Ovarian Cancer

Ovarian cancer is cancer of the ovaries, the eggreleasing and hormone-producing organs of the female reproductive tract. Cancerous, or malignant, cells divide and multiply in an abnormal fashion.

Description

The ovaries are small, almond-shaped organs, located in the pelvic region, one on either side of the uterus. When a woman is in her childbearing years, the ovaries alternate to produce and release an egg each month during the menstrual cycle. The released egg is picked up by the adjacent fallopian tube, and continues down toward the uterus. The ovaries also produce and secrete the female hormones estrogen and progesterone, which regulate the menstrual cycle and pregnancy, as well as support the development of the secondary female sexual characteristics (breasts, body shape, and body hair). During pregnancy and when women take certain medications, such as oral contraceptives, the ovaries are given a rest from their usual monthly duties.

Types of ovarian cancers

Ninety percent of all ovarian cancers develop in the cells lining the surface, or epithelium, of the ovaries and so are called epithelial cell tumors. About 15% of epithelial cancers are considered low malignant potential or LMP tumors. These tumors occur more often in younger women, and are more likely to be caught early, so prognosis is good.

Germ cell tumors develop in the egg-producing cells of the ovary, and comprise about 5% of ovarian tumors. These tumors are usually found in teenage girls or young women. The prognosis is good if found early, but as with other ovarian cancers, early detection is difficult.

Primary peritoneal carcinoma (PPC) is a cancer of the peritoneum, the lining of the abdominal cavity where the internal organs are located. Although it is a distinct disease, it is linked with ovarian cancer. This is because the ovarian and peritoneal cells have the same embryonic origin. This means that the very early cells of the embryo that will ultimately develop into the ovaries and the peritoneum share a common origin. The term "primary" means that the cancer started first in the peritoneum, as opposed to the cancer starting in the ovary and then moving, or metastasizing, into the peritoneum.

Ovarian cancer can develop at any age, but is most likely to occur in women who are 50 years or older. More than half the cases are among women who are aged 65 years and older. Industrialized countries have the highest incidence of ovarian cancer. Caucasian women, especially of Ashkenazi Jewish descent, are at somewhat higher risk; African-American and Asian women are at a slightly lower risk. The risk of developing the disease increases with age. Ovarian cancer is the fifth most common cancer among women in the United States, and the second most common gynecologic cancer. It accounts for 4% of all cancers in women. However, because of poor early detection, the death rate for ovarian cancer is higher than for that of any other cancer among women. The American Cancer Society estimates about 24,000 new cases of ovarian cancer in 2000 in the United States, and about 14,000 deaths.

Only 50% of the women who are diagnosed with ovarian cancer will survive five years after initial diagnosis. This is due to the cancer being at an advanced stage at the time of diagnosis. With early detection, however, survival at five years post diagnosis may be 95%.

Causes and symptoms

Causes

The actual cause of ovarian cancer remains unknown, but several factors are known to increase one's chances of developing the disease. These are called risk factors. Women at a higher risk than average of developing ovarian cancer include women who:

• have never been pregnant or had children,
• are Caucasian, especially of Northern European or Askenazi Jewish descent,
• are over 50 (half of all diagnosed cases are in women over 65),
• have a family history of breast, ovarian, endometrial (uterine), prostate, or colon cancer,
• have had breast cancer,
• have a first-degree relative (mother, daughter, sister) who has had ovarian cancer. (The risk is greater if two or more first-degree relatives had the disease. Having a grandmother, aunt or cousin with ovarian cancer also puts a woman at higher-than-average risk.)
• have the genetic mutation BRCA1 or BRCA2. (Not all women with these genetic breast cancer mutations will develop ovarian cancer. By age 70, a woman who has the BRCA1 mutation carries about a 40–60% risk of developing ovarian cancer. Women with the genetic mutation BRCA2 have a 15% increased risk of developing ovarian cancer. However, heredity only plays a role in about 5–10% of cases of ovarian cancer.)

Women who have a strong familial history may benefit from genetic counseling to better understand their risk factors.

In addition to the above risk factors, the following factors appear to play a role in affecting a women's chances of developing ovarian cancer.

Reproduction and hormones. Early menstruation (before age 12) and late menopause seem to put women at a higher risk for ovarian cancer. This appears to be because the longer, or more often, a woman ovulates, the higher her risk for ovarian cancer. As mentioned above, women who were never pregnant have a higher risk of developing the disease than women with one or more pregnancies. It is not yet clear from research studies whether a pregnancy that ends in miscarriage or stillbirth lowers the risk factor to the same degree as the number of term pregnancies. The use of post-menopausal estrogen supplementation for 10 years or more may double a woman's risk of ovarian cancer. Short-term use does not seem to alter one's risk factor.

Infertility drug-stimulated ovulation. Research studies have reported mixed findings on this issue. It appears that women who take medications to stimulate ovulation, yet do not become pregnant, are at higher risk of developing ovarian cancer. Women who do become pregnant after taking fertility drugs do not appear to be at higher risk. One study reported that the use of the fertility drug clomiphene citrate for more than a year increased the risk of developing LMP tumors. LMP tumors respond better to treatment than other ovarian tumors.

Talc. The use of talcum powder in the genital area has been implicated in ovarian cancer in many studies. It may be because talc contains particles of asbestos, a known carcinogen. Female workers exposed to asbestos had a higher-than-normal risk of developing ovarian cancer. Genital deodorant sprays may also present an increased risk. Not all studies have brought consistent results.

Fat. A high-fat diet has been reported in some studies to increase the risk of developing ovarian cancer. In one study the risk level increased with every 10 grams of saturated fat added to the diet. This may be because of its effect on estrogen production.

Symptoms

Most of the literature on ovarian cancer states that there are usually no early warning symptoms for the disease. Ovarian cancer is often referred to as a silent killer, because women either are unaware of having it, or have symptoms that are not accurately diagnosed until the disease is in an advanced state. However, a November 2000 study reported in the medical journal Cancer analyzed more than 1,700 questionnaires completed by women with stage III and stage IV ovarian cancer. The researchers found that 95% of the women reported having had early symptoms that they brought to their doctors. Most symptoms were somewhat vague and either abdominal or gastrointestinal in nature, and consequently were either not properly diagnosed or were recognized as being ovarian in nature only after a significant length of time had passed.

The following symptoms are warning signs of ovarian cancer, but could also be due to other causes. Symptoms that persist for two to three weeks, or symptoms that are unusual for the particular woman should be evaluated by a doctor right away.

• digestive symptoms, such as gas, indigestion, constipation, or a feeling of fullness after a light meal
• bloating, distention or cramping
• abdominal or low-back discomfort
• pelvic pressure or frequent urination
• unexplained changes in bowel habits
• nausea or vomiting
• pain or swelling in the abdomen
• loss of appetite
• fatigue
• unexplained weight gain or loss
• pain during intercourse
• vaginal bleeding in post-menopausal women

Diagnosis

In the best-case scenario a woman is diagnosed with ovarian cancer while it is still contained in just one ovary. Early detection can bring five-year survival to near 95%. Unfortunately, about 75% of women (3 out of 4) have advanced ovarian cancer at the time of diagnosis. (Advanced cancer is at stage III or stage IV when it has already spread to other organs.) Five-year survival for women with stage IV ovarian cancer may be less than 5%.

Diagnostic tests and techniques

If ovarian cancer is suspected, several of the following tests and examinations will be necessary to make a diagnosis:

• a complete medical history to assess all the risk factors
• a thorough bi-manual pelvic examination
• CA-125 assay
• one or more various imaging procedures
• a lower GI series, or barium enema
• diagnostic laparoscopy

BI-MANUAL PELVIC EXAMINATION. The exam should include feeling the following organs for any abnormalities in shape or size: the ovaries, fallopian tubes, uterus, vagina, bladder, and rectum. Because the ovaries are located deep within the pelvic area, it is unlikely that a manual exam will pick up an abnormality while the cancer is still localized. However, a full examination provides the practitioner with a more complete picture. An enlarged ovary does not confirm cancer, as the ovary may be large because of a cyst or endometriosis. While women should have an annual Pap test, this test screens for cervical cancer. Cancerous ovarian cells, however, might be detected on the slide. Effectiveness of using Pap smears for ovarian cancer detection is about 10-30%.

CA-125 ASSAY. This is a blood test to determine the level of CA-125, a tumor marker. A tumor marker is a measurable protein-based substance given off by the tumor. A series of CA-125 tests may be done to see if the amount of the marker in the blood is staying stable, increasing or decreasing. A rising CA-125 level usually indicates cancer, while a stable or declining value is more characteristic of a cyst. The CA-125 level should never be used alone to diagnose ovarian cancer. It is elevated in about 80% of women with ovarian cancer, but in 20% of cases is not. In addition, it could be elevated because of a non-ovarian cancer, or it can be elevated with non-malignant gynecologic conditions, such as endometriosis or ectopic pregnancy. During menstruation the CA-125 level may be elevated, so the test is best done when the woman is not in her menses.

IMAGING. There are several different imaging techniques used in ovarian cancer evaluation. A fluid-filled structure such as a cyst creates a different image than does a solid structure, such as a tumor. An ultrasound uses high-frequency sound waves that create a visual pattern of echoes of the structures at which they are aimed. It is painless, and is the same technique used to check the developing fetus in the womb. Ultrasound may be done externally through the abdomen and lower pelvic area, or with a transvaginal probe.

Other painless imaging techniques are computed tomography (CT) and magnetic resonance imaging (MRI). Color Doppler analysis provides additional contrast and accuracy in distinguishing masses. It remains unclear whether Doppler is effective in reducing the high number of false-positives with transvaginal ultrasonography. These imaging techniques allow better visualization of the internal organs and can detect abnormalities without having to perform surgery.

LOWER GI SERIES. A lower GI series, or barium enema, uses a series of x rays to highlight the colon and rectum. To provide contrast, the patient drinks a chalky liquid containing barium. This test might be done to see if the cancer had spread to these areas.

DIAGNOSTIC LAPAROSCOPY. This technique uses a thin, hollow, lighted instrument inserted through a small incision in the skin near the belly button to visualize the organs inside of the abdominal cavity. If the ovary is believed to be malignant, the entire ovary is removed (oophorectomy) and its tissue sent for evaluation to the pathologist, even though only a small piece of the tissue is needed for evaluation. If cancer is present, great care must be taken not to cause the rupture of the malignant tumor, as this would cause spreading of the cancer to adjacent organs. If the cancer is completely contained in the ovary, its removal functions also as the treatment. If the cancer has spread or is suspected to have spread, then a saline solution may be instilled into the cavity and then drawn out again. This technique is called peritoneal lavage. The aspirated fluid will be evaluated for the presence of cancer cells. If peritoneal fluid is present, called ascites, a sample of this will also be drawn and examined for malignant cells. If cancer cells are present in the peritoneum, then treatment will be directed at the abdominal cavity as well.

Treatment

Clinical staging

Staging is the term used to determine if the cancer is localized or has spread, and if so, how far and to where. Staging helps define the cancer, and will determine the course of suggested treatment. Staging involves examining any tissue samples that have been taken from the ovary, nearby lymph nodes, as well as from any nearby organs or structures where metastasis was suspected. This may include the diaphragm, lungs, stomach, intestines and omentum (the tissue covering internal organs), and any fluid as described above.

The National Cancer Institute Stages for ovarian cancer are:

• Stage I: Cancer is confined to one or both ovaries.
• Stage II: Cancer is found in one or both ovaries and/or has spread to the uterus, fallopian tubes, and/or other body parts within the pelvic cavity.
• Stage III: Cancer is found in one or both ovaries and has spread to lymph nodes or other body parts within the abdominal cavity, such as the surfaces of the liver or intestines.
• Stage IV: Cancer is found in one or both ovaries and has spread to other organs such as the liver or lung.

The individual stages are also further broken down in detail, such as Ia, Ib, etc. Accurate staging is important for several reasons. Treatment plans are based on staging, in part because of trying to duplicate the best results achieved in prior research trials. When staging is inconsistent, it becomes more difficult to know how different research studies compare, so the results themselves cannot be relied upon.

Treatment offered will primarily depend on the stage of the cancer and the woman's age. It is always appropriate to consider getting a second opinion, especially when treatment involves surgery, chemotherapy, and possible radiation. Before the patient makes her decision as to which course of treatment to take, she should feel that she has the information necessary with which to make an informed decision. The diagnostic tools mentioned above are used to determine the course of treatment. However, the treatment plan may need to be revised if the surgeon sees that the tumor has spread beyond the scope of what was seen during diagnostic tests.

Surgery

Surgery is done to remove as much of the tumor as possible (called tissue debulking), utilizing chemotherapy and/or radiation to target cancer cells that have remained in the body, without jeopardizing the woman's health. This can be hard to balance once the cancer has spread. Removal of the ovary is called oophorectomy, and removal of both ovaries is called bi-lateral oophorectomy. Unless it is very clear that the cancer has not spread, the fallopian tubes are usually removed as well (salpingo-oophorectomy). Removal of the uterus is called hysterectomy.

If the woman is very young, all attempts will be made to spare the uterus. It is crucial that a woman discuss with her surgeon her childbearing plans prior to surgery. Unfortunately, ovarian cancer spreads easily and often swiftly throughout the reproductive tract. It may be necessary to remove all reproductive organs as well as part of the lining of the peritoneum to provide the woman with the best possible chance of long-term survival. Fertility-sparing surgery can be successful if the ovarian cancer is caught very early.

Side effects of the surgery will depend on the extent of the surgery, but may include pain and temporary difficulty with bladder and bowel function, as well as reaction to the loss of hormones produced by the organs removed. A hormone replacement patch may be applied to the woman's skin in the recovery room to help with the transition. An emotional side effect may be the feeling of loss stemming from the removal of reproductive organs.

Chemotherapy

Chemotherapy is used to target cells that have traveled to other organs, and throughout the body via the lymphatic system or the blood stream. Chemotherapy drugs are designed to kill cancer cells, but may also be harmful to healthy cells as well. Chemotherapy may be administered through a vein in the arm (intravenous, IV), may be taken in tablet form, and/or may be given through a thin tube called a catheter directly into the abdominal cavity (intraperitoneal). IV and oral chemotherapy drugs travel throughout the body; intraperitoneal chemotherapy is localized in the abdominal cavity.

Side effects of chemotherapy can vary greatly depending on the drugs used. Currently, chemotherapy drugs are often used in combinations to treat advanced ovarian cancer, and usually the combination includes a platinum-based drug (such as cisplatin) with a taxol agent, such as paclitaxel. Some of the combinations used or being studied include: carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/topotecan, and cisplatin/carboplatin. As new drugs are evaluated and developed, the goal is always for maximum effectiveness with minimum side effects. Side effects include nausea and vomiting, diarrhea, decreased appetite and resulting weight loss, fatigue, headaches, loss of hair, and numbness and tingling in the hands or feet. Managing these side effects is an important part of cancer treatment.

After the full course of chemotherapy has been given, the surgeon may perform a "second look" surgery to examine the abdominal cavity again to evaluate the success of treatment.

Radiation

Radiation uses high-energy, highly focused x rays to target very specific areas of cancer. This is done using a

A stage I tumor of the ovary. (Illustration by Argosy Inc.)

machine that generates an external beam. Very careful measurements are taken so that the targeted area can be as focused and small as possible. Another form of radiation uses a radioactive liquid that is administered into the abdominal cavity in the same fashion as intraperitoneal chemotherapy. Radiation is usually given on a daily Monday though Friday schedule and for several weeks continuously. Radiation is not painful, but side effects can include skin damage at the area exposed to the external beam, and extreme fatigue. The fatigue may hit suddenly in the third week or so of treatment, and may take a while to recover even after treatments have terminated. Other side effects may include nausea, vomiting, diarrhea, loss of appetite, weight loss and urinary difficulties. For patients with incurable ovarian cancer, radiation may be used to shrink tumor masses to provide pain relief and improve quality of life.

Once the full course of treatment has been undertaken, it is important to have regular follow-up care to monitor for any long-term side effects as well as for future relapse or metastases.

Alternative treatment

The term alternative therapy refers to therapy utilized instead of conventional treatment. By definition, these treatments have not been scientifically proven or investigated as thoroughly and by the same standards as conventional treatments. The terms complementary or integrative therapies denote practices used in conjunction with conventional treatment. Regardless of the therapies chosen, it is key for patients to inform their doctors of any alternative or complementary therapies being used or considered. (Some alternative and complementary therapies adversely affect the effectiveness of conventional treatments.) Some common complementary and alternative medicine techniques and therapies include:

• prayer and faith healing
• meditation
• mind/body techniques such as support groups, visualization, guided imagery and hypnosis
• energy work such as therapeutic touch and Reiki
• acupuncture and Chinese herbal medicine
• body work such as yoga, massage and T'ai Chi
• vitamins and herbal supplements
• diets such as vegetarianism and macrobiotic

Mind/body techniques along with meditation, prayer, yoga, T'ai Chi and acupuncture have been shown to reduce stress levels, and the relaxation provided may help boost the body's immune system. The effectiveness of other complementary and alternative treatments is being studied by the National Institutes of Health's National Center for Complementary and Alternative Medicine (NCCAM). For a current list of the research studies occurring, results of recent studies, or publications available, patients can visit the NCCAM web site or call at (888) 644-6226.

Prognosis

Prognosis for ovarian cancer is very dependent on the stage at which it is first diagnosed. While stage I cancer may have a 95% success rate, stages III and IV may have a survival rate of 17-30% at five years post-diagnosis. Early detection remains an elusive, yet hopeful, goal of research. Also, clinical trials are addressing new drug and treatment combinations to prolong survival in women with more advanced disease. Learning one's family history may assist in early detection, and genetic studies may clarify who is at greater risk for the disease.

Research studies are usually designed to compare a new treatment method against the standard method, or the effectiveness of a drug against a placebo (an inert substance that would be expected to have no effect on the outcome). Since the research is experimental in nature, there are no guarantees about the outcome. New drugs being used may have harmful, unknown side effects. Some people participate to help further knowledge about their disease. For others, the study may provide a possible treatment that is not yet available otherwise. If one participates in a study and is in the group receiving the standard care or the placebo, and the treatment group gets clear benefit, it may be possible to receive the experimental treatment once one's original participation role is over. Participants will have to meet certain criteria before being admitted into the study. It is important to fully understand one's role in the study, and weigh the potential risks versus benefits when deciding whether or not to participate.

Prevention

Since the cause of ovarian cancer is not known, it is not possible to fully prevent the disease. However, there are ways to reduce one's risks of developing the disease.

Decrease ovulation. Pregnancy gives a break from ovulation, and multiple pregnancies appear to further reduce the risk of ovarian cancer. The research is not clear as to whether the pregnancy must result in a term delivery to have full benefit. Women who breast-feed their children also have a lower risk of developing the disease. Since oral contraceptives suppress ovulation, women who take birth control pills (BCPs), even for as little as 3 to 6 months have a lower incidence of the disease. It appears that the longer a woman takes BCPs, the lower her risk for ovarian cancer. Also, this benefit may last for up to 15 years after a woman has stopped taking them. However, since BCPs alter a woman's hormonal status, her risk for other hormonally related cancers may change. For this reason it is very important to discuss all the risks and benefits with one's health care provider.

Genetic testing. Tests are available which can help to determine whether a woman who has a family history of breast, endometrial, or ovarian cancer has inherited the mutated BRCA gene that predisposes her to these cancers. If the woman tests positive for the mutation, then she may be able to choose to have her ovaries removed. Even without testing for the mutated gene, some women with strong family histories of ovarian cancer may consider having their ovaries removed as a preventative measure (prophylactic oophorectomy). This procedure diminishes but does not completely remove the risk of cancer, as some women may still develop primary peritoneal carcinoma after oophorectomy.

Surgery. Procedures such as tubal ligation (in which the fallopian tubes are blocked or cut off) and hysterectomy (in which the uterus is removed) appear to reduce the risk of ovarian cancer. However, any removal of the reproductive tract organs has surgical as well as hormonal side effects.

Screening. There are no definitive tests or screening procedures to detect ovarian cancer in its early stages. Women at high risk should consult with their physicians about regular screenings, which may include transvaginal ultrasound and the blood test for the CA-125 protein.

The American Cancer Society recommends annual pelvic examinations for all women after age 40, in order to increase the chances of early detection of ovarian cancer.