor for ovarian cancer cells, can help distinguish which women with ovarian masses have cancer and which have benign conditions. According to preliminary evidence, levels of LPA in blood plasma are elevated in about 90% of women with early ovarian cancer - including premenopausal women - and high levels also indicate a greater likelihood of cancer spread and metastasis. LPA eventually may be used in conjunction with CA-125 to detect ovarian cancers at an early stage while decreasing the number of women subjected to exploratory surgery because of a false-positive test.

RISK AND PREVENTION
Several factors, some under a woman's control and some not, influence her risk of developing ovarian cancer. Keep in mind that this is a relatively rare cancer - one in 55 women will develop ovarian cancer in her lifetime - so doubling the risk means only a 3.4% lifetime chance of ever developing the disease.

Age. Most ovarian cancers occur in postmenopausal women. Ovarian cancer is uncommon before age 40, with rates rising dramatically after age 50 and increasing until age 80.

Ovulation. The risk of ovarian cancer rises along with factors that increase the number of times a woman ovulates. Scientists theorize that each ovulation creates an opportunity for a cancer-causing mutation to occur as epithelial cells rapidly multiply to repair the wound where the egg was released.

A woman's risk of ovarian cancer is higher if she has never been pregnant and is somewhat higher for women with an early menarche or late menopause. The more pregnancies, the lower a woman's risk; it is halved in women who have had four pregnancies and deliveries. Breast-feeding for at least six months, during which time women generally do not ovulate, moderately reduces risk.

Most striking is the reduction in risk for women who use oral contraceptives, which are thought to work by preventing ovulation. Five years on the pill halves the risk of ovarian cancer; even using the pill for six months lowers it. Some scientists credit oral contraceptive use for the recent reduction in the incidence of ovarian cancer. They believe rates will continue to fall as more women who have taken the pill enter the age range when ovarian cancer usually appears, and as doctors begin to prescribe low-dose pills more frequently to women over 35 who have been discouraged from using high-dose pills.

Heredity. About 7% of ovarian cancers are related to inherited factors. Ovarian cancer in a mother, sister, or daughter makes a woman's risk about 5%.

Mutations in two cancer-protective genes - BRCA1 and, less strikingly, BRCA2 - increase the lifetime risk of ovarian cancer to about 20% (estimates range from 16-44%, depending on the mutation), and the cancer occurs, on average, about 20 years earlier. Non-polyposis colorectal cancer - another familial syndrome - involves a mutation that decreases the body's ability to repair genetic damage; the result is a high risk of colorectal and endometrial cancers and an increased risk of ovarian cancer (about 9%).

A woman with two or more family members with breast, ovarian, or colon cancer may wish to consult a genetic counselor about testing to find out if she has inherited a mutation linked with cancer risk in her family. However, most women with a family history of ovarian cancer are not carriers of one of the identified genes.

To minimize the risk, some women who learn they have a mutation decide to have their ovaries and fallopian tubes removed. Although studies indicate this surgery can reduce risk by more than half, women sometimes still develop ovarian cancer that starts on the peritoneal wall. On the other hand, even among women who carry a mutation of BRCA1 or 2, oral contraceptive use seems to lower cancer risk.

Fertility drugs. Some studies have suggested that ovulation-stimulating drugs may increase the risk of ovarian cancer. Recent data have been more reassuring. The issue is complicated by the fact that infertility itself is associated with a higher risk. Within the next two years, results from long-term studies are expected to clarify the medication issue and cancer risk for women with various types of infertility.

Gynecological surgery. Having a tubal ligation may lower the risk of ovarian cancer by up to 70%. Having a hysterectomy may reduce the risk about 30%.

Medical history. Women who develop breast cancer before age 50 have about double the average risk of ovarian cancer. In some studies, women with endometriosis (particularly long-standing ovarian endometriosis) or who have had pelvic inflammatory disease are also at increased risk.

Other lifestyle factors. Several other factors are weakly associated with ovarian cancer risk. Still, the research points to several generally healthful behaviors that might reduce risk: Don't smoke cigarettes. Eat a diet low in fat and high in fruits and vegetables. If you use powder in your genital area, use cornstarch-based powders, not talcum. Epidemiological studies have associated talcum powder with ovarian cancer, although a causal link has not been established. Recently researchers investigating the possible role of epithelial cell inflammation in ovarian cancer suggested talc may be a cause of this type of inflammation.

Ongoing research. In a surprising finding from a study on breast cancer prevention, women who took fenretinide, a nontoxic vitamin A derivative, seemed to have a lessened ovarian cancer risk. To more directly assess its potential as a preventive drug, researchers are studying women at high risk for ovarian cancer who are scheduled to have their ovaries removed. Some will take fenretinide for several months before surgery; their ovaries will be compared with those of women who did not take the drug to see if there are fewer microscopic signs of early cancer.

NEW TREATMENTS AND APPROACHES
Dozens of clinical trials are ongoing to improve current therapy. In addition, intriguing new approaches are emerging from laboratory and animal research:

Surgery. 60% of stage I cancers will not recur, even without chemotherapy. Researchers seek ways to identify women who can be treated safely with surgery alone.

Monoclonal antibodies (MABs). These laboratory-produced substances find and bind to cancer cells, delivering tumor-killing agents without harming normal cells. A recent laboratory study found that a MAB attached to chlorin, a light-sensitive molecule, destroyed ovarian cancer cells after activation with a laser light. Several clinical trials of monoclonal antibodies have begun, including some to determine whether they can prevent or delay recurrence.

Genetic techniques. New biologically based therapies hope to uncover information about mutations in tumor cells. The breast cancer drug Herceptin is being tested in ovarian cancer patients whose tumors over-express the gene HER-2/neu. Some trials are using gene therapy to supply a working copy of the tumor-suppressing gene p53 to those whose tumors have a mutated, inactive version.

Vaccines. Vaccines to boost a woman's immune response to ovarian tumor cells that emerge after treatment also are in development. A MAB called OvaRex is currently on the fast track for FDA approval. It's designed to trigger the patient's immune system to attack cells producing CA-125. Other vaccines under study are created individually from each patient's tumor.

Targeting blood vessel growth. Several drugs are in clinical trials to establish whether they can prevent ovarian tumors from creating the blood supply they need to survive and spread (a process known as angiogenesis). One unique compound targets a specific weakness in tumor blood vessels; last year it showed promising results in human ovarian tumors growing in mice.

New combinations and sequences. Once ovarian cancer recurs, further treatment can usually delay, but not stop, its progression. Scientists are interested in whether some drugs currently used for recurrent cases can cure the disease if given as a first-line treatment. Later this year, a large international study involving 4,000 women with advanced ovarian cancers will begin to compare the standard two-drug combination with four different experimental programs for initial treatment.

Some new combinations pair drugs that interfere with different steps in cancer cell reproduction. For example, in studies of human ovarian tumors in mice, Taxol and beta-lapachone (a product derived from a South American tree) each shrank tumors by about half. But when the drugs were given together, all the tumor masses disappeared and the animals did not develop common ovarian cancer complications.

Hormonal treatments. Selective estrogen receptor modulators (SERMs) act as estrogens in some tissues and as anti-estrogens in others. Some of these are being tested as less toxic alternatives to chemotherapy in women with recurrent disease.

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