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She crowned herself "the Queen of Neurosis," but this time, it was not simply an overactive imagination that made her fear for her health. It was symptoms of the ovarian cancer that eventually claimed her life.
Gilda Radner, one of the original Not Ready for Prime Time Players of television's "Saturday Night Live," claimed in her book It's Always Something that she could get neurotic over any health problem. "I hated to be sick and I had an imagination that could turn a stomachache into the plague."
So, she wrote, when a complete physical examination in January 1986 failed to explain the overwhelming fatigue and general malaise she was feeling, she agreed with the doctor that her symptoms might just be from depression; she had, after all, been going through a rough period in both her personal and professional life. It was not until October--10 months and several symptoms, diagnoses, and failed therapies later--that cancer of the ovaries was confirmed.
Delay in diagnosing ovarian cancer is not unusual. Early detection is difficult because disease confined to the ovary seldom produces symptoms. When symptoms do surface, they are often vague and easily mistaken for other, often minor, ailments.
Radner's cancer was not discovered until it had spread to her bowel and liver. She suffered from fatigue, low-grade fever, pelvic cramping, abdominal bloating, gas, and aches and pains in her upper thighs and legs. Loss of appetite and a feeling of fullness, indigestion, nausea, weight loss, and, less often, vaginal bleeding and low back pain are other symptoms.
As the tumor grows, it may press on the bowel and bladder, causing constipation and frequent urination. Malignant cells can break away from the tumor and spread directly to other organs in the abdomen, such as the stomach, colon and diaphragm (muscle separating the chest cavity from the abdomen), causing a fluid buildup that results in swelling and discomfort. The cells can also enter the bloodstream or lymph system and spread to other parts of the body.
Radner wrote that her complaints had been variously attributed to Epstein-Barr virus infection, depression, stress, and anxiety. She had undergone blood tests, a barium enema, and ultrasound (pelvic sonogram). According to Radner, the sonogram, done in the summer of 1986, showed "congestion" and the "ovaries weren't exactly in the place they were supposed to be, but that wasn't serious." There was no sign of tumor or bowel obstruction.
Aspirin to Acupuncture
Attempting to combat her ills through both mainstream and holistic medicine, Radner tried remedies that ran the gamut from aspirin, anti-inflammatories and antidepressants to health foods, vitamins, acupuncture, and colonics (unconventional type enemas).
"Suddenly, I began to wonder how to please so many people," she wrote. "Do I take the magnesium citrate? What about the coffee enema? Do I do both? Do I do the abdominal massage or the colonic? Do I tell the doctors about each other?"
Then, late in October, an abnormal liver function test prompted more exams. A CAT scan and analysis of fluid from the abdomen confirmed ovarian cancer.
Diagnosed at age 40, Radner was younger than most women with the disease. The chance of developing ovarian cancer increases with age; most cases are found in women who have gone through natural menopause, with the average age at diagnosis being 61. As was true with Radner, however, women with a family history of the disease generally are diagnosed at a younger age.
Each year in the United States, ovarian cancer is diagnosed in about 26,000 women and claims more than 14,000 lives. It is most common in women living in Europe and North America; Asian women have a relatively low incidence. Although Chinese and Japanese women living in the United States have higher rates of ovarian cancer than their counterparts in Asia, the disease is still less common among this group than among the native white population in the United States. Rates among black women in all parts of the world are low.
Certain factors are associated with an increased risk of getting ovarian cancer. Although the lifetime risk for most women is 1 in 70, it doubles for women who have never been pregnant. Also at increased risk are women who have had breast, intestinal, or rectal cancer. Under investigation as possible risk factors are: high-fat diet, early onset and late cessation of menstruation, being of Eastern European Jewish descent, and use of talcum powder in the genital area.
Women with close relatives who have had ovarian cancer are also at greater risk, reaching perhaps a 50 percent chance if they have at least two first-degree relatives (mother, sister or daughter) with the disease. This compares with a 1.4 percent chance in women without a family history. Women who have a first-degree relative and one or more second-degree relatives (aunt, grandmother) who had ovarian cancer have a somewhat lesser risk than those with two first-degree relatives, but are still considered to be at high risk. Radner wrote that her mother had breast cancer and a cousin had both breast and ovarian cancer. Later, it was learned that other of her relatives had ovarian cancer as well.
About 5 to 7 percent of all ovarian cancer is thought to be inherited. In 1994, scientists identified a gene, which they named BRCA1, that related to the development of inherited breast cancer. Changes or abnormalities in this gene are now also considered responsible for about 80 percent of inherited ovarian cancer. The abnormal gene can be inherited from either parent.
The Gilda Radner Familial Ovarian Cancer Registry, established in 1981 at Roswell Park Cancer Institute in Buffalo, N.Y., and named for Gilda Radner after her death in 1989, included 2,946 cases of ovarian cancer in 1,346 families as of January 1997.
Reduced Risk
Factors associated with a reduced risk of ovarian cancer include: giving birth to more than one child, breast-feeding, tubal ligation (female sterilization), and use of birth control pills.
Evidence suggests that hormones may influence development of the disease. The risk of ovarian cancer is reduced in women who have had multiple pregnancies and in those who used birth control pills. The Cancer and Steroid Hormone Study by the national Centers for Disease Control and Prevention and the National Institute of Child Health and Human Services found that use of oral contraceptives for even a few months reduced the risk of ovarian cancer by 40 percent in women 20 to 54 years old.
The study, published in the March 12, 1987, New England Journal of Medicine, also found that the longer a woman used birth control pills, the lower her risk of ovarian cancer, and that the protective effect persisted long after stopping the pill. Based on these data, since 1989, the labeling for oral contraceptives has included decreased incidence of ovarian cancer among the noncontraceptive health benefits of the pill.
On the reverse side of the coin, in January 1993, FDA requested that drug firms revise fertility drug labels to include ovarian cancer as a potential adverse drug reaction. The action was in response to a report in the November 1992 issue of the American Journal of Epidemiology suggesting a possible relationship between use of fertility-enhancing drugs and ovarian cancer. The analysis was based on data from 12 studies comparing women with ovarian cancer to those without the disease. Only three of the studies, however, contained data on the use of fertility drugs and risk of ovarian cancer. (A 1987 article in the same journal reported no association between the drugs and ovarian cancer.)
FDA urged caution in interpreting the findings of the 1992 report because the analysis only included small numbers of women and because the article gave no information about the fertility drugs prescribed, reasons for the infertility, or tumor size or stage of disease at diagnosis.
Search for a Screening Test
According to the registry, if ovarian cancer is diagnosed while still confined to the ovaries, the chance for cure is 85 to 90 percent. According to the American Cancer Society, only 23 percent of all cases are diagnosed at this early stage. Among women whose cancer has spread beyond the ovary by the time it's diagnosed, only 20 to 25 percent survive five years. However, unlike cervical or breast cancer (which may be detected early by a Pap test or mammogram, respectively), ovarian cancer has no approved screening test, though some are under investigation.
"The traditional routine pelvic examination is largely ineffective for early detection," says Julie Beitz, M.D., a medical oncologist in FDA's division of oncology and pulmonary drug products. "Often you can't feel a normal-sized ovary. And even if you can, it's hard to tell if it's enlarged because ovaries vary in size from person to person and day to day. Ovarian cancers start very small, and by the time they're large enough to feel, the cancer is most likely already advanced." The problem with ovarian cancer, she says, is that "you have to detect very small changes, and these are hard to detect on a pelvic exam because it's a very indirect examination."
Researchers are working on developing an accurate test for the BRCA1 gene. The American Society of Human Genetics has recommended that testing for BRCA1 be limited to research in which subjects are members of families at high risk for either ovarian or breast cancer.
Researchers continue looking for tumor markers--substances that may appear in abnormal amounts in the blood or urine--that may prove useful in developing a screening test.
One such marker is CA 125, a substance in the blood that is elevated in patients with advanced ovarian tumors. Doctors now measure CA 125 levels in patients treated for advanced disease to determine if the tumor has shrunk or if disease has recurred. Its value in monitoring treatment prompted scientists to study its potential for early detection. Its use for screening, however, is investigational.
Transvaginal ultrasound is also being studied as a screening tool. With ultrasound, high-frequency sound waves are projected into the body, and the echoes produced are converted by computer into a picture. Unlike abdominal ultrasound, in which the sound wave-emitting device is placed on the outside of the belly, transvaginal ultrasound uses a probe placed in the vagina that can reach within millimeters of the ovaries, producing more detailed images.
"There is uncertainty as to the value of these tools as screening tests and their ultimate impact on mortality," says John Gohagan, Ph.D., chief of the National Cancer Institute's Early Detection Branch in the Division of Cancer Prevention and Control. NCI is conducting a clinical trial including 74,000 women aged 60 to 74 to clarify the issue. The trial is designed to assess the value of CA 125 and transvaginal ultrasound for early detection of ovarian cancer and to measure their impact on mortality.
Women in the trial are randomly assigned to either a screening group or a control group of 37,000 women each. The screening group will have periodic pelvic examinations along with CA 125 and transvaginal ultrasound tests. The control group will have routine medical care.
Diagnostic Procedures
If a woman or her doctor suspects ovarian cancer, diagnosis begins with a medical history of the patient, review of her symptoms, and complete physical examination, including a pelvic exam, in which the physician feels the vagina, ovaries, fallopian tubes, bladder, and rectum to check for any growths. A Pap test may also be done because, even though it cannot reliably detect ovarian cancer, it may detect cancer cells that have migrated to the uterine cervix from the ovaries.
Blood and urine tests may also be done, as well other procedures, depending on the woman's symptoms and results of her physical exam. These procedures include:
If cancer is suspected, the surgeon usually removes the entire affected ovary to avoid cutting through the outer layer, which might cause the tumor to spread.
The tissue is sent to the pathologist for immediate evaluation, and if cancer is confirmed, the surgeon nearly always removes the second ovary, the uterus, and the fallopian tubes. Samples are taken of nearby lymph nodes, the diaphragm, the omentum (a fold of membranous lining in the abdominal cavity), and fluid from the abdomen to see whether the cancer has spread. If no fluid is found, several "washings" are taken: A saline solution is put into the abdomen and then removed to be examined for cancer cells. If there are suspicious lesions, tissue samples are also taken from the liver, small intestine, and large intestine.
Early Treatment Crucial
Trusting her instincts may have saved Jessica Marsh's life. Due in part to her own vigilance and persistence, Marsh (not her real name), a secretary in Rockville, Md., was diagnosed before her cancer had spread beyond the ovary, affording her a brighter prognosis.
For three months in the fall of 1985, Marsh, then 36 years old, had noticed pains in her right side around the time of her menstrual periods. Although the pains were brief and not severe, she decided to have her doctor check it out. A week or so before her appointment, however, a very sharp pain prompted her to call the doctor again. Her gynecologist was out of town, but the doctor on call had her come in.
"He told me that my stomach was distended, gave me a pelvic exam, and then congratulated me, telling me I was three months pregnant," Marsh recalls. "I told him I wasn't pregnant, that I already had two children and knew what it was like to be pregnant, and this was not a pregnancy."
At Marsh's insistence, the physician arranged for her to have a pelvic sonogram that day at a local hospital.
"I had the sonogram and the next thing I knew, the doctor who had examined me at the office came in, repeated the sonogram, and told me there was a mass and he wanted to do some more tests. The next morning, I had surgery to remove my ovaries, uterus, and fallopian tubes."
Although Marsh's experience may not be typical, it illustrates again the difficulty in correctly diagnosing the disease early. Yet, early detection and treatment can mean the difference between life and death.
Treatment Options
Ovarian cancer is always treated surgically, removing as much tumor as is feasible. Chemotherapy (drug treatment) or radiation therapy, or both, may also be given, depending on the extent of disease. Ovarian tumors usually grow outward, with an irregular, cauliflower-like shape. When the cancer spreads, parts of the tumor break off and attach to nearby organs. Cells may then spread to lymph nodes and distant organs.
Cancer limited to the ovaries may be successfully treated with surgery alone, removing the ovaries, fallopian tubes, omentum (a fold of tissue attached to organs in the abdominal cavity), and uterus. Some patients may also receive chemotherapy or radiation therapy to kill any cancer cells remaining after surgery.
Disease that has spread beyond the ovaries almost always requires chemotherapy or radiation therapy in addition to surgery. Radiation therapy may be given by placing a radioactive solution into the pelvis and abdomen through a thin tube, coating the organs and total abdominal contents. Less commonly, external radiation using high-energy x-rays directed to the pelvis and abdomen may be prescribed.
The type of drugs used in chemotherapy depends not only on the extent of disease, but also on the type of cancer. About 85 to 90 percent of ovarian cancers arise from epithelial cells, which form the outer layer of the ovary. The rest derive from other cell types that make up the organ.
FDA has approved several drugs to treat ovarian cancer. Two of the most commonly used are Platinol (cisplatin) and Taxol (paclitaxel). Taxol was approved in April 1998 as a first-line treatment for advanced ovarian cancer. It has been used since December 1992 to treat advanced ovarian cancer that has not responded to other therapies or has progressed after treatment (see "Taxol's Long History"), and is being evaluated for first-line treatment. National Cancer Institute and FDA scientists cooperated in studies to evaluate the safety and effectiveness of Taxol. FDA's research role in drug development is a fairly new concept, designed to help speed the approval process for drugs for life-threatening diseases.
"It's a commitment by the agency to do more than just wait for packages of data to come in [from the drug's sponsor] and review them for approval," says Jerry M. Collins, Ph.D., director of the division of clinical pharmacology research in the Center for Drug Evaluation and Research. "We can't do this for every new drug in every therapeutic area," he says, "but for AIDS and cancer, we have done similar research before."
Since Taxol is given in combination with several other drugs, there was major concern about the potential for serious drug interaction. However, according to Collins, this research demonstrated that "paclitaxel actually had a lower risk of metabolic interactions than most other drugs."
Other chemotherapeutic agents used to treat ovarian cancer include Cytoxan and Neosar (cyclophosphamide), Paraplatin and Adriamycin (doxorubicin), and Hexalen (altretamine). A recent addition is Hycamtin (topotecon, approved in 1996 to treat ovarian cancer that recurs after other chemotherapeutic agents have failed. Hycamtin is the first of a new class of drugs called topoisomerase I inhibitors. They kill cancer cells by inhibiting an enzyme essential to the replication of human DNA.
Side Effects
Surgery, the first-line treatment for ovarian cancer, requires several days' hospitalization and a recuperative period of from four to six weeks. Removing the ovaries, which are the main source of the female hormones estrogen and progesterone, causes immediate menopause, and the symptomatic hot flashes are more severe than when menopause occurs more gradually, as it usually does naturally.
Radiation therapy can cause mild skin reactions, such as redness and drying in treated areas, urinary discomfort, diarrhea, and vaginal dryness. (Menopause can also cause vaginal dryness.) A small percent of patients may develop bowel obstruction, sometimes requiring surgical correction.
Other possible side effects of radiation therapy, commonly experienced with chemotherapy as well, include loss of energy and appetite, nausea, and vomiting.
Chemotherapy may also cause mouth sores, hair loss, and reduced platelet and blood cell counts that can lead to infections, anemia or bleeding. The drugs used to treat ovarian cancer may also have neurologic effects, causing hearing loss, ringing in the ears, nerve damage, and numbness or tingling in the face, fingers and toes. There may also be kidney damage.
Most side effects are temporary, and sometimes dietary changes or medicines can ease the symptoms. There are several drugs approved for countering nausea and vomiting often associated with chemotherapy. They include Zofran (ondansetron hydrochloride), Reglan (metocloparamide), and Marinol (dronabinol).
Transfusions can correct red blood cell and platelet deficiencies. Hematopoietic growth factors such as G-CSF, approved in 1991, stimulate production of infection-fighting white blood cells. GM-CSF, which also received FDA approval in 1991 to increase white blood cell counts after bone marrow transplantation, is now being studied for its effectiveness in stimulating white cells after cancer chemotherapy. Among other drugs now under study for their ability to increase white cell counts, and perhaps platelets as well, are stem cell factor and PIXY 321. PIXY 321 is a genetically engineered product consisting of GM-CSF and another hematopoietic growth factor, interleukin-3.
When therapy is completed, the woman continues to have regular checkups that include pelvic examinations and laboratory tests to measure blood levels of tumor markers such as CA 125. The doctor may recommend a laparotomy or laparoscopy after completion of chemotherapy to inspect the abdomen and pelvis and take multiple tissue biopsies. This "second-look surgery" helps evaluate the effectiveness of chemotherapy and determine whether treatment should be continued or stopped. Often a laparotomy or laparoscopy has been done previously to diagnose ovarian cancer.
Attempts at Prevention
The Gilda Radner Familial Ovarian Cancer Registry advises women with two or more first- or second-degree relatives who have had the disease to have their ovaries removed via video laparoscopy as a precautionary measure by age 35, if they have completed their families. The registry also advises that there is a small increased risk (1.8 percent) of developing primary papillary cancer of the peritoneum for women who have had this prophylactic surgery. The registry also recommends that women with a family history of ovarian cancer receive genetic counseling, beginning in their early 20s, and have pelvic and abdominal examination, CA 125 testing, and transvaginal ultrasound every six months beginning in their early 30s.
Jessica Marsh, seven years after her diagnosis, is today free of cancer and feeling fine. "I've become a much more positive person since my cancer," she says. "Life is too short to worry about little things. If life deals me lemons, I'll make lemonade."
Marian Segal is a former member of FDA's public affairs staff.
The egg travels through the fallopian tube to the uterus. If it is fertilized, it may grow and develop in the womb. If not, hormone changes cause shedding of the uterine lining, and menstruation begins about two weeks later.
Normally, the follicle (or cyst) created by the ovaries each month bursts harmlessly when ovulation occurs. Sometimes, however, this normal physiologic process goes awry. The follicle, instead of bursting and releasing its egg, may continue to swell with fluid, or the corpus luteum (tissue that secretes hormones to prepare for pregnancy) may fail to dissolve even though the egg has not been fertilized. In either of these situations, the result is a "functional," or physiologic, cyst--a fluid-filled sac that may be as small as a grape or as large as a grapefruit.
Functional cysts are the most common ovarian cysts. In a premenopausal woman, such a cyst is always benign (noncancerous) and will frequently disappear spontaneously within a couple of months. Sometimes a functional cyst ruptures, spilling ovarian fluid into the abdominal cavity and causing pain. As the body absorbs the fluid, however, the pain subsides, and surgery is rarely necessary.
Ovarian cysts may be diagnosed by pelvic examination or by ultrasound imaging. A woman who has a functional cyst may have abdominal cramps, nausea, and menstrual irregularity. However, many women have no symptoms at all.
A gynecologist who diagnoses a cyst of less than 6 centimeters (2 1/4 inches) in diameter in a premenopausal woman who is ovulating will usually want to observe the patient for a couple of menstrual cycles to see if the cyst goes away by itself, says Lisa Rarick, M.D., director of FDA's division of reproductive and urologic drug products.
If the cyst doesn't disappear spontaneously, the doctor may recommend that the woman take birth control pills to suppress ovulation. Most birth control pills are combinations of two female sex hormones, estrogen and progestin. In some cases, progestin-only pills (also called "mini-pills") may be prescribed instead of combination pills. Both combination birth control pills and mini-pills work by preventing the release from the brain of other hormones that stimulate ovulation. Deprived of hormonal stimulation, a functional ovarian cyst will often shrink and eventually disappear.
An ovarian cyst that doesn't disappear after a couple of months may be a benign semisolid cyst. This kind of cyst is usually diagnosed by ultrasound imaging. The most common semisolid cyst is a dermoid cyst, so-called because it is made up of skin-like tissue; it can usually be removed by laparoscopic surgery. Occasionally, an ovary containing a dermoid cyst becomes twisted on itself, causing severe pain. Surgical removal of the affected ovary, or oophorectomy, may be necessary if this happens.
Any cyst that is 6 centimeters in diameter--about the size of a peach--or larger in a premenopausal woman should be investigated immediately as a possible malignancy, says Rarick, as should a cyst of any kind in a woman who has completed menopause.
While some doctors will recommend surgical examination of a large ovarian cyst, many gynecologists will examine the mass through a laparoscope, says Rarick. "It's possible to use a needle to puncture the cyst or aspirate its contents. The cyst can even be removed through the laparoscopic incision."
Polycystic ovarian disease, also known as Stein-Leventhal syndrome, is a benign condition characterized by multiple small cysts on the ovaries. This disease has a distinct set of symptoms that may appear as early as adolescence and may include menstrual irregularity, abnormal growth of body hair, lack of breast development, obesity, and infertility.
According to an article in the Sept. 4, 1991, Journal of the American Medical Association, around the turn of the century, a British official in the Indian subcontinent noted that parts of the European yew, Taxus baccata, were used in an Indian clarified butter preparation for treating cancer.
It wasn't until 1962, however, that the U.S. Forest Service delivered crude bark extracts of the Pacific yew, Taxus brevifola, to the National Cancer Institute. A series of NCI experiments showed the extract was effective against several kinds of cancer in mice.
In 1971, researchers at the Research Triangle Institute in Durham, N.C., isolated Taxol from the extract, but interest in the compound waned until the mid-1970s. In 1979, a researcher at Albert Einstein College of Medicine in New York described how Taxol works to defeat cancer by inhibiting cell division.
Today, Taxol--alone or in combination with other drugs--is being studied for a wide variety of adult and childhood cancers. In July 1992, FDA authorized use of the drug for ovarian cancer under a "treatment IND." Treatment INDs permit earlier and wider access to experimental drugs by patients with life-threatening conditions for which there is no satisfactory treatment.
Taxol was approved in December 1992 for advanced disease unresponsive to other therapies. The drug was approved in a record five months.
In April 1998, it was approved as a first-line therapy for advanced ovarian cancer.
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