Ovarian Epithelial Cancer Treatment (PDQ®)


Information for: Patients | Healthcare Professionals

General Information About Ovarian Epithelial Cancer

Ovarian epithelial cancer is a disease in which malignant (cancer) cells form in the tissue covering the ovary.

The ovaries are a pair of organs in the female reproductive system. They are in the pelvis, one on each side of the uterus (the hollow, pear-shaped organ where a fetus grows). Each ovary is about the size and shape of an almond. The ovaries make eggs and female hormones (chemicals that control the way certain cells or organs work).

Anatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina. 
Anatomy of the female reproductive system. The organs in the female reproductive system include the uterus, ovaries, fallopian tubes, cervix, and vagina. The uterus has a muscular outer layer called the myometrium and an inner lining called the endometrium.

 

Ovarian epithelial cancer is one type of cancer that affects the ovary. See the following PDQ treatment summaries for information about other types of ovariantumors:

  • Ovarian Germ Cell Tumors
  • Ovarian Low Malignant Potential Tumors
  • Unusual Cancers of Childhood

Women who have a family history of ovarian cancer are at an increased risk of ovarian cancer.

Anything that increases your risk of getting a disease is called a risk factor. Women who have one first-degree relative (mother, daughter, or sister) with ovarian cancer are at an increased risk of ovarian cancer. This risk is higher in women who have one first-degree relative and one second-degree relative (grandmother or aunt) with ovarian cancer. This risk is even higher in women who have two or more first-degree relatives with ovarian cancer.

Some ovarian cancers are caused by inherited gene mutations (changes).

The genes in cells carry the hereditary information that is received from a person’s parents. Hereditary ovarian cancer makes up about 5% to 10% of all cases of ovarian cancer. Three hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, and ovarian and colon cancers.

There are tests that can detect mutated genes. These genetic tests are sometimes done for members of families with a high risk of cancer. See the following PDQ summaries for more information:

  • Ovarian Cancer Screening
  • Ovarian Cancer Prevention
  • Genetics of Breast and Ovarian Cancer

Women with an increased risk of ovarian cancer may consider surgery to prevent it.

Some women who have an increased risk of ovarian cancer may choose to have a prophylactic oophorectomy (the removal of healthy ovaries so that cancer cannot grow in them). In high-risk women, this procedure has been shown to greatly decrease the risk of ovarian cancer. (See the PDQ summary on Ovarian Cancer Prevention for more information.)

Possible signs of ovarian cancer include pain or swelling in the abdomen.

Early ovarian cancer may not cause any symptoms. When symptoms do appear, ovarian cancer is often advanced. Symptoms of ovarian cancer may include the following:

  • Pain or swelling in the abdomen.
  • Pain in the pelvis.
  • Gastrointestinal problems, such as gas, bloating, or constipation.

These symptoms also may be caused by other conditions and not by ovarian cancer. If the symptoms get worse or do not go away on their own, check with your doctor so that any problem can be diagnosed and treated as early as possible. When found in its early stages, ovarian epithelial cancer can often be cured.

Women with any stage of ovarian cancer should think about taking part in a clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

Tests that examine the ovaries, pelvic area, blood, and ovarian tissue are used to detect (find) and diagnose ovarian cancer.

The following tests and procedures may be used:

  • Pelvic exam

    An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. The doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and the other hand is placed over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. A speculum is also inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test or Pap smear of the cervix is usually done. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.

    Pelvic exam; drawing shows a side view of the female reproductive anatomy during a pelvic exam. The uterus, left fallopian tube, left ovary, cervix, vagina, bladder, and rectum are shown. Two gloved fingers of one hand of the doctor or nurse are shown inserted into the vagina, while the other hand is shown pressing on the lower abdomen. The inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.  
    Pelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.

     

  • Ultrasound exam

    A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The picture can be printed to be looked at later.

    An abdominal ultrasound may be done.

    Abdominal ultrasound; drawing shows a woman on an exam table during an abdominal ultrasound procedure. A diagnostic sonographer (a person trained to perform ultrasound procedures) is shown passing a transducer (a device that makes sound waves that bounce off tissues inside the body) over the surface of the patient’s abdomen. A computer screen shows a sonogram (computer picture). 
    Abdominal ultrasound. An ultrasound transducer connected to a computer is passed over the surface of the abdomen. The ultrasound transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).

     

    Other patients may have a transvaginal ultrasound.

    Transvaginal ultrasound; drawing shows a side view of the female reproductive anatomy during a transvaginal ultrasound procedure. An ultrasound probe (a device that makes sound waves that bounce off tissues inside the body) is shown inserted into the vagina. The bladder, uterus, right fallopian tube, and right ovary are also shown. The inset shows the diagnostic sonographer (a person trained to perform ultrasound procedures) examining a woman on a table, and a computer screen shows an image of the patient’s internal tissues. 
    Transvaginal ultrasound. An ultrasound probe connected to a computer is inserted into the vagina and is gently moved to show different organs. The probe bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).

     

  • CA 125assay

    A test that measures the level of CA 125 in the blood. CA 125 is a substance released by cells into the bloodstream. An increased CA 125 level is sometimes a sign of cancer or other condition.

  • Barium enema

    A series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metalliccompound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series.

  • Intravenous pyelogram (IVP)

    A series of x-rays of the kidneys, ureters, and bladder to find out if cancer has spread to these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.

  • CT scan (CAT scan)

    :A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

  • Biopsy

    The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. The tissue is removed in a procedure called a laparotomy (a surgicalincision made in the wall of the abdomen).

Certain factors affect treatment options and prognosis (chance of recovery).

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The type and size of the tumor.
  • Whether all of the tumor can be removed by surgery.
  • The patient’s age and general health.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Stages of Ovarian Epithelial Cancer

After ovarian epithelial cancer has been diagnosed, tests are done to find out if cancer cells have spread within the ovaries or to other parts of the body.

The process used to find out if cancer has spread within the ovary or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following procedures may be done:

  • Laparotomy: The doctor cuts into the abdomen and carefully looks at all the organs to see if they contain cancer. The doctor will also do a biopsy (cut out small pieces of tissue so they can be looked at under a microscope to see whether they contain cancer). Usually the doctor will remove the cancer and organs that contain cancer during the laparotomy. (See the Treatment Options by Stage section.)
  • Thoracentesis: The removal of fluid from the space between the lining of the chest and the lung, using a needle. A pathologist views the fluid under a microscope to look for cancer cells.

There are three ways that cancer spreads in the body.

The three ways that cancer spreads in the body are:

  • Through tissue. Cancer invades the surrounding normal tissue.
  • Through the lymph system. Cancer invades the lymph system and travels through the lymph vessels to other places in the body.
  • Through the blood. Cancer invades the veins and capillaries and travels through the blood to other places in the body.

When cancer cells break away from the primary (original) tumor and travel through the lymph or blood to other places in the body, another (secondary) tumor may form. This process is called metastasis. The secondary (metastatic) tumor is the same type of cancer as the primary tumor. For example, if breast cancer spreads to the bones, the cancer cells in the bones are actually breast cancer cells. The disease is metastatic breast cancer, not bone cancer.

The following stages are used for ovarian epithelial cancer:

Stage I

Three-panel drawing of stage IA, IB, and IC ovarian cancer; first panel shows a stage IA tumor inside one ovary. The second panel shows two stage IB tumors, one inside each ovary. The third panel shows two stage IC tumors, one inside each ovary, and one tumor has a ruptured capsule. An inset shows cancer cells floating in the peritoneal fluid surrounding abdominal organs. Also shown are the fallopian tubes, uterus, cervix, and vagina. 
Ovarian cancer stage IA, IB, and IC. In stage IA, cancer is found inside a single ovary. In stage IB, cancer is found inside both ovaries. In stage IC, cancer is found in one or both ovaries and one of the following is true: (a) cancer is found on the outside surface of one or both ovaries, (b) the capsule (outer covering) of the ovary has broken open, or (c) cancer cells are found floating in the peritoneal fluid surrounding abdominal organs or in washings of the peritoneum.

In stage I, cancer is found in one or both ovaries. Stage I is divided into stage IA, stage IB, and stage IC.

  • Stage IA: Cancer is found inside a single ovary.
  • Stage IB: Cancer is found inside both ovaries.
  • Stage IC: Cancer is found inside one or both ovaries and one of the following is true:
    • cancer is also found on the outside surface of one or both ovaries; or
    • the capsule (outer covering) of the ovary has ruptured (broken open); or
    • cancer cells are found in the fluid of the peritoneal cavity (the body cavity that contains most of the organs in the abdomen) or in washings of the peritoneum (tissue lining the peritoneal cavity).
     

Stage II

Three-panel drawing of stage IIA, IIB, and IIC ovarian cancer; first panel shows two stage IIA tumors, one inside each ovary, that have spread to the uterus and fallopian tube. The second panel shows two stage IIB tumors, one inside each ovary, that have spread to the uterus, fallopian tube,  and  colon. The third panel shows two stage IIC tumors, one inside each ovary, that have spread to the uterus and colon. An inset shows cancer cells floating in the peritoneal fluid surrounding abdominal organs. Also shown are the cervix and vagina. 
Ovarian cancer stage IIA, IIB, and IIC. In stage IIA, cancer is found inside one or both ovaries and has spread to the uterus and/or the fallopian tubes. In stage IIB, cancer is found inside one or both ovaries and has spread to other tissues within the pelvis. In stage IIC, cancer is found inside one or both ovaries and has spread to the uterus and/or fallopian tubes and/or other tissue within the pelvis, and one of the following is true: (a) cancer is found on the outside surface of one or both ovaries, (b) the capsule (outer covering) of the ovary has broken open, or (c) cancer cells are found floating in the peritoneal fluid surrounding abdominal organs or in washings of the peritoneum.

In stage II, cancer is found in one or both ovaries and has spread into other areas of the pelvis. Stage II is divided into stage IIA, stage IIB, and stage IIC.

  • Stage IIA: Cancer has spread to the uterus and/or the fallopian tubes (the long slender tubes through which eggs pass from the ovaries to the uterus).
  • Stage IIB: Cancer has spread to other tissue within the pelvis.
  • Stage IIC: Cancer is found in one or both ovaries and has spread to the uterus and/or fallopian tubes, or to other tissue within the pelvis. Also, one of the following is true:
    • cancer is also found on the outside surface of one or both ovaries; or
    • the capsule (outer covering) of the ovary has ruptured (broken open); or
    • cancer cells are found in the fluid of the peritoneal cavity (the body cavity that contains most of the organs in the abdomen) or in washings of the peritoneum (tissue lining the peritoneal cavity).
     
Tumor size compared to everyday objects; shows various measurements of a tumor compared to a pea, peanut, walnut, and lime 
Pea, peanut, walnut, and lime show tumor sizes.

Stage III

In stage III, cancer is found in one or both ovaries and has spread outside the pelvis to other parts of the abdomen and/or nearby lymph nodes. Stage III is divided into stage IIIA, stage IIIB, and stage IIIC.

  • Stage IIIA: The tumor is found in the pelvis only, but cancer cells that can be seen only with a microscope have spread to the surface of the peritoneum (tissue that lines the abdominal wall and covers most of the organs in the abdomen), the small intestines, or the tissue that connects the small intestines to the wall of the abdomen.
    Stage IIIA ovarian cancer; drawing shows tumors inside both ovaries that have spread to the uterus, colon, and the surface of the peritoneum. Also shown are the fallopian tubes, small intestine, and bladder. 
    Stage IIIA ovarian cancer. In stage IIIA, cancer is found in one or both ovaries and has spread to other tissue within the pelvis. Cancer cells that can only be seen with a microscope have spread to the surface of the peritoneum. Cancer that has spread to the surface of the liver is also considered to be stage III.
  • Stage IIIB: Cancer has spread to the peritoneum and the cancer in the peritoneum is 2 centimeters or smaller.
    Stage IIIB ovarian cancer; drawing shows tumors inside both ovaries that have spread to the uterus, colon, small intestine, and the peritoneum, where they are 2 centimeters or smaller in diameter. An inset shows 2 centimeters is about the size of a peanut. Also shown are the fallopian tubes and bladder. 
    Stage IIIB ovarian cancer. In stage IIIB, cancer is found in one or both ovaries and has spread to other tissue within the abdomen and to the peritoneum, where it is 2 centimeters or smaller in diameter. Cancer that has spread to the surface of the liver is also considered to be stage III.
  • Stage IIIC: Cancer has spread to the peritoneum and the cancer in the peritoneum is larger than 2 centimeters and/or cancer has spread to lymph nodes in the abdomen.
    Stage IIIC ovarian cancer; drawing shows tumors inside both ovaries that have spread to the uterus, colon, small intestine, lymph nodes in the abdomen, and the surface of the peritoneum, where they are larger than 2 centimeters in diameter. An inset shows 2 centimeters is about the size of a peanut. Also shown are the fallopian tubes and bladder. 
    Stage IIIC ovarian cancer. In stage IIIC, cancer is found in one or both ovaries and has spread to (a) the peritoneum, where it is larger than 2 centimeters in diameter, and/or (b) lymph nodes in the abdomen. Cancer that has spread to the surface of the liver is also considered to be stage III.

Cancer that has spread to the surface of the liver is also considered stage III ovarian cancer.

Stage IV

Stage IV ovarian cancer; drawing shows parts of the body where ovarian cancer may spread, including the liver, lung, lymph nodes, and bone. An inset shows a close-up of cancer spreading through the blood and lymph to other parts of the body. 
Stage IV ovarian cancer. Cancer is found in one or both ovaries and may spread to other parts of the body, such as the lymph nodes, lung, liver, and bone. Cancer cells may also be found in an area between the lungs and the chest wall that has filled with fluid.

In stage IV, cancer has spread beyond the abdomen to other parts of the body, such as the lungs or tissue inside the liver.

Cancer cells in the fluid around the lungs is also considered stage IV ovarian cancer.

Recurrent or Persistent Ovarian Epithelial Cancer

Recurrentovarian epithelial cancer is cancer that has recurred (come back) after it has been treated. Persistent cancer is cancer that does not go away with treatment.

Treatment Option Overview

There are different types of treatment for patients with ovarian epithelial cancer.

Different types of treatment are available for patients with ovarian epithelial cancer. Some treatments are standard, and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the treatment currently used as standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Three kinds of standard treatment are used. These include the following:

Surgery

Most patients have surgery to remove as much of the tumor as possible. Different types of surgery may include:

  • Hysterectomy: Surgery to remove the uterus and, sometimes, the cervix. When only the uterus is removed, it is called a partial hysterectomy. When both the uterus and the cervix are removed, it is called a total hysterectomy. If the uterus and cervix are taken out through the vagina, the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out through a large incision (cut) in the abdomen, the operation is called a total abdominal hysterectomy. If the uterus and cervix are taken out through a small incision (cut) in the abdomen using a laparoscope, the operation is called a total laparoscopic hysterectomy.
    Hysterectomy; drawing shows the female reproductive anatomy, including the ovaries, uterus, vagina, fallopian tubes, and cervix. Dotted lines show which organs and tissues are removed in a total hysterectomy, a total hysterectomy with salpingo-oophorectomy, and a radical hysterectomy. An inset shows the location of two possible incisions on the abdomen: a low transverse incision is just above the pubic area and a vertical incision is between the navel and the pubic area. 
    Hysterectomy. The uterus is surgically removed with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are removed. In a total hysterectomy with salpingo-oophorectomy, (a) the uterus plus one (unilateral) ovary and fallopian tube are removed; or (b) the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures are done using a low transverse incision or a vertical incision.
  • Unilateral salpingo-oophorectomy: A surgical procedure to remove one ovary and one fallopian tube.
  • Bilateral salpingo-oophorectomy: A surgical procedure to remove both ovaries and both fallopian tubes.
  • Omentectomy: A surgical procedure to remove the omentum (a piece of the tissue lining the abdominal wall).
  • Lymph nodebiopsy: The removal of all or part of a lymph node. A pathologist views the tissue under a microscope to look for cancer cells.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Some women receive a treatment called intraperitoneal radiation therapy, in which radioactive liquid is put directly in the abdomen through a catheter.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy).

A type of regional chemotherapy used to treat ovarian cancer is intraperitoneal (IP) chemotherapy. In IP chemotherapy, the anticancer drugs are carried directly into the peritoneal cavity (the space that contains the abdominal organs) through a thin tube.

Treatment with more than one anticancer drug is called combination chemotherapy.

The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Ovarian Cancer for more information.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.

Monoclonal antibodytherapy is a type of targeted therapy that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

Bevacizumab is a monoclonal antibody being studied in treating ovarian epithelial cancer.

PARP inhibitors are targeted therapy drugs that block DNA repair and may cause cancer cells to die. PARP inhibitor therapy is being studied in treating ovarian epithelial cancer that remains after chemotherapy.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options by Stage

A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your doctor for clinical trials that are not listed here but may be right for you.

Stage I and II Ovarian Epithelial Cancer

Treatment of stage I and stage IIovarian epithelial cancer may include the following:

  • Hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Lymph nodes and other tissues in the pelvis and abdomen are removed and examined under the microscope to look for cancercells.
  • Unilateral salpingo-oophorectomy may be done in certain women who wish to have children.
  • A clinical trial of internal or external radiation therapy.
  • A clinical trial of chemotherapy.
  • A clinical trial of surgery followed by chemotherapy or watchful waiting (closely monitoring a patient's condition without giving any treatment until symptoms appear or change).
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I ovarian epithelial cancer and stage II ovarian epithelial cancer. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Stage III and IV Ovarian Epithelial Cancer

Treatment of stage III and stage IVovarian epithelial cancer may be surgery to remove the tumor, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. After surgery, treatment depends on how much tumor remains.

When the tumor that remains is 1 centimeter or smaller, treatment is usually combination chemotherapy, including intraperitoneal (IP) chemotherapy.

When the tumor that remains is larger than 1 centimeter, treatment may include the following:

  • Combination chemotherapy, including intraperitoneal (IP) chemotherapy.
  • A clinical trial of combination chemotherapy, including IP chemotherapy, before and after second-look surgery (surgery performed after the initial surgery to determine whether tumor cells remain).
  • A clinical trial of biologic therapy or targeted therapy following combination chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III ovarian epithelial cancer and stage IV ovarian epithelial cancer. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Treatment Options for Recurrent or Persistent Ovarian Epithelial Cancer

Treatment of recurrentovarian epithelial cancer may include the following:

  • Chemotherapy using one or more anticancer drugs, with or without surgery.
  • A clinical trial of surgery.
  • A clinical trial of targeted therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent ovarian epithelial cancer. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

To Learn More About Ovarian Epithelial Cancer

For more information from the National Cancer Institute about ovarian epithelial cancer, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:

About PDQ

PDQ is a comprehensive cancer database available on NCI's Web site.  

PDQ is the National Cancer Institute's (NCI's) comprehensive cancer information database. Most of the information contained in PDQ is available online at NCI's Web site. PDQ is provided as a service of the NCI. The NCI is part of the National Institutes of Health, the federal government's focal point for biomedical research.

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PDQ also contains information on clinical trials.  

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become "standard." Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Listings of clinical trials are included in PDQ and are available online at NCI's Web site. Descriptions of the trials are available in health professional and patient versions. Many cancer doctors who take part in clinical trials are also listed in PDQ. For more information, call the Cancer Information Service 1-800-4-CANCER (1-800-422-6237).


This information is provided by the National Cancer Institute.

This information was last updated on November 14, 2012.


General Information About Ovarian Epithelial Cancer

Incidence and Mortality

Estimated new cases and deaths from ovarian cancer in the United States in 2013:[1]

  • New cases: 22,240.
  • Deaths: 14,030.

Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women older than 65 years.[2] Approximately 5% to 10% of ovarian cancers are familial, and three distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers.[3] The most important risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. The highest risk appears in women with two or more first-degree relatives with ovarian cancer.[4] The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.

In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21.[5][6][7]BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.[8] The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over the general population.[9][10] Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared with BRCA1 mutation-negative women.[11][12][Level of evidence: 3iiiA] The majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, these women may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.

For women at increased risk, prophylactic oophorectomy may be considered after the age of 35 if childbearing is complete. In a family-based study among women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, two of them (0.8%) developed subsequent papillary serous peritoneal carcinoma, and six of them (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a higher than 90% reduction in the risk of ovarian cancer (relative risk [RR], 0.04; 95% confidence interval [CI], 0.01–0.16), with an average follow-up of 9 years;[13] however, family-based studies may be associated with biases resulting from case selection and other factors that may influence the estimate of benefit.[14] (Refer to the Evidence of Benefit section in the PDQ summary on Ovarian Cancer Prevention for more information.)

After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer.[15] The prognostic information presented below deals only with epithelial carcinomas. Stromal and germ cell tumors are relatively uncommon and comprise less than 10% of cases. (Refer to the PDQ summaries on Ovarian Germ Cell Tumor Treatment and Ovarian Low Malignant Potential Tumor Treatment for more information.)

Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported to be as much as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.[16] In this study, the pelvic nodes were involved as often as the para-aortic nodes. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Also, transdiaphragmatic spread to the pleura is common.

Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include:[17][18][19][20][21]

  • Younger age.
  • Good performance status.
  • Cell type other than mucinous and clear cell.
  • Lower stage.
  • Well-differentiated tumor.
  • Smaller disease volume prior to any surgical debulking.
  • Absence of ascites.
  • Smaller residual tumor following primary cytoreductive surgery.

For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites.[22] DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients.[23] Patients with clear cell histology appear to have a worse prognosis.[24] Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.[25]

Although the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease.[26] For patients whose elevated CA 125 normalizes with chemotherapy, more than one subsequent elevated CA 125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.[27][28]

Case-control studies suggest that BRCA1 and BRCA2 mutation carriers have improved responses to chemotherapy when compared with patients with sporadic epithelial ovarian cancer. This may be the result of a deficient homologous DNA repair mechanism in these tumors, which leads to increased sensitivity to chemotherapy agents.[29][30]

Most patients with ovarian cancer have widespread disease at presentation. This may be partly explained by relatively early spread (and implantation) of high-grade papillary serous cancers to the rest of the peritoneal cavity.[31] Conversely, symptoms such as abdominal pain and swelling, gastrointestinal symptoms, and pelvic pain often go unrecognized, leading to delays in diagnosis. Screening procedures such as gynecologic assessment, vaginal ultrasound, and CA 125 assay have had low predictive value in detecting ovarian cancer in women without special risk factors.[32][33] Efforts have been made to enhance physician and patient awareness of the occurrence of these nonspecific symptoms.[34][35][36][37][38] (Refer to the PDQ summaries on Pain and Gastrointestinal Complications for more information.) As a result of these confounding factors, yearly mortality in ovarian cancer is approximately 65% of the incidence rate. Long-term follow-up of suboptimally debulked stage III and stage IV patients showed a 5-year survival rate of less than 10% with platinum-based combination therapy prior to the current generation of trials including taxanes.[17] By contrast, optimally debulked stage III patients treated with a combination of intravenous taxane and intraperitoneal platinum plus taxane achieved a median survival of 66 months in a Gynecologic Oncology Group trial.[39] Numerous clinical trials are in progress to refine existing therapy and test the value of different approaches to postoperative drug and radiation therapy. Patients with any stage of ovarian cancer are appropriate candidates for clinical trials.[40][41] Information about ongoing clinical trials is available from the NCI Web site.

Related Summaries

Other PDQ summaries containing information related to ovarian epithelial cancer include the following:

  • Genetics of Breast and Ovarian Cancer
  • Ovarian Cancer Prevention
  • Ovarian Cancer Screening
  • Unusual Cancers of Childhood (childhood cancer of the ovarian epithelium)

References:

  1. American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed February 8, 2013.

  2. Yancik R: Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71 (2 Suppl): 517-23, 1993.

  3. Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer 71 (2 Suppl): 573-81, 1993.

  4. Piver MS, Goldberg JM, Tsukada Y, et al.: Characteristics of familial ovarian cancer: a report of the first 1,000 families in the Gilda Radner Familial Ovarian Cancer Registry. Eur J Gynaecol Oncol 17 (3): 169-76, 1996.

  5. Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994.

  6. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.

  7. Steichen-Gersdorf E, Gallion HH, Ford D, et al.: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet 55 (5): 870-5, 1994.

  8. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.

  9. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995.

  10. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.

  11. Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996.

  12. Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998.

  13. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.

  14. Klaren HM, van't Veer LJ, van Leeuwen FE, et al.: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 95 (13): 941-7, 2003.

  15. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.

  16. Burghardt E, Girardi F, Lahousen M, et al.: Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 40 (2): 103-6, 1991.

  17. Omura GA, Brady MF, Homesley HD, et al.: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 9 (7): 1138-50, 1991.

  18. van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME, et al.: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7 (6): 769-73, 1989.

  19. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al.: Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 27 (11): 1367-72, 1991.

  20. Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992.

  21. Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience. Cancer 71 (2 Suppl): 606-14, 1993.

  22. Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990.

  23. Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71 (3): 787-95, 1993.

  24. Young RC, Walton LA, Ellenberg SS, et al.: Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 322 (15): 1021-7, 1990.

  25. Gershenson DM, Silva EG, Mitchell MF, et al.: Transitional cell carcinoma of the ovary: a matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol 168 (4): 1178-85; discussion 1185-7, 1993.

  26. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992.

  27. Högberg T, Kågedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992.

  28. Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996.

  29. Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011.

  30. Safra T, Borgato L, Nicoletto MO, et al.: BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10 (10): 2000-7, 2011.

  31. Hogg R, Friedlander M: Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. J Clin Oncol 22 (7): 1315-27, 2004.

  32. Partridge E, Kreimer AR, Greenlee RT, et al.: Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 113 (4): 775-82, 2009.

  33. van Nagell JR Jr, Miller RW, DeSimone CP, et al.: Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol 118 (6): 1212-21, 2011.

  34. Goff BA, Mandel L, Muntz HG, et al.: Ovarian carcinoma diagnosis. Cancer 89 (10): 2068-75, 2000.

  35. Friedman GD, Skilling JS, Udaltsova NV, et al.: Early symptoms of ovarian cancer: a case-control study without recall bias. Fam Pract 22 (5): 548-53, 2005.

  36. Smith LH, Morris CR, Yasmeen S, et al.: Ovarian cancer: can we make the clinical diagnosis earlier? Cancer 104 (7): 1398-407, 2005.

  37. Goff BA, Mandel LS, Melancon CH, et al.: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 291 (22): 2705-12, 2004.

  38. Goff BA, Mandel LS, Drescher CW, et al.: Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 109 (2): 221-7, 2007.

  39. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006.

  40. Ozols RF, Young RC: Ovarian cancer. Curr Probl Cancer 11 (2): 57-122, 1987 Mar-Apr.

  41. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.

Cellular Classification of Ovarian Epithelial Cancer

The following is a list of ovarian epithelial cancer histologic classifications.

  • Serous cystomas:
    • Serous benign cystadenomas.
    • Serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
    • Serous cystadenocarcinomas.
     
  • Mucinous cystomas:
    • Mucinous benign cystadenomas.
    • Mucinous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
    • Mucinous cystadenocarcinomas.
     
  • Endometrioid tumors (similar to adenocarcinomas in the endometrium):
    • Endometrioid benign cysts.
    • Endometrioid tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
    • Endometrioid adenocarcinomas.
     
  • Clear cell (mesonephroid) tumors:
    • Benign clear cell tumors.
    • Clear cell tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
    • Clear cell cystadenocarcinomas.
     
  • Unclassified tumors that cannot be allotted to one of the above groups.
  • No histology.
  • Other malignant tumors (malignant tumors other than those of the common epithelial types are not to be included with the categories listed above).

(Refer to the PDQ summary on Ovarian Low Malignant Potential Tumor Treatment for more information.)

Stage Information for Ovarian Epithelial Cancer

In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires surgery. The role of surgery in patients with stage IV disease and extra-abdominal disease is yet to be established. If disease appears to be limited to the ovaries or pelvis, it is essential at laparotomy to examine and biopsy or to obtain cytologic brushings of the diaphragm, both paracolic gutters, the pelvic peritoneum, para-aortic and pelvic nodes, and infracolic omentum, and to obtain peritoneal washings.[1]

The serum CA 125 level is valuable in the follow-up and restaging of patients who have elevated CA 125 levels at the time of diagnosis.[2][3][4] While an elevated CA 125 level indicates a high probability of epithelial ovarian cancer, a negative CA 125 level cannot be used to exclude the presence of residual disease.[5] CA 125 levels can also be elevated in other malignancies and benign gynecologic problems such as endometriosis, and CA 125 levels should be used with a histologic diagnosis of epithelial ovarian cancer.[6][7]

Definitions: FIGO

The Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define ovarian epithelial cancer; the FIGO system is most commonly used.[8][9]

Table 1. Carcinoma of the Ovarya

Stage

 

I

Growth limited to the ovaries.

Ia

Growth limited to one ovary; no ascites present containing malignant cells. No tumor on the external surface; capsule intact.

Ib

Growth limited to both ovaries; no ascites present containing malignant cells. No tumor on the external surfaces; capsules intact.

Icb 

Tumor either stage Ia or Ib, but with tumor on surface of one or both ovaries, or with capsule ruptured, or with ascites present containing malignant cells, or with positive peritoneal washings.

II

Growth involving one or both ovaries with pelvic extension.

IIa

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

IIb

Extension to other pelvic tissues.

IIcb 

Tumor either stage IIa or IIb, but with tumor on surface of one or both ovaries, or with capsule(s) ruptured, or with ascites present containing malignant cells, or with positive peritoneal washings.

III

Tumor involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis and/or positive regional lymph nodes. Superficial liver metastases equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum.

IIIa

Tumor grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologic proven extension to small bowel or mesentery.

IIIb

Tumor of one or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative.

IIIc

Peritoneal metastasis beyond the pelvis >2 cm in diameter and/or positive regional lymph nodes.

IV

Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.

aAdapted from FIGO Committee on Gynecologic Oncology.[8]

bIn order to evaluate the impact on prognosis of the different criteria for allotting cases to stage Ic or IIc, it would be of value to know if rupture of the capsule was spontaneous, or caused by the surgeon; and if the source of malignant cells detected was peritoneal washings, or ascites.

References:

  1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.

  2. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992.

  3. Högberg T, Kågedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992.

  4. Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996.

  5. Makar AP, Kristensen GB, Børmer OP, et al.: CA 125 measured before second-look laparotomy is an independent prognostic factor for survival in patients with epithelial ovarian cancer. Gynecol Oncol 45 (3): 323-8, 1992.

  6. Berek JS, Knapp RC, Malkasian GD, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstet Gynecol 67 (5): 685-9, 1986.

  7. Atack DB, Nisker JA, Allen HH, et al.: CA 125 surveillance and second-look laparotomy in ovarian carcinoma. Am J Obstet Gynecol 154 (2): 287-9, 1986.

  8. FIGO Committee on Gynecologic Oncology.: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 105 (1): 3-4, 2009.

  9. Ovary and primary peritoneal carcinoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 419-28.

Stage I and Stage II Ovarian Epithelial Cancer Treatment

Treatment options:  

  1. If the tumor is well differentiated or moderately well differentiated, surgery alone may be adequate treatment for patients with stage IA and IB disease. Surgery should include hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Additionally, the undersurface of the diaphragm should be visualized and biopsied; pelvic and abdominal peritoneal biopsies and pelvic and para-aortic lymph node biopsies are required and peritoneal washings should be obtained routinely.[1] In selected patients who desire childbearing and have grade I tumors, unilateral salpingo-oophorectomy may be associated with a low risk of recurrence.[2]
  2. If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and death from ovarian cancer is as much as 30%.[3][4][5][6] Clinical trials evaluating the following treatment approaches have been performed:
    • Intraperitoneal P-32 or radiation therapy.[1][7][8]
    • Systemic chemotherapy based on platinums alone or in combination with alkylating agents.[1][7][9][10][11]
    • Systemic chemotherapy based on platinums with paclitaxel.
     

In two large European trials, European Organization for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm (EORTC-ACTION) and International Collaborative Ovarian Neoplasm (MRC-ICON1 [NCT00002477]), patients with stage IA and stage IB (grades II and III), all stage IC and stage II, and all stage I and stage IIA clear cell carcinoma were randomly assigned to adjuvant chemotherapy or observation. Data were reported individually and in pooled form.[12][13][14]

The EORTC-ACTION trial required at least four cycles of carboplatin or cisplatin-based chemotherapy as treatment. Although surgical staging criteria were monitored, inadequate staging was not an exclusion criterion. Recurrence-free survival (RFS) was improved in the adjuvant chemotherapy arm (hazard ratio [HR], 0.63; P = .02), but overall survival (OS) was not affected (HR, 0.69; 95% confidence interval [CI], 0.44–1.08; P = .10). OS was improved by chemotherapy in the subset of patients with inadequate surgical staging.

The MRC-ICON1 trial randomly assigned patients to six cycles of single-agent carboplatin or cisplatin or platinum-based chemotherapy (usually cyclophosphamide, doxorubicin, and cisplatin) versus observation and had similar entry criteria to the EORTC-ACTION trial; however, the MRC-ICON1 trial did not monitor whether adequate surgical staging was performed. Both RFS and OS were significantly improved; 5-year survival figures were 79% with adjuvant chemotherapy versus 70% without adjuvant chemotherapy.

The pooled data from both studies indicated significant improvement in RFS (HR, 0.64; 95% CI, 0.50–0.82; P = .001) and OS (HR, 0.67; 95% CI, 0.50–0.90; P = .008). These pooled data provided for an OS at 5 years of 82% with chemotherapy and 74% with observation, with a 95% CI in the difference of 2% to 12%. An accompanying editorial emphasized that the focus of subsequent trials must be to identify patients who do not require additional therapy among the early ovarian cancer subset.[15][Level of evidence: 1iA] Optimal staging is one way to better identify these patients. Except for the most favorable subset (patients with stage IA well-differentiated disease), Gynecologic Oncology Group (GOG) trials, and the evidence above, which is based on double-blinded, randomized controlled trials with total mortality endpoints, support treatment with cisplatin, carboplatin, and paclitaxel (in the United States).

In future trials, the Ovarian Committee of the GOG has opted to include patients with stage II disease in advanced ovarian cancer trials and not to include further study of patients with stage I disease at this time.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I ovarian epithelial cancer and stage II ovarian epithelial cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Young RC, Decker DG, Wharton JT, et al.: Staging laparotomy in early ovarian cancer. JAMA 250 (22): 3072-6, 1983.

  2. Zanetta G, Chiari S, Rota S, et al.: Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 104 (9): 1030-5, 1997.

  3. Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990.

  4. Ahmed FY, Wiltshaw E, A'Hern RP, et al.: Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 14 (11): 2968-75, 1996.

  5. Monga M, Carmichael JA, Shelley WE, et al.: Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecol Oncol 43 (3): 195-7, 1991.

  6. Kolomainen DF, A'Hern R, Coxon FY, et al.: Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 21 (16): 3113-8, 2003.

  7. Vergote IB, Vergote-De Vos LN, Abeler VM, et al.: Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69 (3): 741-9, 1992.

  8. Piver MS, Lele SB, Bakshi S, et al.: Five and ten year estimated survival and disease-free rates after intraperitoneal chromic phosphate; stage I ovarian adenocarcinoma. Am J Clin Oncol 11 (5): 515-9, 1988.

  9. Bolis G, Colombo N, Pecorelli S, et al.: Adjuvant treatment for early epithelial ovarian cancer: results of two randomised clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P). G.I.C.O.G.: Gruppo Interregionale Collaborativo in Ginecologia Oncologica. Ann Oncol 6 (9): 887-93, 1995.

  10. Piver MS, Malfetano J, Baker TR, et al.: Five-year survival for stage IC or stage I grade 3 epithelial ovarian cancer treated with cisplatin-based chemotherapy. Gynecol Oncol 46 (3): 357-60, 1992.

  11. McGuire WP: Early ovarian cancer: treat now, later or never? Ann Oncol 6 (9): 865-6, 1995.

  12. Trimbos JB, Parmar M, Vergote I, et al.: International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95 (2): 105-12, 2003.

  13. Trimbos JB, Vergote I, Bolis G, et al.: Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 95 (2): 113-25, 2003.

  14. Colombo N, Guthrie D, Chiari S, et al.: International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 95 (2): 125-32, 2003.

  15. Young RC: Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 95 (2): 94-5, 2003.

Stage III and Stage IV Ovarian Epithelial Cancer Treatment

Treatment options for patients with all stages of ovarian epithelial cancer have consisted of surgery followed by chemotherapy.

Surgery

Patients diagnosed with stage III and stage IV disease are treated with surgery and chemotherapy; however, the outcome is generally less favorable for patients with stage IV disease. The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage III disease are applied. The options for intraperitoneal (IP) regimens are also less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed at destroying microscopic disease in the peritoneal cavity) in patients with stage IV disease.

Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed. While primary cytoreductive surgery may not correct for biologic characteristics of the tumor, considerable evidence indicates that the volume of disease left at the completion of the primary surgical procedure is related to patient survival.[1] A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.[1][Level of evidence: 3iA]

Results of a retrospective analysis of 349 patients with postoperative residual masses no larger than 1 cm suggested that patients who present at the outset with large-volume disease and achieve small-volume disease by surgical debulking have poorer outcomes than similar patients who present with small-volume disease.[2] Gradual improvement in survival with decreasing residual tumor volume is likely. Although the association may not be causal, retrospective analyses, including a meta-analysis of patients receiving platinum-based chemotherapy, have found cytoreduction to be an independent prognostic variable for survival.[3][4]

A study led by the European Organization for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada (NCIC) Clinical Trials Group (EORTC-55971 [NCT00003636]) between 1998 and 2006 included 670 women with stage IIIC and IV ovarian, tubal, and primary peritoneal cancers.[5] The women were randomly assigned to primary debulking surgery followed by at least six courses of platinum-based chemotherapy or to three courses of neoadjuvant platinum-based chemotherapy followed by so-called interval debulking surgery, and at least three more courses of platinum-based chemotherapy. Methods included efforts to ensure accuracy of diagnosis (vis-à-vis peritoneal carcinomatosis of gastrointestinal origin) and stratification by largest preoperative tumor size (excluding ovaries) (<5 cm, >5 cm–10 cm, >10 cm–20 cm, or >20 cm). Other stratification factors were for institution, method of biopsy (i.e., image-guided, laparoscopy, laparotomy, or fine-needle aspiration), and tumor stage (i.e., stages IIIC or IV). The primary endpoint of the study was overall survival (OS), with primary debulking surgery considered the standard.

Median OS for the primary debulking surgery was 29 months, compared with 30 months for patients assigned to neoadjuvant chemotherapy. The hazard ratio (HR) for death in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84–1.13; P = .01 for noninferiority).[5][Level of evidence: 1iiA] Perioperative and postoperative morbidity and mortality were higher in the primary-surgery group (7.4% severe hemorrhage and 2.5% deaths, contrasting with 4.1% severe hemorrhage and 0.7% deaths in the neoadjuvant group). The strongest independent predictor of prolonged survival was the absence of residual tumor after surgery. The subset of patients achieving optimal cytoreduction (≤1 cm residuum) whether after primary debulking surgery or after neoadjuvant chemotherapy followed by interval debulking surgery had the best median OS.

For the past 3 decades, the Gynecologic Oncology Group (GOG) has conducted separate trials for women whose disease has been optimally cytoreduced (most recently defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum). The extent of residual disease following the initial surgery is a determinant of outcome in most series [1][2][3][4] and has been used in the design of clinical trials, particularly by the GOG.

On the basis of these findings, the standard treatment approaches are subdivided into the following:

  1. Treatment options for patients with optimally cytoreduced stage III disease.
  2. Treatment options for patients with suboptimally cytoreduced stage III and stage IV disease.

Treatment Options for Patients With Optimally Cytoreduced Stage III Disease

IP chemotherapy

The pharmacologic basis for the delivery of anticancer drugs by the IP route was established in the late 1970s and early 1980s. When several drugs were studied, mostly in the setting of minimal residual disease at reassessment after patients had received their initial chemotherapy, cisplatin alone and in combination received the most attention. Favorable outcomes from IP cisplatin were most often seen when tumors had shown responsiveness to platinums and with small-volume tumors (usually defined as tumors <1 cm).[6] In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the intravenous route. IP cisplatin was the common denominator of these randomized trials.

The use of IP cisplatin as part of the initial up-front approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (SWOG-8501, GOG-0114, and GOG-0172).[7][8][9] These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen. In the three studies, superior progression-free survival (PFS) and OS favoring the IP arm was documented. Specifically, the most recent study, GOG-0172, resulted in a median survival rate of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03).[9][Level of evidence:1iiA] Toxic effects were greater in the IP arm, contributed to in large part by the cisplatin dose per cycle (100 mg/m2) and by sensory neuropathy from the additional IP as well as from the IV administration of paclitaxel. The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects and catheter-related problems.[10]

Notwithstanding these problems, IP therapy for patients with optimally debulked ovarian cancer is receiving wider adoption, and efforts are under way by the GOG to examine some modifications of the IP regimen used in GOG-0172 to improve its tolerability (e.g., to reduce by ≥25% the total 3-hour amount of cisplatin given; a shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration). A Cochrane-sponsored meta-analysis of all randomized IP versus IV trials shows an HR of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms.[11] In another meta-analysis of seven IP versus IV randomized trials that were conducted by Cancer Care of Ontario, the relative ratio (RR) of progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% CI, 0.85–0.98) and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.81–0.95).[10]

Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease

Cytoreductive surgery

The value of interval cytoreductive surgery has been the subject of two large phase III trials. In the first study, performed by the EORTC, patients subjected to debulking after four cycles of cyclophosphamide and cisplatin (with additional cycles given later) had an improved survival rate compared with patients who completed six cycles of this chemotherapy without surgery.[12][Level of evidence: 1iiB] The GOG-0162 trial was designed to answer a very similar question but used the then-standard paclitaxel-plus-cisplatin regimen as the chemotherapy.[13] This trial did not demonstrate any advantage from the use of interval cytoreductive surgery. The divergence of results may be caused by the efficacy of the chemotherapy obscuring any effects of interval cytoreduction, the wider use of maximal surgical effort at the time of diagnosis by U.S. gynecologic oncologists, or unknown factors. Although many patients with stage IV disease also undergo cytoreductive surgery at diagnosis, whether this improves survival has not been established.

Systemic chemotherapy

First-line treatment of ovarian cancer is cisplatin, given IV, or its second-generation analog, carboplatin, given either alone or in combination with other drugs. Clinical response rates from these drugs regularly exceed 60%, and median time-to-recurrence usually exceeds 1 year in this subset of suboptimally debulked women. Trials by various cooperative groups in the subsequent 2 decades addressed issues of optimal dose-intensity [14][15][16] for both cisplatin and carboplatin,[17] schedule,[18] and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.[19] With the introduction of the taxane paclitaxel, two trials confirmed the superiority of cisplatin combined with paclitaxel to the previous standard of cisplatin plus cyclophosphamide; however, two trials that compared the agent with either cisplatin or carboplatin as a single agent failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (see Table 2).

Table 2. Paclitaxel/Platinum Combinations Versus Comparator Arms in Trials

Trial

Treatment Regimens

No. of Patients

% Early Crossover

Progression-free Survival (mo)

Overall Survival (mo)

GOG-132

Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)

201

22%

14.2

26.6

Cisplatin (100 mg/m2)

200

40%

16.4

30.2

Paclitaxel (200 mg/m2, 24 h)

213

23%

11.2a 

26

MRC-ICON3[20]

Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6

478

23%

17.3

36.1

Carboplatin AUC 6

943

25%

16.1

35.4

Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6

232

23%

17

40

Cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) and cisplatin (50 mg/m2)

421

20%

17

40

GOG-111[21]

Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)

184

None

18

38

Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)

202

None

13a 

24a 

EORTC-55931[22]

Paclitaxel (175 mg/m2, 3 h) and cisplatin (75 mg/m2)

162

None

15.5

35.6

Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)

161

4%

11.5a 

25.8a 

AUC = area under the curve.

aStatistically inferior result (P < .001–< .05).

Nevertheless, for patients with ovarian cancer, the combination of cisplatin or carboplatin and paclitaxel has been used as the initial treatment (defined as induction chemotherapy) for several reasons:

  • GOG-132 was regarded by many as showing that sequential treatment with cisplatin and paclitaxel was equivalent to the combination because many patients crossed over before progression; moreover, the cisplatin only arm was more toxic because it utilized a 100 mg/m2 dose.
  • The Medical Research Council (MRC-ICON3) study, while having fewer early crossovers, could be interpreted similarly in regard to the impact on survival of sequential treatment.
  • Data from MRC-ICON4 have shown a survival advantage for patients treated with the combination treatment regimen versus those treated with single-agent carboplatin upon recurrence (see Table 3).
  • In past trials, single-agent platinums were not superior to platinum combined with an alkylating agent; therefore, the explanation of a detrimental effect of cyclophosphamide is unlikely.

Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:

  • Noninferiority for carboplatin plus paclitaxel versus cisplatin plus paclitaxel.[21][22][23]
  • Noninferiority for carboplatin plus paclitaxel versus carboplatin plus docetaxel.[24]
  • No advantage but increased toxic effects by adding epirubicin to the carboplatin plus paclitaxel doublet.[25]
  • Noninferiority for carboplatin plus paclitaxel versus sequential carboplatin-containing doublets with either gemcitabine or topotecan; or, triplets with the addition of gemcitabine or pegylated liposomal doxorubicin to the reference doublet as shown below:[26][27]
    • From February 2001 to September 2004, the Gynecologic Cancer InterGroup trial GOG-0182 randomly assigned 4,312 women with stage III or stage IV epithelial ovarian or primary peritoneal cancer to four different experimental arms and to a reference treatment consisting of carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 3 weeks for eight cycles.[26] Stratification factors were residual-disease status and the intention to perform interval debulking surgery. Lethal events attributable to treatment occurred in less than 1% of patients without clustering to any one regimen. None of the experimental regimens were inferior. With a median duration of follow-up of 3.7 years, the adjusted relative risk of death ranged from 0.952 to 1.114, with the control arm achieving a PFS of 16.0 months and a median OS of 44.1 months.

      In this large study consisting of 84% to 87% of patients with the Féderation Internationale de Gynécologie et d’Obstétrique stage III disease, as expected, the extent of cytoreduction was an important prognostic factor in OS. Results of PFS in patients with residuum greater than 1cm, less than or equal to 1 cm, or microscopic were 13, 16, and 29 months, respectively; whereas for OS, the results were 33, 40, and 68 months, respectively.[26]

     

Consolidation and/or maintenance therapy

Trials of consolidation and/or maintenance therapy have been carried out with drugs that contribute to the treatment of recurrent ovarian cancer. Presently, not one of the treatments given after the initial platinum/paclitaxel induction has been shown to improve survival; these treatments include the following:

  • IP cisplatin (four cycles).[28]
  • Yttrium-labeled radioimmunoconjugate plus IP chemotherapy.[29]
  • IV topotecan (four cycles).[30]
  • Oregovomab vaccination (randomized trial vs. placebo).[31]
  • High-dose chemotherapy with hematopoietic support.[32]
  • Monthly paclitaxel (12 cycles).[33][34]
  • Olaparib, an oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (phase II trial).[35]

A GOG-178 study of 277 patients compared three doses versus twelve doses of monthly paclitaxel given every 4 weeks following a clinically defined complete response at the time of completion of platinum/paclitaxel induction. However, the study was stopped early because of a very significant difference in PFS (28 months vs. 21 months).[33][Level of evidence: 1iiDiii] Subsequent updates of this data have raised the possibility that a subset of patients with low CA 125 levels might show a survival benefit.[36] A trial to confirm the value of maintenance with taxanes versus observation is being conducted by the GOG.

A smaller Italian study entered 200 patients over 7 years who were randomly assigned to either 12 similar courses of monthly paclitaxel or observation; patients were in clinical complete response (n = 95) or pathologic complete response (n = 105) after induction therapy at the time of their random assignment.[34] Sensory neuropathy was the most prominent toxicity and was grade 2 in 21.3% of the patients and grade 3 in 6.7% of the patients. The median PFS for the maintenance paclitaxel arm was 34 months (95% CI, 20–43 months) and 30 months (95% CI, 17–53 months) for the observation arm. Neither PFS nor OS differences were significant.[34]

An accompanying editorial points out the weaknesses of both studies in order to draw conclusions (both stopped early and were noninformative for survival endpoint).[37] Also, although both studies addressed the issue of maintenance paclitaxel administered monthly, the patient populations differed. This was reflected by the considerably better outcome in both arms of the Italian study. Taken together, paclitaxel maintenance is of unproven value and requires validation by the ongoing and larger GOG-178 study cited above.

Bevacizumab

Two phase III trials (GOG-0218 [NCT00262847] and ICON 7 [NCT00483782]) have evaluated the role of bevacizumab in first-line therapy for ovarian, fallopian tube, and primary peritoneal cancers following surgical cytoreduction.[38][39] Both trials showed a modest improvement in PFS when bevacizumab was added to initial chemotherapy and continued every 3 weeks for 16 and 12 additional cycles, respectively, as a maintenance phase.

GOG-0218 was a double blind, randomized, controlled trial that included 1,873 women with stage III or IV disease, all of whom received chemotherapy—carboplatin (AUC 6) and paclitaxel (175 mg/m2 for six cycles).[38] Participants were randomly assigned to receive:

  • Chemotherapy plus placebo (cycles 2 through 22) (i.e., control).
  • Chemotherapy plus bevacizumab (15 mg/kg cycles 2 through 6), followed by placebo (cycles 7 through 22) (i.e., bevacizumab initiation).
  • Chemotherapy plus bevacizumab (15mg/kg cycles 2 through 22) (i.e., bevacizumab throughout).

The women were enrolled with a primary endpoint of PFS; 40% of the patients had suboptimally resected stage III disease, and 26% had stage IV disease. There was no difference in PFS between the control group and the bevacizumab-initiation group. There was a statistically significant increase in PFS in the bevacizumab-throughout group when compared with the control group (14.1 vs. 10.3 months), with a HR of progression or death of 0.717 in the bevacizumab-throughout group (95% CI, 0.625–0.824; P < .001). Median OS was 39.3, 38.7, and 39.7 months for the control group, bevacizumab-initiation group, and the bevacizumab-throughout group, respectively. Quality of life was not different between the three groups. Hypertension grade 2 or greater was more common with bevacizumab than with the placebo. There were more treatment-related deaths in the bevacizumab-throughout arm (10 of 607, 2.3%) than in the control arm (6 of 601, 1.0%).[38][Level of evidence: 1iDiii]

ICON 7 randomly assigned 1,528 women after initial surgery to chemotherapy—carboplatin (AUC 5 or 6) plus paclitaxel (175 mg/m2 for six cycles)—or to chemotherapy plus bevacizumab (7.5 mg/kg for six cycles), followed by bevacizumab alone for an additional 12 cycles. The women were randomly assigned, and PFS was the main outcome measure; 9% of patients had early-stage, high-grade tumors, and 70% had stage IIIC or IV disease. Twenty-six percent had more than 1 cm of residual tumor prior to initiating chemotherapy. Median PFS was 17.3 months in the control group and 19 months in the bevacizumab group. HR for progression or death in the bevacizumab group was 0.81 (95% CI, 0.70–0.94; P= .004). Bevacizumab was associated with an increase in bleeding, hypertension (grade 2 or higher), thromboembolic events (grade 3 or higher), and gastrointestinal perforations. Grade 3 or greater adverse events were more common in the bevacizumab group. Quality of life was not different between the two groups.[39][Level of evidence: 1iiDiii]

A third trial, OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases [NCT00434642]), assessed the role of bevacizumab in the treatment of platinum-sensitive recurrences (see Table 3 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine + carboplatin) with or without bevacizumab for recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer, 242 patients were randomly assigned per arm.[40] Median PFS for patients receiving bevacizumab was 12.4 months versus 8.4 months for those receiving a placebo. The effect of bevacizumab on HR to progression in patients assigned to the bevacizumab arm compared with placebo was 0.484 (95% CI, 0.388–0.605; P <.0001). Objective responses to chemotherapy were increased when combined with bevacizumab (78.5% vs. 57.4%; P < .0001).

In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance. A subsequent analysis will appear when additional survival data become mature; however, at the time of publication, differences in median survival were not apparent, and crossover from a placebo to bevacizumab had occurred in 31% of the patients. Bevacizumab-associated toxicities such as hypertension and proteinuria were more prominent than in the first-line trials, but feared safety issues, such as gastrointestinal perforations, did not occur during the study. Discontinuing treatment because of adverse events was more common with bevacizumab (n = 55 vs. n = 12 for placebo) but fewer patients discontinued treatment because of disease progression (n = 104 vs. n = 160 for placebo).[40][Level of evidence: 1iiDiii]

These three studies confirm the effect of improving PFS when bevacizumab is added to chemotherapy for ovarian cancer. In the OCEANS trial, the HR for progression was even more prominent than in the first-line trials, and a significant effect was seen when the bevacizumab and chemotherapy combination was extended beyond six cycles until progression. Without additional data, a statement about how bevacizumab should be used in ovarian cancer treatment is not possible because of the uncertain impact on OS, lack of clear delineation of who derives the greatest benefit, and prominent, associated toxicities.[41]

At this time, the evidence does not support the use of bevacizumab as front-line therapy, because the gain in PFS comes with increased toxicity without improvement in OS or quality of life.

Treatment Options Under Clinical Evaluation

  • Additional IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy.

Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III ovarian epithelial cancer and stage IV ovarian epithelial cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.

  2. Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992.

  3. Hoskins WJ, McGuire WP, Brady MF, et al.: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170 (4): 974-9; discussion 979-80, 1994.

  4. Bristow RE, Tomacruz RS, Armstrong DK, et al.: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 20 (5): 1248-59, 2002.

  5. Vergote I, Tropé CG, Amant F, et al.: Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363 (10): 943-53, 2010.

  6. Howell SB, Zimm S, Markman M, et al.: Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy. J Clin Oncol 5 (10): 1607-12, 1987.

  7. Alberts DS, Liu PY, Hannigan EV, et al.: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335 (26): 1950-5, 1996.

  8. Markman M, Bundy BN, Alberts DS, et al.: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19 (4): 1001-7, 2001.

  9. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006.

  10. Elit L, Oliver TK, Covens A, et al.: Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses. Cancer 109 (4): 692-702, 2007.

  11. Jaaback K, Johnson N: Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev (1): CD005340, 2006.

  12. van der Burg ME, van Lent M, Buyse M, et al.: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 332 (10): 629-34, 1995.

  13. Goodman HM, Harlow BL, Sheets EE, et al.: The role of cytoreductive surgery in the management of stage IV epithelial ovarian carcinoma. Gynecol Oncol 46 (3): 367-71, 1992.

  14. Markman M, Reichman B, Hakes T, et al.: Impact on survival of surgically defined favorable responses to salvage intraperitoneal chemotherapy in small-volume residual ovarian cancer. J Clin Oncol 10 (9): 1479-84, 1992.

  15. Markman M: Intraperitoneal chemotherapy. Semin Oncol 18 (3): 248-54, 1991.

  16. Levin L, Simon R, Hryniuk W: Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis. J Natl Cancer Inst 85 (21): 1732-42, 1993.

  17. McGuire WP, Hoskins WJ, Brady MF, et al.: Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 13 (7): 1589-99, 1995.

  18. Bolis G, Favalli G, Danese S, et al.: Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 15 (5): 1938-44, 1997.

  19. Alberts DS, Green S, Hannigan EV, et al.: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10 (5): 706-17, 1992.

  20. The International Collaborative Ovarian Neoplasm Group.: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 360 (9332): 505-15, 2002.

  21. du Bois A, Lück HJ, Meier W, et al.: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95 (17): 1320-9, 2003.

  22. Neijt JP, Engelholm SA, Tuxen MK, et al.: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18 (17): 3084-92, 2000.

  23. Ozols RF, Bundy BN, Greer BE, et al.: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21 (17): 3194-200, 2003.

  24. Vasey PA, Jayson GC, Gordon A, et al.: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96 (22): 1682-91, 2004.

  25. Kristensen GB, Vergote I, Stuart G, et al.: First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin. Int J Gynecol Cancer 13 (Suppl 2): 172-7, 2003 Nov-Dec.

  26. Bookman MA, Brady MF, McGuire WP, et al.: Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol 27 (9): 1419-25, 2009.

  27. Hoskins PJ: Triple cytotoxic therapy for advanced ovarian cancer: a failed application, not a failed strategy. J Clin Oncol 27 (9): 1355-8, 2009.

  28. Piccart MJ, Bertelsen K, James K, et al.: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 92 (9): 699-708, 2000.

  29. Verheijen RH, Massuger LF, Benigno BB, et al.: Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 24 (4): 571-8, 2006.

  30. Pfisterer J, Weber B, Reuss A, et al.: Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 98 (15): 1036-45, 2006.

  31. Berek JS, Taylor PT, Gordon A, et al.: Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. J Clin Oncol 22 (17): 3507-16, 2004.

  32. Stadtmauer EA, O'Neill A, Goldstein LJ, et al.: Phase III randomized trial of high-dose chemotherapy (HDC) and stem cell support (SCT) shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphamide, methotrexate and 5-fluorourcil (CMF) for women with metastatic breast cancer who are responding to conventional induction chemotherapy: the 'Philadelphia' Intergroup study (PBT-1). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A1, 1a, 1999.

  33. Markman M, Liu PY, Wilczynski S, et al.: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21 (13): 2460-5, 2003.

  34. Pecorelli S, Favalli G, Gadducci A, et al.: Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1. J Clin Oncol 27 (28): 4642-8, 2009.

  35. Ledermann J, Harter P, Gourley C, et al.: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366 (15): 1382-92, 2012.

  36. Liu PY, Alberts DS, Monk BJ, et al.: An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. J Clin Oncol 25 (24): 3615-20, 2007.

  37. McGuire WP: Maintenance therapy for ovarian cancer: of Helsinki and Hippocrates. J Clin Oncol 27 (28): 4633-4, 2009.

  38. Burger RA, Brady MF, Bookman MA, et al.: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365 (26): 2473-83, 2011.

  39. Perren TJ, Swart AM, Pfisterer J, et al.: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365 (26): 2484-96, 2011.

  40. Aghajanian C, Blank SV, Goff BA, et al.: OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 30 (17): 2039-45, 2012.

  41. Muggia F: Bevacizumab in ovarian cancer: unanswered questions. Drugs 72 (7): 931-6, 2012.

Recurrent or Persistent Ovarian Epithelial Cancer Treatment

Overall, approximately 80% of patients diagnosed with ovarian epithelial cancer will relapse after first-line platinum-based and taxane-based chemotherapy and may benefit from subsequent therapies. Early detection of persistent disease by second-look laparotomies after completing first-line treatment is no longer practiced; when the outcomes in the 50% of institutions practicing such procedures were informally compared with the outcomes in those institutions not using such procedures, additional lack of support for them grew, as was found in the case for patients entered in GOG-0158.[1] However, the practice of close follow-up of patients completing treatment by serial CA 125s at intervals of 1 to 3 months was nearly universally adopted. In patients who are in clinical complete remission, increases in CA 125 from their initial treatment represent the most common method to detect disease that will eventually relapse clinically.

A trial by the Medical Research Council and European Organization for Research and Treatment of Cancer (MRC-OV05, which is now closed) examined the consequences of early institution of treatment for recurrence versus treatment delayed until clinical symptoms appeared.[2] Patients in clinical complete remission after platinum-based chemotherapy were registered and followed with CA 125s only and clinical visits. Upon detection of a twofold elevation over the normal range, patients were randomly assigned to disclosure of the result (and early treatment for recurrence) versus continued blinding and treatment upon development of signs and symptoms indicative of clinical relapse. The number of randomly assigned patients was to exceed 500 in order to yield a superior survival outcome at 2 years with early institution of therapy; this required 1,400 registrations, which were accrued between May 1996 and August 2005. Among 1,442 registrants, 29% continued to show no evidence of relapse, 19% relapsed without evidence of CA 125 doubling beyond normal or at the same time, and another 4% died prior to becoming eligible for random assignment. Registrants had stage III and stage IV disease in 67% of the cases, whereas these stages represented 80% of the randomly assigned patients. The median survival of all patients registered was 70.8 months.

Median survival for patients randomly assigned to early treatment (n = 265) was 25.7 months compared with 27.1 months for those patients in the delayed-treatment group (n = 264) (HR, 0.98; 95% CI, 0.8–1.2). The median delay in instituting second-line chemotherapy was 4.8 months, and the median delay in instituting third-line chemotherapy was 4.6 months. Treatments for second-line chemotherapy were comparable among the two groups (mostly platinum- and taxane-based), whereas third-line treatments were less often applied to the delayed-treatment group. The study concluded that there was no benefit in the detection of early presence of disease by CA 125; this is consistent with the failure of second-look surgeries to provide improved outcomes after early detection of persistent disease. Monitoring CA 125 levels in follow-up may play a role in identifying appropriate candidates for secondary cytoreduction, although this strategy awaits confirmation with a randomized trial.

Local Modalities: Surgery and Radiation Therapy

Cytoreduction is often employed,[3] but such intervention only now is being studied in the setting of a randomized clinical trial (GOG-0213). The role of radiation therapy in patients with recurrent ovarian cancer has not been defined.

Systemic treatment options for patients with recurrent disease are subdivided as follows:

  1. Platinum-sensitive recurrence: for patients whose disease recurs more than 6 months after cessation of the induction (usually retreated with a platinum [cisplatin or carboplatin] and referred to as platinum sensitive).
  2. Platinum-refractory or platinum-resistant recurrence: for patients who progress prior to cessation of induction therapy (platinum refractory) or within 6 months after cessation (platinum resistant); in these patients, platinums are generally deemed toxic and not sufficiently useful to be part of the treatment plan.

Platinum-Sensitive Recurrence

Table 3. Regimens Used in First Relapse

Eligibility (mo)

Regimen

Patient Number

Comparator

Comments on Outcome (mo)

Most Commonly Used  

Platinum sensitive (>6)

Cisplatin or carboplatin + paclitaxel

802

Single or nontaxane + platinums

PFS 11 vs. 9; OS 24 vs. 19 [5]

Platinum sensitive (>6)

Carboplatin + gemcitabine

356

Carboplatin

PFS 8.6 vs. 5.8; OS 18 vs. 17 [6]

Platinum sensitive (> 6)

Carboplatin + pegylated liposomal doxorubicin

976

Carboplatin + paclitaxel

PFS 11.3 vs 9.4; OS not reported [7]

 

Other Regimens  

Platinum sensitive (>6)

Carboplatin + epirubicin

190

Carboplatin

Powered for response differences; OS 17 vs. 15 [5]

Platinum sensitive (≥12)

Cisplatin + doxorubicin + cyclophosphamide

97

Paclitaxel

PFS 15.7 vs. 9; OS 34.7 vs. 25.8 [6]

Platinum sensitive + resistant

PLD + trabectedina 

672

PLD

PFS 7.3 vs. 5.8; OS 20.5 vs. 19.4b 

OS = overall survival; PFS = progression-free survival; PLD = pegylated liposomal doxorubicin.

aTrabectedin has been approved for use in treating recurrent ovarian cancer in Europe and Canada.

bOS data were not mature at the time the manuscript was published.[4]

Carboplatin was approved in 1987 for the treatment of patients with ovarian cancer whose disease recurred after treatment with cisplatin, based on improved survival with etoposide or 5-fluorouracil.[8] In a randomized, phase II trial of paclitaxel, a currently used second-line drug, the cisplatin-containing combination of cisplatin plus doxorubicin plus cyclophosphamide (CAP) yielded a superior survival outcome. This, and subsequent studies (see Table 3), have reinforced using carboplatin as the treatment core for patients with platinum-sensitive recurrences. Cisplatin is occasionally used, particularly in combination with other drugs, because of its lesser myelosuppression, but this advantage over carboplatin is counterbalanced by its greater intolerance. Oxaliplatin, initially introduced with the hope that it would overcome platinum resistance, has activity mostly in platinum-sensitive patients [9] but has not been compared with carboplatin alone or in combinations.

With all platinums, outcome is generally better the longer the initial interval without recurrence from the initial platinum-containing regimens.[10] Therefore, on occasion, patients with platinum-sensitive recurrences relapsing within 1 year have been included in trials of nonplatinum drugs. In one such trial, comparing the pegylated liposomal doxorubicin (PLD) to topotecan, the subset of patients who were platinum sensitive had better outcomes with either drug (and in particular with PLD) relative to the platinum-resistant cohort.[11]

Several randomized trials have addressed whether the use of a platinum in combination with other chemotherapy agents is superior to single agents (see Table 3). In an analysis of data examining jointly the results of three trials performed by the Medical Research Council/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and ICON investigators (known as ICON-4), a platinum-plus-paclitaxel combination yielded a superior outcome, in terms of response rates, progression-free survival (PFS), and overall survival (OS), compared with carboplatin as a single agent or other platinum-containing combinations as controls. Platinum plus paclitaxel was compared with several control regimens, although 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (HR, 0.76; 95% CI, 0.66–0.89; P = .004) and OS (HR, 0.82; 95% CI, 0.69–0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.[5]; [12][Level of evidence: 1iiA] The AGO had previously compared the combination of epirubicin plus carboplatin to carboplatin alone and had not found significant differences in outcome.

Another trial by European and Canadian groups compared gemcitabine plus carboplatin to carboplatin. The PFS of 8.6 months with the combination was significantly superior to 5.8 months for the carboplatin alone (HR, 0.72; 95% CI, 0.58–0.90; P = .003). The study was not powered to detect significant differences in OS, and the median survival for both arms was 18 months (HR, 0.96; CI, 0.75–1.23; P = .73).[7]

Carboplatin plus paclitaxel has been considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurological toxic effects. The GOG-0213 trial is comparing this regimen to the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.

In a phase III trial, carboplatin plus PLD (CD) was compared to carboplatin plus paclitaxel (CP) in patients with platinum-sensitive recurrence (>6 months). The primary endpoint was PFS with a median PFS for the CD arm of 11.3 months versus 9.4 months for the CP arm (HR, 0.823; 95% CI, 0.72–0.94; P = .005).[13][Level of evidence: 1iiDiii] The CP arm was associated with increased severe neutropenia, alopecia, neuropathy, and allergic reaction; the CD arm was associated with increased severe thrombocytopenia, nausea, and hand-foot syndrome. Although OS data have not been reported, given its toxicity profile and noninferiority to the standard regimen, CD is an important option for patients with platinum-sensitive recurrence.

Platinum-Refractory or Platinum-Resistant Recurrence

Clinical recurrences that take place within 6 months of completion of a platinum-containing regimen are considered platinum-refractory or platinum-resistant recurrences. Anthracyclines (particularly when formulated as PLD), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences based on activity and their favorable therapeutic indices relative to agents listed in Table 4. The long list underscores the marginal benefit, if any, generally conveyed by these agents. Patients with platinum-resistant disease should be encouraged to enter clinical trials.

Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[14][15][16][17][18] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable to those achieved with paclitaxel.[19] Topotecan was compared with PLD in a randomized trial of 474 patients and demonstrated similar response rates, PFS, and OS at the time of the initial report, which was contributed primarily by the platinum-resistant subsets.[20]

Drugs used to treat platinum-refractory or platinum-resistant recurrence:

  1. Topotecan. In phase II studies, topotecan administered intravenously on days 1 to 5 of a 21-day cycle yielded objective response rates ranging from 13% to 16.3% and other outcomes that were equivalent or superior to paclitaxel.[19][21][22][23] Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and asthenia. A number of schedules and oral formulations are under evaluation. (Refer to the PDQ summary on Nausea and Vomiting for more information.)

    The combination of weekly topotecan and biweekly bevacizumab was evaluated in a phase II study that showed an objective response rate of 25% (all partial responses) in a platinum-resistant patient population.[24] The most common grade 3 and grade 4 toxicities were hypertension, neutropenia, and gastrointestinal (GI) toxicity, though no bowel perforations occurred.

  2. PLD. A phase II study of encapsulated doxorubicin given IV once every 21 to 28 days demonstrated one complete response and eight partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (response rate, 25.7%).[25] In general, liposomal doxorubicin has few acute side effects other than hypersensitivity. The most frequent toxic effects are usually observed after the first cycle and are more pronounced following dose rates exceeding 10 mg/m2 per week and include stomatitis and hand-foot syndrome. Neutropenia and nausea are minimal, and alopecia rarely occurs.[25]

    Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.[20] Response rates (19.7% vs. 17.0%; P = .390), PFS (16.1 wk vs. 17.0 wk; P = .095), and OS (60 wk vs. 56.7 wk; P = .341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.[20][Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.[11]

  3. Docetaxel. This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.[26]
  4. Gemcitabine. Several phase II trials of gemcitabine as a single agent administered IV on days 1, 8, and 15 of a 28-day cycle have been reported. The response rate ranges from 13% to 19% in evaluable patients. Responses have been observed in patients whose disease is platinum refractory and/or paclitaxel refractory as well as in patients with bulky disease. Leukopenia, anemia, and thrombocytopenia are the most common toxic effects. Many patients report transient flu-like symptoms and a rash following drug administration. Other toxic effects, including nausea, are usually mild.[27][28][29] (Refer to the anemia section in the PDQ summary on Fatigue and refer to the PDQ summary on Nausea and Vomiting for more information.)

    A randomized trial of gemcitabine versus PLD showed noninferiority and no advantage in therapeutic index of one drug over the other.[30]

  5. Paclitaxel. Patients generally received paclitaxel in front-line induction regimens. Retreatment with paclitaxel, particularly in weekly schedules, indicates an activity comparable to those of the preceding drugs. If there is residual neuropathy upon recurrence, this may shift the choice of treatment towards other agents.

    In a phase III study, 235 patients who did not respond to initial treatment with a platinum-based regimen but who had not previously received paclitaxel or topotecan, were randomly assigned to receive either topotecan as a 30-minute infusion daily for 5 days every 21 days or paclitaxel as a 3-hour infusion every 21 days.[19] The overall objective response rate was 20.5% for those patients who were randomly assigned to treatment with topotecan and 13.2% for those patients who were randomly assigned to treatment with paclitaxel (P = .138). Both groups experienced myelosuppression and GI toxic effects. Nausea and vomiting, fatigue, and infection were observed more commonly following treatment with topotecan, whereas alopecia, arthralgia, myalgia, and neuropathy were observed more commonly following paclitaxel.[19] (Refer to the PDQ summary on Gastrointestinal Complications for information on gastrointestinal toxic effects; refer to the PDQ summary on Nausea and Vomiting and the PDQ summary on Fatigue; and, refer to the PDQ summary on Pain for information on arthralgia, myalgia, and neuropathy.)

  6. Bevacizumab. Three phase II studies have shown activity for this antibody to vascular endothelial growth factor (VEGF).

    The first study (GOG-0170D) included 62 patients who had received only one or two prior treatments (these last patients had received one additional platinum-based regimen because of an initial interval of 12 months or greater after first-line regimens and also had to have a performance status of 0 or 1).[31] Patients received a dose of 15 mg/kg every 21 days; there were two complete responses and 11 partial responses, a median PFS of 4.7 months, and an OS of 17 months. This activity was noted in both platinum-sensitive and platinum-resistant subsets.

    The second study only included patients with platinum-resistant disease using an identical dose schedule, but the study was stopped because five of 44 patients experienced bowel perforations, one of them fatal; seven partial responses had been observed.[32] This increased risk of bowel perforations was associated with three or more prior treatments.[33][34][35][Level of evidence: 3iiiDii]

    The third study (CCC-PHII-45) included 70 patients who received 50 mg of oral cyclophosphamide daily, in addition to bevacizumab (10 mg/kg every 2 wk); 17 partial responses were observed and four patients had intestinal perforations.[36]

  7. Pemetrexed. A randomized, double-blind, phase II European trial with 102 patients evaluated pemetrexed at two doses: standard (500 mg/m2) versus high-dose (900 mg/m2) IV every 3 weeks.[37] The response rate was 9.3% for the standard dose and 10.4% for the high dose. The toxicity profile favored the standard dose with fatigue, and nausea and vomiting, as the most common severe toxicities.

    A phase II study by the Gynecologic Oncology Group utilized pemetrexed (900 mg/m2) IV every 3 weeks in 51 patients with platinum-resistant recurrent disease.[38] The response rate was 21% in a heavily pretreated population in which 39% had five or more prior regimens. Myelosuppression and fatigue were the most common severe toxicities.

Other drugs used to treat platinum-refractory or platinum-resistant recurrence  

This group includes drugs that are not fully confirmed to have activity in a platinum-resistant setting, have a less desirable therapeutic index, and have a level of evidence lower than 3iiiDiv.

Table 4. Other Drugs That Have Been Used in the Setting of Recurrent Ovarian Cancer (Efficacy Not Well Defined After Failure of Platinum-Containing Regimens)

Drugs

Drug Class

Major Toxicities

Comments

Etoposide

Topoisomerase II inhibitor

Myelosuppression; alopecia

Oral; rare leukemia dampens interest

Cyclophosphamide and several other bischloroethylamines

Alkylating agents

Myelosuppression; alopecia (only the oxazaphosphorines)

Leukemia and cystitis; uncertain activity after platinums

Hexamethylmelamine (Altretamine)

Unknown but probably alkylating prodrugs

Emesis and neurotoxicity

Oral; uncertain activity after platinums

Irinotecan

Topoisomerase I inhibitor

Diarrhea and other gastrointestinal symptoms

Cross-resistant to topotecan

Oxaliplatin

Platinum

Neuropathy, emesis, myelosuppression

Cross-resistant to usual platinums, but less so

Vinorelbine

Mitotic inhibitor

Myelosuppression

Erratic activity

Fluorouracil and capecitabine

Fluoropyrimidine antimetabolites

Gastrointestinal symptoms and myelosuppression

Capecitabine is oral; may be useful in mucinous tumors

Tamoxifen

Antiestrogen

Thromboembolism

Oral; minimal activity, perhaps more in subsets

Treatment Options for Patients with Recurrent or Persistent Disease

  1. Secondary cytoreduction has been advocated, but it remains controversial.[3] The GOG-0213 trial, active in 2008, is attempting to define its role.
  2. For patients with platinum-sensitive disease (i.e., ≥6–12 mo between completion of a platinum-based regimen and the development of recurrent disease), retreatment with a platinum or platinum-containing combination, such as carboplatin, should be considered (see Table 3).
  3. For patients with platinum-refractory or platinum-resistant disease (i.e., disease that has progressed while on a platinum-based regimen or has recurred within 6 months of completion of a platinum-based regimen), clinical trials should be considered. For patients who are not entering a trial, treatment with one of the drugs listed above should be considered.
  4. Other agents that have shown activity in phase II trials are listed in Table 4 and may also be used alone or in combination with other drugs, but such treatments are best done in prospective trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent ovarian epithelial cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Ozols RF, Bundy BN, Greer BE, et al.: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21 (17): 3194-200, 2003.

  2. Rustin GJ, van der Burg ME, Griffin CL, et al.: Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 376 (9747): 1155-63, 2010.

  3. Hoskins WJ, Rubin SC, Dulaney E, et al.: Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 34 (3): 365-71, 1989.

  4. Monk BJ, Herzog TJ, Kaye SB, et al.: Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol 28 (19): 3107-14, 2010.

  5. Bolis G, Scarfone G, Giardina G, et al.: Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer. Gynecol Oncol 81 (1): 3-9, 2001.

  6. Cantù MG, Buda A, Parma G, et al.: Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 20 (5): 1232-7, 2002.

  7. Pfisterer J, Plante M, Vergote I, et al.: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24 (29): 4699-707, 2006.

  8. Muggia FM: Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Semin Oncol 16 (2 Suppl 5): 7-13, 1989.

  9. Piccart MJ, Green JA, Lacave AJ, et al.: Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol 18 (6): 1193-202, 2000.

  10. Markman M, Markman J, Webster K, et al.: Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol 22 (15): 3120-5, 2004.

  11. Gordon AN, Tonda M, Sun S, et al.: Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 95 (1): 1-8, 2004.

  12. Parmar MK, Ledermann JA, Colombo N, et al.: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 361 (9375): 2099-106, 2003.

  13. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al.: Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 28 (20): 3323-9, 2010.

  14. Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 86 (1): 18-24, 1994.

  15. McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111 (4): 273-9, 1989.

  16. Einzig AI, Wiernik PH, Sasloff J, et al.: Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 10 (11): 1748-53, 1992.

  17. Thigpen JT, Blessing JA, Ball H, et al.: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 12 (9): 1748-53, 1994.

  18. Trimble EL, Adams JD, Vena D, et al.: Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 11 (12): 2405-10, 1993.

  19. ten Bokkel Huinink W, Gore M, Carmichael J, et al.: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15 (6): 2183-93, 1997.

  20. Gordon AN, Fleagle JT, Guthrie D, et al.: Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19 (14): 3312-22, 2001.

  21. Kudelka AP, Tresukosol D, Edwards CL, et al.: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14 (5): 1552-7, 1996.

  22. Creemers GJ, Bolis G, Gore M, et al.: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 14 (12): 3056-61, 1996.

  23. Bookman MA, Malmström H, Bolis G, et al.: Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16 (10): 3345-52, 1998.

  24. McGonigle KF, Muntz HG, Vuky J, et al.: Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study. Cancer 117 (16): 3731-40, 2011.

  25. Muggia FM, Hainsworth JD, Jeffers S, et al.: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15 (3): 987-93, 1997.

  26. Berkenblit A, Seiden MV, Matulonis UA, et al.: A phase II trial of weekly docetaxel in patients with platinum-resistant epithelial ovarian, primary peritoneal serous cancer, or fallopian tube cancer. Gynecol Oncol 95 (3): 624-31, 2004.

  27. Friedlander M, Millward MJ, Bell D, et al.: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 9 (12): 1343-5, 1998.

  28. Lund B, Hansen OP, Theilade K, et al.: Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86 (20): 1530-3, 1994.

  29. Shapiro JD, Millward MJ, Rischin D, et al.: Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 63 (1): 89-93, 1996.

  30. Mutch DG, Orlando M, Goss T, et al.: Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 25 (19): 2811-8, 2007.

  31. Burger RA, Sill MW, Monk BJ, et al.: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25 (33): 5165-71, 2007.

  32. Cannistra SA, Matulonis UA, Penson RT, et al.: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25 (33): 5180-6, 2007.

  33. Vasey PA, McMahon L, Paul J, et al.: A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer. Br J Cancer 89 (10): 1843-8, 2003.

  34. Monk BJ, Han E, Josephs-Cowan CA, et al.: Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol 102 (2): 140-4, 2006.

  35. Kaye SB: Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 25 (33): 5150-2, 2007.

  36. Garcia AA, Hirte H, Fleming G, et al.: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26 (1): 76-82, 2008.

  37. Vergote I, Calvert H, Kania M, et al.: A randomised, double-blind, phase II study of two doses of pemetrexed in the treatment of platinum-resistant, epithelial ovarian or primary peritoneal cancer. Eur J Cancer 45 (8): 1415-23, 2009.

  38. Miller DS, Blessing JA, Krasner CN, et al.: Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol 27 (16): 2686-91, 2009.


This information is provided by the National Cancer Institute.

This information was last updated on February 15, 2013.


 
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