Ovarian Cancer In-Depth

Introduction

The ovaries are two small, almond-shaped organs located on either side of the uterus. They are key components of a woman's reproductive system:

• Ovaries store between 200,000 - 400,000 follicles, tiny sacs, present from birth, that nurture immature eggs (ova).
• During each normal (usually monthly) reproductive cycle, a follicle in one ovary bursts and releases a mature or "ripened" egg. The egg travels down the fallopian tube into the uterus, where it either is fertilized by a man's sperm or, if unfertilized, breaks down and is excreted as part of the menstrual cycle.
• Ovaries also secrete the important reproductive hormones estrogen and progesterone.

The uterus, commonly called the womb, is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Ovarian Cancers

Ovarian cancers are potentially life-threatening malignancies that develop in one or both ovaries. Malignant ovarian tumors generally fall into three primary classes:

• Epithelial tumors
• Germ cell tumors
• Stromal tumors

Epithelial Tumors. Epithelial tumors account for up to 90% of all ovarian cancers and therefore are the primary focus of this report. These cancers develop in a layer of cube-shaped cells known as the germinal epithelium, which surrounds the outside of the ovaries.

Germ Cell Tumors. Germ cell tumors, which account for about 3% of all ovarian cancers, are found in the egg-maturation cells of the ovary. They occur most often in teenagers and young women. Although they progress rapidly, they are very sensitive to treatments. About 90% of patients with germ cell malignancies can be cured, often preserving fertility.

Stromal Tumors. Stromal tumors, which account for 6% of all ovarian cancers, develop from connective tissue cells that hold the ovary together and that produce the female hormones, estrogen and progesterone. Stromal tumors do not usually spread, in which case the prognosis is good. If they spread, however, they can be more difficult to treat than others.

Click the icon to see an image of ovarian cancer.

Ovarian Cancer Progression

Ovarian cancer is called the silent killer because it progress almost silently, with vague symptoms. By the time symptoms do appear, the ovarian tumor may have grown large enough to shed cancer cells throughout the abdomen. At such an advanced stage, the cancer is more difficult to cure.

Ovarian cancer cells that have spread outside the ovaries are referred to as metastatic ovarian cancers. Ovarian tumors tend to spread to the following locations:

• Diaphragm
• Intestine
• Omentum (a fatty layer that covers and pads organs in the abdomen)

Cancer cells can also spread to other organs through lymph channels and the bloodstream.

Other Ovarian Growths

Not all ovarian tumors are malignant. Benign cysts, dermoid tumors, and borderline malignant tumors all are distinct from ovarian cancer.

Benign Cysts. Benign cysts are common and typically develop in one of two ways:

• Follicular Cysts. During normal ovulation, follicles (the little sacs in the ovary) expel eggs. If the egg is not expelled associated fluids and other substances can build up inside the follicle, forming a follicular cyst.
• Corpus Luteum Cysts. Benign cysts may form when an egg has been released, but the emptied follicle (now called the corpus luteum) does not break down normally but fills with blood from nearby blood vessels.

Both follicular cysts and corpus luteum cysts are normal parts of the menstrual cycle and nearly always resolve within one or two cycles without treatment.

Dermoid Tumors. Dermoid tumors are benign growths that occur when an egg begins to develop without fertilization by a sperm; they can contain hair, teeth, and cartilage. They are easily removed by surgery.

Borderline Ovarian Tumors. About 15% of ovarian tumors are referred to as "borderline" because their appearance and behavior under the microscope is between benign and malignant. These tumors are often referred to as carcinomas of low malignant potential because they rarely metastasize or cause death. Even when borderline carcinomas do spread outside the ovary, only 10 - 20% are fatal.

Symptoms

Ovarian cancer grows quickly and can progress from early to advanced stages within a year. Early symptoms are often vague and may resemble those of less serious conditions, such as menstrual disorders and intestinal illnesses. Still, a 2005 study found that many women complain of abdominal swelling and pain at least 6 - 12 months before a diagnosis.

Only around 20% of ovarian cancers are found at an early stage. Paying attention to symptoms can help improve a woman’s chances of being diagnosed and treated promptly. Women should report any of the following persistent symptoms to their doctor:

• Abdominal swelling (this is caused by fluid or a mass within the abdomen)
• Pelvic pressure or cramps
• Digestive problems such as gas, bloating, indigestion and stomach pain
• Bowel and bladder problems such as constipation and frequent urination
• Loss of appetite or feeling of fullness even after a very light meal
• Unusual vaginal bleeding
• Back pain or leg pain

Based on the symptoms and physical examination, the doctor may order pelvic imaging tests or a CA-125 blood test. Researchers are working to develop other screening tests to help improve early ovarian cancer diagnosis.

Causes

About 20,180 new cases of ovarian cancer are expected in the United States in 2006. Evidence suggests that the incidence of ovarian cancer is declining. The average age for the onset of ovarian cancer is about 60, although ovarian cancer can develop in women from the ages of 20 to 90. The lifetime risk of ovarian cancer in women with no family history of the disease is approximately one in 70 (1.4%).

Women with a history of ovarian cancer in one first-degree relative (mother or sister) have an overall 5% risk of developing the disease, but it may be higher in women with specific genetic factors. The majority of women with ovarian cancer have no family history of the disease, however, meaning that genetic inheritance is not the only risk factor.

Genetic mutations causing abnormal cell growth and differentiation are the basis for all cancer. The great majority of genetic defects that cause cancer are due to unknown causes. Most likely overexposure to environmental assaults or errors that occur during cell division play a role in many cases.

The Role of Hormones and Ovarian Stimulation

Several circumstances that create hormonal changes may increase the risk of ovarian cancer.

Number of Ovulations. Risk of ovarian cancer is directly related to the number of times a woman ovulates, which is indicated by the total number of menstrual periods she has had. A lower number of ovulations occur when the menstrual periods are shut off (as in pregnancy), so the risk of developing ovarian cancer is reduced.

The following women have a lower risk for ovarian cancer:

• Women with a history of multiple pregnancies.
• Women who took birth control pills (these shut off the menstrual period).
• Women who breast-fed. (The body usually does not release eggs while a woman is breast-feeding.)

Some researchers theorize that ovarian cancer develops in women with a higher number of ovulations because of persistent damage to the epithelial cells as the egg passes through during ovulation. Researchers postulate that the recurring cell division needed to heal these tiny wounds to the ovaries, month after month and year after year, creates opportunities for errors in cell reproduction that lead to the formation of cancerous cells. Therefore, the more ovulations, the more risk of ovarian cancer. Ovulation temporarily ceases during pregnancy, breast-feeding, and birth control pill use.

Gonadotropins and Fertility Drugs. Gonadotropins are hormones produced in the pituitary gland that stimulate the ovaries to secrete estrogen and cause the follicles to produce and release eggs.

The pituitary is a gland attached to the base of the brain which secretes hormones that govern the onset of puberty, sexual development and reproductive function.

In a few studies, elevated levels of gonadotropins have been associated with an increased risk for ovarian cancer. These hormones are the basis for many fertility drugs, including human menopausal gonadotropin (Pergonal, Repronal, Metrodin) and clomiphene (Clomid, Serophene). Although there has been concern about an increased risk for ovarian cancers in women, a growing body of evidence is finding no higher risk from the drugs themselves. Instead, evidence suggests that ovarian cancers are most likely caused by factors contributing to the infertility -- not the drugs used to treat it.

Hormone Replacement Therapy (HRT). Although some studies have reported a weak increased risk for certain ovarian cancers in women taking HRT, others have found no association either with short- or long-term use of HRT.

Inherited Genetic Factors

Family history plays a role in 5 - 10% of women who have ovarian cancer. Certain genes are being investigated and identified that are responsible for some of these cases. Depending on the particular genetic type, the lifetime risk for ovarian cancer in women who carry these genes ranges from 16 - 65%.

BRCA1 and 2 Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are now believed to be responsible for 30 - 50% of breast cancers, ovarian cancers, or both in patients with a strong family history of these cancers.

According to some studies, the risks are as follows:

• Studies indicate that about 25 - 40% of women who carry the abnormal BRCA1 gene may develop ovarian cancer.
• The risk for women with the BRCA2 gene mutation is generally believed to be lower, about 9 - 15%.

The mutated genes are linked to an even higher risk for developing breast cancer. These mutations are present in only about 0.5% of the U.S. population overall but occur in about 2.5% of all Jewish women of Eastern European (Ashkenazi) descent. These mutations are not restricted to the Ashkenazi population and may occur in women of any ethnicity, including women of Asian and African descent.

Either a mother or father can pass down BRCA mutations to the daughter. These mutations may also occur in 5 - 10% of ovarian cancer patients who have no family history of breast or ovarian cancer. A number of studies have suggested that women with BRCA-mutated ovarian cancers tend to have better survival rates than other women.

A reassuring 2005 study in the Journal of the National Cancer Institute indicated that women who have a family history of breast cancer, but no history of BRCA genetic mutations, are not at increased risk for ovarian cancer.

Other Genetic Mutations. Women who carry the hereditary nonpolyposis colorectal cancer (HNPCC) gene have about a 9% chance of developing ovarian cancer.

Sporadic Genetic Factors

Most ovarian cancers are the result of genetic mutations that are not inherited but occur from environmental or other factors that cause damage to genetic material over time. Such genetic changes are referred to as sporadic (as opposed to inherited). Genetic alterations that have been observed in ovarian cancers involve the p53 tumor suppressor gene, the HER2/neu gene, and the PIC3KA gene.

Ethnic Factors

Some research indicates that ovarian cancer occurs more often in North America and Northern Europe and among middle to upper socioeconomic class women from highly industrialized countries. Ovarian cancer is also much more common in Caucasian women than in African American women. Japan has a low, but rising, number of ovarian cancer cases. One study observed that when Japanese women immigrate to the United States, they and their daughters have an incidence of ovarian cancer that approaches that of Caucasian women, although another study did not support such findings.

Other Factors

Pregnancy. Women who have never had children are more likely to develop ovarian cancer than women who have had children. The more children a woman has had, the lower her risk for ovarian cancer.

Obesity. Obesity may increase the risk of developing more aggressive types of ovarian tumors. A 2006 study indicated that a higher body mass index (BMI) was associated with poorer survival.

Endometriosis. Women with endometriosis may have some higher risk for ovarian cancer. However, endometriosis is very common and ovarian cancer is not, so the risk is still very low. Some research suggests that ovarian cancer associated with endometriosis may differ from most ovarian cancer cases and, in fact, have a better outlook.

Click the icon to see an image of endometriosis.

Fat Intake. Fats have been under scrutiny for some time for putting some women at higher risk for ovarian cancer. A 2001 review reported an association between a high intake in animal fats and a greater risk. However, other studies on this subject have found no correlation between fat intake and ovarian cancer.

Prevention

No specific lifestyle factors are proven to protect against ovarian cancer, although the following study results suggest some lower or higher risk:

• Some studies have suggested a lower rate of ovarian cancer in women who eat a diet rich in vegetables. The American Cancer Society recommends that women eat 5 servings of fruits and vegetables a day, and limit consumption of high-fat red meat.
• A 2005 study of more than 61,000 women suggested that tea consumption may reduce the risk of ovarian cancer. Women in the study who drank at least 2 cups of tea a day (mainly black tea) had a lower risk of ovarian cancer than women who did not drink tea.
• Exercise, which protects against many diseases and even some cancers, appears to have no effect on ovarian cancer. However, obesity is associated with poorer ovarian cancer survival. Women who are obese also have a higher risk for breast cancer. Regular exercise is a good idea in any case.
• Smokers should quit. Although evidence of an association with ovarian cancer is weak, it is always wise to stop smoking.

Limiting Ovulation

In general, factors or behaviors that limit stimulation of the ovaries or inhibit ovulation appear to be protective.

Pregnancy. The more times a woman has been pregnant the less likely she is to develop ovarian cancer. One study indicated that ovarian cancer was reduced by 40% with one pregnancy and by an additional 14% with each subsequent pregnancy.

Breastfeeding. Breastfeeding, even for only 1 - 2 months, may also reduce the risk for ovarian cancer by as much as 40%. A longer duration of breastfeeding does not appear to increase its protective benefits.

Oral Contraceptives (OCs) and Progestin. Studies have suggested that routine use of birth control pills that contain the female hormones estrogen and progestin, even low-dose forms, reduces a woman's risk of ovarian cancer by about 50% when compared to women who have never taken oral contraceptives. The longer a woman takes oral contraceptives the greater the protection and the longer protection lasts after stopping OCs.

Click the icon to see an illustrated series detailing the birth control pill.

Birth control pills should not be taken by pregnant women or women with breast cancer. Other conditions that may preclude taking oral contraceptives include:

• Liver disease
• Migraines
• Coronary artery disease and any risk factors for heart disease or stroke (particularly smoking, obesity, high blood pressure, blood clotting disorders, or diabetes)

Tubal Ligation. Tubal ligation, a method of sterilization that ties off the fallopian tubes, has been associated with a decreased risk for ovarian cancer in some -- but not all -- studies. A 2001 study specifically reported a significantly lower risk in women who carried the BRCA1 mutation.

Click the icon to see an image of tubal ligation.

Removal of Ovaries (Oophorectomy)

Surgical removal of the ovaries, called oophorectomy, significantly reduces the risk for ovarian cancer. When it is used to specifically prevent ovarian cancer in high-risk women, the procedure is called a prophylactic oophorectomy. Prophylactic oophorectomy is approximately 95% protective against ovarian cancer. It is sometimes recommended for women at high risk for ovarian cancer. These women generally have the BRCA1 or BRCA2 genetic mutation, or have two or more first-degree relatives who have had ovarian cancer.

Bilateral oophorectomy is the removal of both ovaries. Bilateral salpingo-oophorectomy is the removal of both fallopian tubes plus both ovaries. Several recent studies indicate that salpingo-oophorectomy is very effective in reducing risk for ovarian cancer in women who carry the BRCA1 or BRCA2 mutation.

A 2006 Journal of the American Medical Association study reported that bilateral salpingo-oophorectomy reduces ovarian cancer risk by 80% for women with certain mutations in the BRCA1 and BRCA2 genes. A study presented at the 2006 meeting of the American Society of Clinical Oncology (ASCO) indicated that this procedure is most effective for reducing ovarian cancer risk in women with the BRCA1 gene mutation. For women with BRCA2 gene mutation, the procedure was better at reducing the risk for breast cancer.

Even after oophorectomy, women in high-risk groups for ovarian cancer still have a risk for the development of cancer in the peritoneum (the sac inside the abdomen that holds the intestines, uterus, and ovaries).

Premenopausal women should realize that oophorectomy causes immediate menopause, which poses a risk for several health problems, including osteoporosis, heart disease, and reduction in muscle tone. Estrogen replacement can help offset these problems. Women who have a bilateral oophorectomy and do not receive hormone replacement therapy may experience more severe hot flashes than women who enter menopause naturally.

Diagnosis

Up to 95% of women diagnosed with ovarian cancer will survive longer than 5 years if their cancers are treated before they have spread beyond the ovaries. Unfortunately, there are no screening tests for ovarian cancer that are the equivalent to mammography for early detection of breast cancer. Therefore, only about 25% of ovarian cancer cases are diagnosed at such early stages. It is possible to perform genetic screening in high-risk women, but this raises some complex issues.

Annual Gynecologic Checkup

Every woman should have a regular annual examination with her doctor that includes:

Pelvic examination. Routine exams called bimanual pelvic examinations are a reasonable precaution, although they are not perfect screening methods due to their low sensitivity. This exam can be performed two ways. In the more common method, the doctor inserts two fingers into the vagina while palpating the abdomen with the other hand. The other method, called a bimanual rectovaginal exam, involves the insertion of one finger into the vagina and another into the rectum.

Either exam enables the doctor to assess the size of the ovaries as well as the contour and mobility of the uterus and to feel for masses and growths. The rectovaginal exam may reveal rectal lesions that may otherwise go unnoticed and is particularly important for women over 50. A mass felt on pelvic exam often requires further evaluation by ultrasound and sometimes requires surgery to make a definitive diagnosis.

Pap smear. This test is specifically designed to detect cervical cancer. In very rare instances, however, it may reveal abnormal ovarian cells, which might indicate the presence of an ovarian cancer.

Click the icon to see an image of a pap smear.

Unfortunately, ovarian cancer rarely produces changes that are detectable during a regular checkup.

Ruling Out Benign Conditions

An estimated 290,000 women are hospitalized each year in the United States because of ovarian growths or lesions. Many more women find out about some ovarian abnormality during their annual ob/gyn check up. The vast majority of conditions are noncancerous. They include:

• Benign functional ovarian cysts
• Abscesses and infection
• Fibroids

Click the icon to see an image of a fibroid tumor.

• Endometriosis
• Polycystic ovaries

Click the icon to see an image of a polycystic ovary.

• Ectopic pregnancies

Click the icon to see an image of an ectopic pregnancy.

• Meig's syndrome (which involves a benign ovarian growth associated with fluid buildup in the abdomen and around the lungs)
• Ovarian hyperstimulation syndrome following fertility treatments.

Once a growth is detected, additional tests as outlined below may help the doctor gauge the risk for it being cancerous.

Transvaginal Ultrasound and Other Imaging Tests

Ultrasound. Ultrasound is a noninvasive diagnostic tool that can evaluate tumors and masses discovered during the rectovaginal exam:

• Typically, a probe is placed in the vagina and emits sound waves (ultrasound). The sound waves bounce off tissues, organs, and masses in the pelvic cavity. These echoes are collected and converted into a picture of the area called a sonogram.

Click the icon to see an image of transvaginal ultrasound.

• The ultrasound probe may also be placed on abdominal walls above the ovaries (transabdominal ultrasound), but it does not provide as clear a picture of the ovaries. Healthy tissue, fluid-filled cysts, and solid tumors produce different sound waves.

Ultrasound is not helpful for identifying early-stage ovarian cancer in high-risk women. (Researchers hope that blood tests for protein markers may eventually provide a better method for diagnosing early-stage ovarian cancer.) In addition, ultrasound does not provide enough specific information to reliably determine which abnormal masses are cancerous or noncancerous.

• Studies suggest that small so-called simple cysts (fluid-filled without an associated mass) are usually noncancerous, particularly when they appear in premenopausal women whose blood tests for the protein CA-125 are normal. Such women are sometimes given oral contraceptives and observed for a few months to see if the cyst goes away.
• Postmenopausal women with small simple cysts and normal CA-125 levels may sometimes be observed for a time if they have no other risk factors or symptoms of ovarian cancer.
• In contrast, a "complex" cyst (one that shows a mass or other abnormalities) is often surgically removed, since it has a higher chance of being malignant. Only a small percentage of these cysts turn out to be cancerous. (In one study 6% of complex cysts were actually cancerous.)

Click the icon to see an image of an ovarian cyst.

Other Imaging Techniques. Other imaging techniques are less common for the diagnosis or evaluation of suspected ovarian cancer but may help determine if cancer has spread to other parts of the body:

• Computed tomography (CT). Computed tomography records x-ray absorption rates of tissue and bone. These data are converted into clear images on a screen. CT scans help determine if cancer has spread to the lymph nodes, abdominal organs, abdominal fluid, and the liver.

Click the icon to see an image of a CT scan.

• Magnetic resonance imaging (MRI). MRI creates multiple cross-sectional images of the pelvis and abdominal organs, which are assembled into three-dimensional images. An MRI is not usually used to diagnose ovarian cancer, but may help determine if cancer has spread to the brain or spinal cord.

Click the icon to see an image of a MRI scan.

• Chest x-rays. Find cancer that has spread to the lungs.

Click the icon to see an image of an x-ray machine.

CA-125 Blood Test

CA-125 is a protein that is secreted by ovarian cancer cells and is elevated in over 80% of patients with ovarian cancer. The CA-125 blood test is not approved for screening in the general population. Oncologists will usually only obtain a blood test for this protein if ovarian cancer is strongly suspected or has been diagnosed. In general, a CA-125 level is considered to be normal if it is less than 35 U/mL (microns per milliliter). The test may also be useful for evaluating tumor growth and predicting survival in patients with recurrent cancer who have been treated with topotecan or paclitaxel-carboplatin chemotherapy regimens.

The test is not useful for diagnosis or early screening, however. In about half of women with very early ovarian cancer, CA-125 levels are not elevated above the normal standard at all. Furthermore, an elevated level can be caused by a number of other conditions including:

• Endometriosis (which may be a risk factor for ovarian cancer)
• Fibroids
• Noncancerous ovarian cysts
• Pregnancy
• Pelvic inflammatory disease
• Liver diseases
• Other tumors, such as breast, colon, lung, and pancreatic cancers
• Age and menstrual status can also affect the levels of CA-125

Investigational Tests

Research is underway to find better tests that will detect this cancer in early stages.

Proteomics. A promising new approach relies on a technique called proteomics. Proteomics is the analysis of certain proteins. In this approach, researchers are looking at a unique pattern of proteins produced by ovarian cancer cells. Studies suggest this set of proteins serves as an early biomarker for detecting ovarian cancer. Scientists at the NCI and FDA have developed a blood test to check for the presence of these abnormal proteins. In one study, the proteomics tool identified 100% of patients with ovarian cancer and incorrectly diagnosed cancer in only 3 out of 66 of women who were actually cancer-free. A clinical trial is now underway comparing the proteomics test to the CA-125 test. OvaCheck, another investigational ovarian cancer blood test, is based on principles similar to the NCI and FDA platform, but is being developed independently by a private corporation.

Osteopontin. Scientists are also looking into the possibility that the protein osteopontin may be a biomarker for ovarian cancer. Studies have shown that osteopontin is overexpressed in tumors and serum of women with ovarian cancer.

Other Biomarkers. Researchers have also had preliminary success with blood test that measures osteopontin along with three additional protein markers in blood: leptin, prolactin, and insulin-like growth factor-II. In early trials, prolactin and osteopontin levels were significantly elevated in women with early ovarian cancer. The other two proteins were greatly reduced. When measured collectively, these four proteins completely distinguished between healthy women and those with early ovarian cancer, according to the results published in the May 2005 journal of the Proceedings of the National Academy of Sciences.

Exploratory Surgery

An exploratory surgical procedure called laparotomy generally is required for the definitive diagnosis of ovarian cancer. Laparotomy involves the following steps:

• It requires general anesthesia and employs standard surgical techniques to make a vertical, midline incision from the pubic bone to the navel.
• Such an incision ensures careful evaluation of the entire abdominal area. After the incision is made, the surgeon assesses the fluid and cells in the abdominal cavity.
• During this procedure, cysts or other suspicious areas will be removed and biopsied (tested for cancer).
• If the lesion is cancerous, the surgeon continues with a process called surgical staging to find out how far the cancerous tumor has spread and to remove the ovaries and any cancerous tissue.

Investigators are also studying laparoscopy -- instead of more invasive surgery -- for initial surgical evaluation (staging).

Click the icon to see an image of pelvic laparoscopy.

Prognosis

Ovarian cancer ranks behind lung, breast, and colorectal cancer as the fourth most common cause of female cancer death in this country. About 15,310 American women are expected to die from ovarian cancer in 2006.

In general, overall 5-year survival rates (all stages combined) increased from 37% in 1974 to greater than 50% currently. Survival rates vary depending on different factors, including age and the stage at which it is detected.

The survival rate also varies according to the cancer stage:

• Five-year survival rates are over 90% if the cancer is still confined to the ovary at diagnosis.
• If it has spread to nearby regions in the pelvis, the survival rate drops to 60 - 80%.
• If it has spread to sites outside the pelvis, the 5-year survival rates are only 10 - 30%.

Unfortunately, most patients with ovarian cancer are not diagnosed until the disease is advanced. This usually means the cancer has spread to the upper abdomen. In order to establish a prognosis and determine treatment, the doctor needs to know the cell type, stage, and grade of the disease.

Prognosis by Cell Type

About 90% of ovarian epithelial cancers fall into one of four major subtypes based on their origin and shape as viewed under a microscope:

• Serous. (This is the most common type.)
• Endometrioid. (This is sometimes associated with endometriosis and tends to have a more favorable outlook.)
• Mucinous. (The presence of malignant mucinous cells indicates a poorer outlook if the disease is advanced.)
• Clear cell. (Clear cell carcinomas are the most difficult to treat even when the malignancy is still confined to the ovary.)

The remaining 10% of common epithelial cancers are referred to as undifferentiated, because their exact cell of origin cannot be determined microscopically. These epithelial ovarian carcinomas tend to grow and spread quickly.

Prognosis by Stage

Cancers are staged (I through IV) according to whether they are still localized (remaining in the ovary) or have spread beyond the original site.

Prognosis by Grade

Tumors are also graded according to how well or poorly organized they are (their differentiation). Ovarian tumors are graded on a scale of 1, 2, or 3. Grade 1 tends to closely resemble normal tissue and has a better prognosis than grade 3, which indicates very abnormal, poorly defined tissue.

Other Prognostic Factors

Age. In general, younger women have a better prognosis than older women although stage and grade of tumor also are important to the prognosis.

BRCA Carriers. Some studies have reported that women who carry mutated BRCA genes may have better survival rates than non-carriers. The survival advantages may be due to having a slower course or being more responsive to therapies than sporadic ovarian cancers, although this is controversial.

Angiogenesis. Experimentally, the level of biochemicals stimulating the formation of new blood vessels that support tumor growth (angiogenesis) appears to correlate with prognosis. The more angiogenic factors present in a tumor population, the more new blood vessels will form, encouraging both tumor growth and metastasis.

Hormone Receptor. In a 2000 study, women with ovarian cancer cells with progesterone receptors had higher survival rates than those with estrogen, both progesterone and estrogen, or no hormone receptors. Nevertheless, assessment of hormone receptor status is not usually necessary in ovarian cancer management.

Overexpression of p53 Mutations. High levels of a defective p53 gene (which regulates cell growth) are associated with a poorer outlook.

Consequences for Survivors

Women who survive ovarian cancer have a high risk for psychological stress. Support groups can be very helpful.

Treatment

In general, the course of treatment is determined by the stage of the cancer. Stages range from I to IV based on the cancer's specific characteristics, such as whether it has spread beyond the ovaries.

Stage I

In stage I, the cancer has not spread. It is confined to one ovary (stage IA) or both ovaries (stage IB). In stages IA and IB, the ovarian capsules are intact and there are no tumors on the surface. Stage IC can affect one or both ovaries, but the tumors are on the surface, or the capsule is ruptured, or there is evidence of tumor cells in abdominal fluid (ascites). The overall 5-year survival rate for stage IA or IB can be as high as 90%, but the presence of other factors may affect this rate. For example, non-clear-cell pt well-differentiated cancer cells or borderline tumors have a favorable prognosis. Clear cells or those that are more poorly differentiated have a worse outlook. Stage IC has a poorer outlook than the earlier stages. It is very important that women receive an accurate staging assessment, including a pathologic review conducted by a gynecologic pathologist.

Treatment Options: Treatment for most women with stage IA and IB includes surgical removal of the uterus and both ovaries and fallopian tubes (total hysterectomy and bilateral salpingo-oophorectomy), partial removal of the omentum (the fatty layer that covers and pads organs in the abdomen), and surgical staging of the lymph nodes and other tissues in the pelvis and abdomen. (Carefully selected premenopausal women in stage I with the lowest-grade tumors in one ovary may sometimes be treated only with the removal of the diseased ovary and tube in order to preserve fertility.) Patients with stage IA or B disease, grade 1 (or sometimes grade 2), usually do not need further therapy after surgery. However, higher risk patients (stage IC, stage I/grade 3) are usually treated with platinum-based chemotherapy to reduce their risk of subsequent relapse.

A 2005 study suggested that adjuvant (chemotherapy added to surgical treatment) platinum-based chemotherapy can improve survival and reduce cancer recurrence. With the considerable adverse effects of chemotherapy, more research is needed to determine which stage 1 patients would benefit most from this adjuvant treatment.

Click the icon to see an illustrated series detailing hysterectomy.

Stage II

In stage II, the cancer has spread to other areas in the pelvis. It may have advanced to the uterus or fallopian tubes (stage IIA), or other areas within the pelvis (stage IIB), but is still limited to the pelvic area. Stage IIC indicates capsular involvement, rupture, or positive washings (that is, they contain malignant cells). The 5-year survival rate for stage II is about 60 - 80%.

Treatment Options: Surgical management for most women in this stage is total hysterectomy, bilateral salpingo-oophorectomy, and removal of as much cancer in the pelvic area as possible (tumor debulking). Surgical staging should be performed.

After the operation, treatment with chemotherapy is usually necessary in an attempt to eradicate residual cancer and decrease the chance for relapse.

Stage III

In stage III, one or both of the following are present: (1) The cancer has spread beyond the pelvis to the omentum (the fatty layer that covers and pads organs in the abdomen) and other areas within the abdomen, such as the surface of the liver or intestine. (2) The cancer has spread to the lymph nodes. The average 5-year survival rate for this stage is 20%.

Click the icon to see an image of the lymph system located near the ovaries.

Treatment Options: Surgical management for most women in this stage is total hysterectomy and bilateral salpingo-oophorectomy and removal of as much cancer as possible (tumor debulking).

Following surgery, chemotherapy is usually needed for any remaining cancer cells. Several approaches are under investigation for reducing high rates of recurrence (about 80%). These approaches include the following:

• Experimental chemotherapy drugs
• Anti-angiogenic therapies
• Gene and biological therapies
• Intraperitoneally administered high-dose chemotherapy
• Neoadjuvant therapy (chemotherapy before surgery)
• High-dose chemotherapy
• Peripheral blood stem cell transplantation (to date this approach has proven to be very toxic with no convincing improvement in survival)

Stage IV

Stage IV is the most advanced cancer stage. The cancer may have spread to the inside of the liver or spleen. There may be distant spreading of the cancer, such as ovarian cancer cells in the fluid around the lungs. The average 5-year survival rate for this stage is less than 10%.

Treatment Options: Tumor debulking may be performed before chemotherapy.

Although not standard practice in the United States, a surgical procedure called retroperitoneal lymphadenectomy is sometimes performed. This procedure involves removal of aortic and pelvic lymph nodes from the rear of the abdomen. Results from a 2005 randomized controlled trial suggest that while retroperitoneal lymphadenectomy does help reduce cancer progression, it does not prolong survival.

Recurrent Ovarian Cancer

Treatment Options: If ovarian cancer returns, chemotherapy is the mainstay of treatment, although it is not generally curative in the setting of relapsed disease.

If the interval between the last platinum-containing chemotherapy (carboplatin or cisplatin) and relapse is long (greater than 6 months), it is reasonable to attempt a repeat trial of platinum-based chemotherapy, with or without paclitaxel.

If the interval is short, or if these drugs fail to control the tumor, then other second-line drugs may be useful in achieving a response. They include topotecan, liposomal doxorubicin, etoposide, docetaxel, gemcitabine, or tamoxifen. There is no evidence as yet that second-line drug combinations are any more effective than single drugs, although they are generally more toxic.

Clinical trials using various investigative approaches are under way. It is not clear if there is a role of a second debulking surgical procedure. A 2004 study published in the New England Journal of Medicine found that additional debulking did not prevent cancer progression or prolong survival.

Surgery

Surgery for ovarian cancer uses laparotomy, which is a major abdominal operation. It is the primary diagnostic tool for ovarian cancer and also plays a role in treatment. Complete surgical intervention includes the following:

• Surgical staging (examining all tissues and organs in the pelvic cavity for accurate assessment of the disease stage).
• Debulking (removal of as much of the cancerous tissue as possible). This is an important component of ovarian cancer management and should be performed by a surgeon trained in cancer surgery techniques.

Patients with ovarian cancer should see a qualified gynecologic oncologist (a surgical specialist in female reproductive cancers) and a qualified medical oncologist with special expertise in the chemotherapeutic management of gynecologic cancer.

Surgical Staging

Surgical staging includes biopsies of the following:

• The undersurface of the diaphragm
• The omentum (the fatty layer that covers and pads organs in the abdomen)
• Sometimes lymph nodes along the abdominal aorta

An abdominal wash is performed by injecting a salt solution into the abdominal cavity to facilitate microscopic detection of cancerous cells not visible to the naked eye. The surgeon then evaluates the pelvis and abdomen and removes suspected cancer tissue. The entire affected ovary is usually removed (oophorectomy) during surgical staging if the surgeon believes it might be cancerous. The tissue is sent to a laboratory for an immediate evaluation called a frozen section diagnosis. The doctor will also examine the bowel and bladder for cancer invasion.

Preservation Surgery in Premenopausal Women with Early Cancer

If the tumor is in an early stage on one ovary and a young woman wants to retain her ability to have children, the surgeon may be able to remove only the affected ovary and perform surgical staging. Chemotherapy follows in selected patients. Studies indicate that in carefully selected young patients, many can expect normal fertility afterward. However, most women with ovarian cancer are not candidates for this procedure.

Total Hysterectomy and Bilateral Salpingo-Oophorectomy and Debulking

The goal of surgery is to remove as much of the tumor as possible (called debulking or cytoreductive surgery) for improving symptoms and increasing the effectiveness of chemotherapy. The surgery itself is typically performed as follows:

• In premenopausal women in later stages, and in all postmenopausal women, the surgeon usually removes the uterus (a hysterectomy) and both ovaries and fallopian tubes (a bilateral salpingo-oophorectomy).
• In addition, the surgeon usually removes the omentum (omentectomy), any growths on the diaphragm and intestine, and possibly certain lymph nodes (lymphadenectomy).

If surgical staging reveals that the cancer has invaded the bowel, a portion of the intestine may have to be removed as well.

Postoperative Care in the First Few Days after Hysterectomy

Postoperative Care. If possible, a patient should ask a family member or friend to help out for the first few days at home. The following are some of the precautions and tips for postoperative care:

• For 1 -2 days after surgery, the patient is given medications to prevent nausea and pain killers to relieve pain at the incision site.
• As soon as the doctor recommends it, usually within a day of the operation, the patient should get up and walk in order to help prevent pneumonia, reduce the risk of blood-clot formation, and to hasten recovery.
• Walking and slow, deep breathing exercises may help to relieve gas pains, which can cause major distress for the first few days.
• Coughing can cause pain, which may be reduced by holding a pillow over a surgical abdominal wound or by crossing the legs after vaginal surgery.
• Patients are advised not to lift heavy objects (including small children), not to douche or take baths, and not to climb stairs or drive for several weeks.
• For the first few days after surgery, many women weep frequently and unexpectedly. These mood swings may be due to depression from the loss of reproductive capabilities and form abrupt changes in hormones, particularly if the ovaries have been removed.

The patient should talk to their doctor about when they can start exercise programs that more intense than walking. The abdominal muscles are important for supporting the upper body, and recovering strength may take a long time. Even after the wound has healed, the patient may experience an on-going feeling of overall weakness, which can be demoralizing, particularly in women used to physical health. Some women do not feel completely well for as long as a year. Others may recover in only a few weeks.

Complications Following the Procedure. Minor complications after hysterectomy are very common:

• Women may develop minor and treatable urinary tract infections.
• There is usually light vaginal bleeding and pain after the operation, which can be well-controlled with pain medications.

More serious complications are uncommon but patients should be aware of their symptoms and call the doctor immediately if they occur:

• Infection occurs in 10 - 15% of patients, with the risk being higher with abdominal than with vaginal surgery. Symptoms might include continuing or increasingly severe pain, fever, heavy discharge, or bleeding. Antibiotics given at the time of surgery help to reduce this risk. Other risk factors for infection include obesity, a longer than normal operative time, and low socioeconomic status.
• There is a slight risk for small blood clots, usually in veins of the legs (thrombophlebitis). A sudden swelling or discoloration in the leg can indicate this condition and requires immediate medical attention.

This picture shows a red and swollen thigh and leg caused by a blood clot (thrombus) in the deep veins in the groin (ileofemoral veins), preventing normal return of blood from the leg to the heart.

• Other serious and even life-threatening complications are rare, but include pulmonary embolism (blood clots that travel to the lung), abscesses, perforation of the bowel, fistulas (a passage that bores from an organ to the skin or to another organ), or dehiscence (the opening of the surgical wound).

Treating Menopausal Symptoms and Premature Menopause after Hysterectomy. After hysterectomy, premenopausal women usually experience hot flashes, a symptom of menopause. Symptoms come on abruptly and may be more intense than those of natural menopause. Symptoms include hot flashes, vaginal dryness and irritation, and insomnia. A significant number of women gain weight.

The most important complications that occur in women who have had their ovaries removed are due to estrogen loss, which places women at risk for osteoporosis (loss of bone density) and a possible increase in risks for heart disease. Women have typically taken hormone replacement therapy (HRT) after surgery if their ovaries have been removed. There have been concerns however about health risks, including the risk for breast cancer and stroke, that have now limited its use. Such risks in premenopausal women who have had a hysterectomy have not yet been clarified. Fortunately, several nonhormonal drugs can help protect both bones and heart.

Second-Look Laparotomy

After chemotherapy has been completed, surgeons used to perform an exploratory procedure called second-look laparotomy. Although this procedure is the most sensitive way of detecting residual cancer that remains after chemotherapy, it has no proven impact on patient survival. Its use is restricted to patients being treated in clinical trials.

Surgery for Bowel Obstruction

Bowel obstruction is common in ovarian cancer. Surgery can be very helpful for selected patients with this problem.

Medications

Following surgery, patients (other than those with early-stage, low-grade disease) usually have chemotherapy. Unlike surgery and radiation, which treat the cancerous tumor and the area surrounding it, drug therapy destroys rapidly dividing cells throughout the body, so it is as systemic therapy.

Ovarian cancers are very sensitive to chemotherapy and often respond well initially. Unfortunately, in most cases, ovarian cancer recurs. With treatment advances, however, more than half of women now survive 5 years or longer. Doctors are now approaching this disease as a chronic and potentially long-term illness that requires the folloiwng

• Identifying the disease recurrence as soon as possible
• Administering treatments that are as effective as possible without causing suffering
• Partnering with the patient in determining her own best course

Drugs Used in Chemotherapy

Standard Chemotherapy. The standard initial chemotherapy uses a combination of the following:

• A platinum-based drug, such as carboplatin (Paraplatin) or cisplatin (Platinol). At this time carboplatin is preferred over cisplatin in the combination because carboplatin is as effective as cisplatin but is less toxic and can be administered in a more convenient, outpatient regimen.
• A taxane, such as paclitaxel (Taxol) and docetaxel (Taxotere). Currently paclitaxel is the drug most often used as initial therapy in combination with a platinum drug. Docetaxel, however, is less toxic to the nervous system (but has more adverse effects on blood cell production). Taxotere is now commonly substituted for Taxol.

About 70% of women will experience a response (reduction in tumor size) to paclitaxel-carboplatin chemotherapy. Older women (over age 60) may benefit as much as younger ones from this regimen.

Other drugs that may prove to be useful first-line drugs are gemcitabine and pegylated liposomal doxorubicin (which are discussed below). An important 2006 study indicated that topotecan following paclitaxel-carboplatin therapy is not helpful as a first-line treatment for advanced ovarian cancer. Topetcan did not help prolong survival, and it caused many serious side effects, including anemia and infections.

Chemotherapy Drugs Studied for Relapsed or Refractory Cancer. Unfortunately, some ovarian tumors are resistant to platinum drugs. Even in patients who respond, the disease eventually becomes resistant to the first-line drugs, and the cancer returns. Various approaches for increasing responsiveness to these drugs are being investigated. Investigators are studying two approaches for preventing relapse after remission:

• Developing more effective drug combination regimens to increase initial response rates and duration of the response.
• Developing maintenance drugs to prevent or delay relapse.

Once cancer recurs or continues to progress, several second-line chemotherapies are available or under investigation. The following lists some drugs that are being used, usually as single drugs, for relapsed or refractory cancers:

• Nucleoside analogs, including gemcitabine (Gemzar). In 2006, gemcitabine was approved as a treatment for recurrent ovarian cancer. It is used in combination with carboplatin for women with advanced ovarian cancer that has relapsed at least 6 months after initial therapy.
• Paclitaxel or carboplatin alone or in combination. A landmark study published in the July 2003 Journal of Clinical Oncology, found that extended use of paclitaxel significantly delayed disease progression in women with advanced ovarian cancer.
• Pegylated liposomal doxorubicin (Doxil) is a form of doxorubicin that remains in the bloodstream longer, tends to spare the bone marrow, and moves selectively through the tumor. It is showing promise in clinical trials and also may have fewer toxic effects than standard doxorubicin and other drugs used for ovarian cancer. Studies show that Doxil is very well tolerated with a total response rate of about 20 - 30% in patients with recurrent cancer. This compares favorably with other drugs, such as topotecan, carboplatin, and taxol.
• Topoisomerase I inhibitors, including topotecan (Hycamtin) and irinotecan (Campto).
• Topoisomerase II alpha inhibitors, including etoposide (VePesid).
• Alkaloids, including vinorelbine (Navelbine).
• Hormonal drugs: tamoxifen (Nolvadex) or anastrozole (Arimidex).
• Other drugs. Valspodar and capecitabine (Xeloda) are oral drugs that may help improve response to other drugs, although data are preliminary.

Administration of Chemotherapy

In addition to studying individual drugs in different combinations, investigators are looking for the optimal sequence, dosages and timing of administering them. In general, the typical regimen is as follows:

• Paclitaxel and carboplatin are administered in an outpatient clinic within several weeks of the surgery.
• Each treatment takes about 4 -5 hours to complete.
• It is repeated every 3 weeks for a total of six times. (Each 3-week interval is known as a cycle of chemotherapy.)

Such chemotherapy is usually administered intravenously (by vein). However, an important 2006 study in the New England Journal of Medicine found that patients with stage III ovarian cancer who received intraperitoneal chemotherapy had a significant survival advantage compared with patients who received standard intravenous chemotherapy. (Intraperitoneal chemotherapy involves administering the drugs directly into the abdominal cavity.) Patients in the intraperitoneal group did have more severe side effects than those who had intravenous chemotherapy. Researchers are continuing to investigate ways to reduce these side effects. Another 2006 study noted that intraperitoneal chemotherapy requires careful catheter insertion and maintenance, and that doctors need to be well trained to perform this procedure.

Side Effects of Chemotherapy

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment. Some may be long-lasting. In a 2002 study of ovarian cancer survivors, 20% had long-term treatment side effects, such as gynecologic and abdominal problems. Even so, most enjoyed a high quality of life that was comparable to other cancer survivors and peers without a history of cancer.

Common side effects include:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs.
• Diarrhea
• Temporary hair loss
• Weight loss
• Fatigue
• Depression

Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. The following list includes some of these complications and a few of their treatments:

• Anemia. Erythropoietin stimulates red blood cell production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp stays in the blood longer than epoetin alfa, so fewer injections are needed.
• Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection in selected patients.
• Liver and kidney damage.
• Abnormal bleeding (thrombocytopenia).
• Allergic reaction, particularly to platinum-based drugs.
• Rarely, secondary cancers such as leukemia.
• Between a quarter and a third of women report problems in concentration, motor function, and memory. These problems may be long-term and may be due to reductions in estrogen levels after treatments.
• Cumulative doses of anthracyclines can damage heart muscles over time and increase the risk for heart failure. An encapsulated form doxorubicin (Myocet, Doxil) may reduce the risk for toxic effects on the heart.
• Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur. Talking a corticosteroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, which is relievable with corticosteroids.

Gauging Success or Detecting Recurrence

Physical Exam and CA-125 Blood Test. During treatment, the effectiveness of the chemotherapy is evaluated primarily with a physical examination and the CA-125 blood test. Falling CA-125 levels indicate effective treatment and persistently elevated levels indicate resistance to the chemotherapy.

Second Look Laparotomy. Second-look laparotomy is sometimes considered after completion of chemotherapy for patients who are participating in clinical trials.

Comparative CT Scans. Another method for evaluating the success of chemotherapy is to compare CT scans of the pelvis and abdomen before and after chemotherapy to check the size of any residual tumors that persisted after the original surgery. CT scanning is not always required, however.

Positron Emission Tomography (PET). At present, PET scans have no proven role in the management of patients with ovarian cancer. More study is needed in order to determine their utility in diagnosing relapsed disease.

Investigational Drugs

Patients with any stage of ovarian cancer are candidates for clinical trials. In addition to testing high-dose or combinations of chemotherapy, drugs with unique actions are being investigated.

HER Dimerization Inihibitors. Pertuzumab (Omnitarg) is the first of a new class of drugs called HER dimerization inhibitors. It is designed to inhibit tumor growth for tumors that express the HER2 receptor protein. Pertuzumab is currently in Phase II trials

Multiple signal transduction regulators (MSTRs). Phenoxodiol is an MSTR that is being developed as a broad-spectrum anti-cancer drug. It is currently being evaluated in Phase II clinical trials, in combination with other drugs such as docetaxel, for its ability to shrink tumors or stop tumor growth in women with ovarian or fallopian cancer who have failed other forms of chemotherapy.

LH-RH Agonists. Luteinizing hormone-releasing hormones (LH-RH) agonists (also called GnRH agonists) include leuprolide (Lupron), goserelin (Zoladex), and deslorelin. These drugs are able to block the release of two major reproductive hormones, and there is some indication that this action may help prevent cell proliferation.

Immunotherapy. Several therapies under investigation use drugs that boost the body's own immune response to specifically attack ovarian cancer cells. To date, they have produced only minor effects. Experimental therapies that are in clinical trials include a vaccinations that use specially designed antibodies (called monoclonal antibodies or MAbs) to boost the immune responses against tumor-associated factors, such as CA125 or HER-2/neu. Vaccines against HERS/neu are also being investigated.

Gene Therapy. Gene therapies generally work in one of two ways:

• One approach involves genes that are used to convert inactive drugs into cancer-fighting drugs.
• The other major approach uses genetic therapies to repair molecular defects that are causing uncontrolled cell proliferation. For example, some investigators are using techniques to deliver a normal p53 gene, which suppresses cancer cell growth, into ovarian cancer cells.

Antiangiogenesis drugs. Angiogenesis, the formation of new blood vessels that feed the growth of a cancerous tumor, is a critical process in the spread of ovarian cancer. Drugs that block this process are under investigation for ovarian cancer. Such drugs include thalidomide, gefinitib (Iressa), and carboxyamido-triazole (CAI).

Aromatase inhibitors. Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many body tissues. The include anastrozole (Arimidex) and letrozole (Femara). A 2002 study suggested they might benefit certain patients who have biologic markers indicating that their cancer cells are sensitive to these drugs.

Retinoids. Laboratory studies have found that retinoids, which are compounds derived from vitamin A, inhibit ovarian cancer cell growth. Certain retinoids, including fenretinide, are being investigated for treating and preventing ovarian cancer.

Epothilones. Epothilones are a new class of anti-cancer drugs that are similar to taxanes (paclitaxel) but are more potent. Currently one of these drugs, called only BMS-247550, is being studied in a late-phase trial for ovarian cancer.

Radiation Therapy

Radiation therapy is not typically used in ovarian cancer. This is because radiation would need to be given to the entire abdomen and pelvis, increasing its toxicity. Radiation is sometimes useful to treat isolated areas of tumor that are causing pain and are no longer responsive to chemotherapy.

Lots More Information

Resources

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.aacr.org -- American Association for Cancer Research
• www.asco.org -- American Society of Clinical Oncology
• www.oncolink.org -- Oncolink
• www.ovarian.org -- National Ovarian Cancer Coalition
• www.ovariancancer.org -- Ovarian Cancer National Alliance
• www.sgo.org -- Society of Gynecologic Oncologists
• www.wcn.org -- Women's Cancer Network
• www.ovariancancer.com -- The Gilda Radner Familial Ovarian Cancer Registry
• www.cancer.gov/clinicaltrials -- Find clinical trials

References

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