Cervical Cancer Treatment (PDQ®)


Information for: Patients | Healthcare Professionals

General Information About Cervical Cancer

Cervical cancer is a disease in which malignant (cancer) cells form in the tissues of the cervix.

The cervix is the lower, narrow end of the uterus (the hollow, pear-shaped organ where a fetus grows). The cervix leads from the uterus to the vagina (birth canal).

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.

Cervical cancer usually develops slowly over time. Before cancer appears in the cervix, the cells of the cervix go through changes known as dysplasia, in which cells that are not normal begin to appear in the cervicaltissue. Later, cancer cells start to grow and spread more deeply into the cervix and to surrounding areas.

Cervical cancer in children is rare. For more information, see the PDQ summary on Unusual Cancers of Childhood.

Human papillomavirus (HPV) infection is the major risk factor for cervical cancer.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk.

Infection of the cervix with human papillomavirus (HPV) is almost always the cause of cervical cancer. Not all women with HPV infection, however, will develop cervical cancer. Women who do not regularly have tests to detect HPV or abnormal cells in the cervix are at increased risk of cervical cancer.

Other possible risk factors include the following:

  • Giving birth to many children.
  • Having many sexual partners.
  • Having first sexual intercourse at a young age.
  • Smoking cigarettes.
  • Using oral contraceptives ("the Pill").
  • Having a weakened immune system.

There are usually no noticeable signs or symptoms of early cervical cancer but it can be detected early with regular check-ups.

Early cervical cancer may not cause noticeable signs or symptoms. Women should have regular check-ups, including tests to check for HPV or abnormal cells in the cervix. The prognosis (chance of recovery) is better when the cancer is found early.

Signs and symptoms of cervical cancer include vaginal bleeding and pelvic pain.

These and other signs and symptoms may be caused by cervical cancer or by other conditions. Check with your doctor if you have any of the following:

  • Vaginal bleeding.
  • Unusual vaginal discharge.
  • Pelvic pain.
  • Pain during sexual intercourse.

Tests that examine the cervix are used to detect (find) and diagnose cervical cancer.

The following procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • 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 places the other hand 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 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.
  • Pap test: A procedure to collect cells from the surface of the cervix and vagina. A piece of cotton, a brush, or a small wooden stick is used to gently scrape cells from the cervix and vagina. The cells are viewed under a microscope to find out if they are abnormal. This procedure is also called a Pap smear.
    Pap test; drawing shows a side view of the female reproductive anatomy during a Pap test. A speculum is shown widening the opening of the vagina. A brush is shown inserted into the open vagina and touching the cervix at the base of the uterus. The rectum is also shown. One inset shows the brush touching the center of the cervix. A second inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.  
    Pap test. A speculum is inserted into the vagina to widen it. Then, a brush is inserted into the vagina to collect cells from the cervix. The cells are checked under a microscope for signs of disease.
  • Human papillomavirus (HPV) test: A laboratory test used to check DNA or RNA for certain types of HPV infection. Cells are collected from the cervix and DNA or RNA from the cells is checked to find out if an infection is caused by a type of human papillomavirus that is linked to cervical cancer. This test may be done using the sample of cells removed during a Pap test. This test may also be done if the results of a Pap test show certain abnormal cervical cells.
  • Endocervical curettage: A procedure to collect cells or tissue from the cervical canal using a curette (spoon-shaped instrument). Tissue samples may be taken and checked under a microscope for signs of cancer. This procedure is sometimes done at the same time as a colposcopy.
  • Colposcopy: A procedure in which a colposcope (a lighted, magnifying instrument) is used to check the vagina and cervix for abnormal areas. Tissue samples may be taken using a curette (spoon-shaped instrument) and checked under a microscope for signs of disease.
  • Biopsy: If abnormal cells are found in a Pap test, the doctor may do a biopsy. A sample of tissue is cut from the cervix and viewed under a microscope by a pathologist to check for signs of cancer. A biopsy that removes only a small amount of tissue is usually done in the doctor’s office. A woman may need to go to a hospital for a cervical cone biopsy (removal of a larger, cone-shaped sample of cervical tissue).

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

The prognosis (chance of recovery) depends on the following:

  • The patient's age and general health.
  • Whether or not the patient has a certain type of human papillomavirus.
  • The stage of the cancer (whether it affects part of the cervix, involves the whole cervix, or has spread to the lymph nodes or other places in the body).
  • The type of cervical cancer.
  • The size of the tumor.

Treatment options depend on the following:

  • The stage of the cancer.
  • The size of the tumor.
  • The patient's desire to have children.
  • The patient’s age.

Treatment of cervical cancer during pregnancy depends on the stage of the cancer and the stage of the pregnancy. For cervical cancer found early or for cancer found during the last trimester of pregnancy, treatment may be delayed until after the baby is born.

Stages of Cervical Cancer

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

The process used to find out if cancer has spread within the cervix 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 tests and procedures may be used in the staging process:

  • 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.
  • PET scan (positron emission tomography scan): A procedure to find malignanttumorcells in the body. A small amount of radioactiveglucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • 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.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Cystoscopy: A procedure to look inside the bladder and urethra to check for abnormal areas. A cystoscope is inserted through the urethra into the bladder. A cystoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
  • Laparoscopy: A surgical procedure to look at the organs inside the abdomen to check for signs of disease. Small incisions (cuts) are made in the wall of the abdomen and a laparoscope (a thin, lighted tube) is inserted into one of the incisions. Other instruments may be inserted through the same or other incisions to perform procedures such as removing organs or taking tissue samples to be checked under a microscope for signs of disease.
  • Pretreatment surgical staging: Surgery (an operation) is done to find out if the cancer has spread within the cervix or to other parts of the body. In some cases, the cervical cancer can be removed at the same time. Pretreatment surgical staging is usually done only as part of a clinical trial.

The results of these tests are viewed together with the results of the original tumor biopsy to determine the cervical cancer stage.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if cervical cancer spreads to the lung, the cancer cells in the lung are actually cervical cancer cells. The disease is metastatic cervical cancer, not lung cancer.

The following stages are used for cervical cancer:

Carcinoma in Situ (Stage 0)

In carcinoma in situ (stage 0), abnormalcells are found in the innermost lining of the cervix. These abnormal cells may become cancer and spread into nearby normal tissue.

Millimeters; drawing shows millimeters (mm) using everyday objects. A sharp pencil point shows 1 mm, a new crayon point shows 2 mm, and a new pencil-top eraser shows 5 mm.  
Millimeters (mm). A sharp pencil point is about 1 mm, a new crayon point is about 2 mm, and a new pencil eraser is about 5 mm.

Stage I

In stage I, cancer is found in the cervix only. Stage I is divided into stages IA and IB, based on the amount of cancer that is found.

  • Stage IA:
    Stage IA1 and IA2 cervical cancer; drawing shows a cross-section of the cervix and vagina. An inset shows cancer in the cervix that is up to 5 mm deep, but not more than 7 mm wide. 
    Stage IA1 and IA2 cervical cancer. A very small amount of cancer that can only be seen with a microscope is found in the tissues of the cervix. In stage IA1, the cancer is not more than 3 millimeters deep and not more than 7 millimeters wide. In stage IA2, the cancer is more than 3 but not more than 5 millimeters deep, and not more than 7 millimeters wide.
    A very small amount of cancer that can only be seen with a microscope is found in the tissues of the cervix. Stage IA is divided into stages IA1 and IA2, based on the size of the tumor.
    • In stage IA1, the cancer is not more than 3 millimeters deep and not more than 7 millimeters wide.
    • In stage IA2, the cancer is more than 3 but not more than 5 millimeters deep, and not more than 7 millimeters wide.
     
  • Stage IB is divided into stages IB1 and IB2.
    Stage IB1 and IB2 cervical cancer shown in three cross-section drawings of the cervix and vagina. An inset on the left shows stage IB1 cancer that is 7 mm wide and more than 5 mm deep. Drawing in the middle shows stage IB1 cancer that is smaller than 4 cm. Drawing on the right shows stage IB2 cancer that is larger than 4 cm. 
    Stage IB1 and IB2 cervical cancer. In stage IB1, the cancer can only be seen with a microscope and is more than 5 mm deep and more than 7 mm wide OR the cancer can be seen without a microscope and is 4 cm or smaller. In stage IB2, the cancer is larger than 4 cm.
    • In stage IB1:
      • the cancer can only be seen with a microscope and is more than 5 millimeters deep and more than 7 millimeters wide; or
      • the cancer can be seen without a microscope and is 4 centimeters or smaller.
       
    • In stage IB2, the cancer can be seen without a microscope and is larger than 4 centimeters.
     

Stage II

Stage II cervical cancer; drawing shows a cross-section of the uterus, cervix and vagina. In stages IIA1 and IIA2, cancer that is 4 cm is shown in the cervix and in the upper third of the vagina. In stage IIB, cancer is shown in the cervix, the upper two thirds of the vagina, and in the tissues around the uterus.  
Stage II cervical cancer. Cancer has spread beyond the cervix but not to the pelvic wall or to the lower third of the vagina. In stages IIA1 and IIA2, cancer has spread beyond the cervix to the vagina. In stage IIA1, the tumor can be seen without a microscope and is 4 centimeters or smaller. In stage IIA2, the tumor can be seen without a microscope and is larger than 4 centimeters. In stage IIB, cancer has spread beyond the cervix to the tissues around the uterus.

In stage II, cancer has spread beyond the cervix but not to the pelvic wall (the tissues that line the part of the body between the hips) or to the lower third of the vagina. Stage II is divided into stages IIA and IIB, based on how far the cancer has spread.

  • Stage IIA: Cancer has spread beyond the cervix to the upper two thirds of the vagina but not to tissues around the uterus. Stage IIA is divided into stages IIA1 and IIA2, based on the size of the tumor.
    • In stage IIA1, the tumor can be seen without a microscope and is 4 centimeters or smaller.
    • In stage IIA2, the tumor can be seen without a microscope and is larger than 4 centimeters.
     
  • Stage IIB: Cancer has spread beyond the cervix to the tissues around the uterus.

Stage III

In stage III, cancer has spread to the lower third of the vagina, and/or to the pelvic wall, and/or has caused kidney problems. Stage III is divided into stages IIIA and IIIB, based on how far the cancer has spread.

  • Stage IIIA:
    Stage IIIA cervical cancer; drawing shows a cross-section of the cervix and vagina. Cancer is shown in the cervix and in the full length of the vagina. 
    Stage IIIA cervical cancer. Cancer has spread to the lower third of the vagina but not to the pelvic wall.
    Cancer has spread to the lower third of the vagina but not to the pelvic wall.
  • Stage IIIB:
    Stage IIIB cervical cancer; drawing shows cancer in the cervix, the vagina, and  the pelvic wall, blocking the ureter on the right. The uterus and kidneys are also shown. 
    Stage IIIB cervical cancer. Cancer has spread to the pelvic wall; and/or the tumor has become large enough to block the ureters (the tubes that connect the kidneys to the bladder). The drawing shows the ureter on the right blocked by the cancer. This blockage can cause the kidney to enlarge or stop working.
    • Cancer has spread to the pelvic wall; and/or
    • the tumor has become large enough to block the ureters (the tubes that connect the kidneys to the bladder). This blockage can cause the kidneys to enlarge or stop working.
     

Stage IV

In stage IV, cancer has spread to the bladder, rectum, or other parts of the body. Stage IV is divided into stages IVA and IVB, based on where the cancer is found.

  • Stage IVA:
    Stage IVA cervical cancer; drawing and inset show that cancer has spread from the cervix to the bladder and rectal wall. 
    Stage IVA cervical cancer. Cancer has spread to nearby organs, such as the bladder or rectum.
    Cancer has spread to nearby organs, such as the bladder or rectum.
  • Stage IVB:
    Stage IVB cervical cancer; drawing shows the places in the body where stage IV cervical cancer may spread, including the lymph nodes, lung, liver, intestinal tract, cervix, abdominal wall, and bone. Also shown is an inset of cancer that has spread to a lymph node and through the blood to other parts of the body. 
    Stage IVB cervical cancer. Cancer has spread to parts of the body away from the cervix, such as the liver, intestines, lungs, or bones.
    Cancer has spread to other parts of the body, such as the liver, lungs, bones, or distant lymph nodes.

Recurrent Cervical Cancer

Recurrentcervical cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the cervix or in other parts of the body.

Treatment Option Overview

There are different types of treatment for patients with cervical cancer.

Different types of treatment are available for patients with cervical cancer. Some treatments are standard (the currently used treatment), 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 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 types of standard treatment are used:

Surgery

Surgery (removing the cancer in an operation) is sometimes used to treat cervical cancer. The following surgical procedures may be used:

  • Conization: A procedure to remove a cone-shaped piece of tissue from the cervix and cervical canal. A pathologist views the tissue under a microscope to look for cancer cells. Conization may be used to diagnose or treat a cervical condition. This procedure is also called a cone biopsy.
  • Total hysterectomy: Surgery to remove the uterus, including the cervix. 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 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.
  • Radical hysterectomy: Surgery to remove the uterus, cervix, part of the vagina, and a wide area of ligaments and tissues around these organs. The ovaries, fallopian tubes, or nearby lymph nodes may also be removed.
  • Modified radical hysterectomy: Surgery to remove the uterus, cervix, upper part of the vagina, and ligaments and tissues that closely surround these organs. Nearby lymph nodes may also be removed. In this type of surgery, not as many tissues and/or organs are removed as in a radical hysterectomy.
  • Bilateral salpingo-oophorectomy: Surgery to remove both ovaries and both fallopian tubes.
  • Pelvic exenteration: Surgery to remove the lower colon, rectum, and bladder. In women, the cervix, vagina, ovaries, and nearby lymph nodes are also removed. Artificial openings (stoma) are made for urine and stool to flow from the body to a collection bag. Plastic surgery may be needed to make an artificial vagina after this operation.
  • Cryosurgery: A treatment that uses an instrument to freeze and destroy abnormal tissue, such as carcinoma in situ. This type of treatment is also called cryotherapy.
  • Laser surgery: A surgical procedure that uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or to remove a surface lesion such as a tumor.
  • Loop electrosurgical excision procedure (LEEP): A treatment that uses electrical current passed through a thin wire loop as a knife to remove abnormal tissue or cancer.

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 radiationtherapy 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.

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

See Drugs Approved to Treat Cervical Cancer for more information.

New types of treatment are being tested in clinical trials.

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

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

Carcinoma in Situ (Stage 0)

Treatment of carcinoma in situ (stage 0) may include the following:

  • Loop electrosurgical excision procedure (LEEP).
  • Laser surgery.
  • Conization.
  • Cryosurgery.
  • Total hysterectomy for women who cannot or no longer want to have children. This is done only if the tumor cannot be completely removed by excision.
  • Internal radiation therapy for women who cannot have surgery.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IA Cervical Cancer

Treatment of stage IA cervical cancer may include the following:

  • Total hysterectomy with or without bilateral salpingo-oophorectomy.
  • Conization.
  • Modified radical hysterectomy and removal of lymph nodes.
  • Internal radiationtherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IA cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IB Cervical Cancer

Treatment of stage IB cervical cancer may include the following:

  • Radical hysterectomy and removal of lymph nodes.
  • Radical hysterectomy and removal of lymph nodes followed by radiation therapy plus chemotherapy.
  • Radiation therapy plus chemotherapy.
  • A combination of internal radiation therapy and external radiation therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IB cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IIA Cervical Cancer

Treatment of stage IIA cervical cancer may include the following:

  • A combination of internal radiation therapy and external radiation therapy plus chemotherapy.
  • Radical hysterectomy and removal of lymph nodes.
  • Radical hysterectomy and removal of lymph nodes followed by radiation therapy plus chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIA cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IIB Cervical Cancer

Treatment of stage IIB cervical cancer may include internal and external radiation therapy combined with chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIB cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage III Cervical Cancer

Treatment of stage III cervical cancer may include internal and external radiation therapy combined with chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IVA Cervical Cancer

Treatment of stage IVA cervical cancer may include internal and external radiation therapy combined with chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVA cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IVB Cervical Cancer

Treatment of stage IVB cervical cancer may include the following:

  • Radiation therapy as palliative therapy to relieve symptoms caused by the cancer and improve quality of life.
  • Chemotherapy.
  • Clinical trials of new anticancer drugs or drug combinations.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVB cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Treatment Options for Recurrent Cervical Cancer

Treatment of recurrentcervical cancer may include the following:

  • Pelvic exenteration followed by radiation therapy combined with chemotherapy.
  • Chemotherapy as palliative therapy to relieve symptoms caused by the cancer and improve quality of life.
  • Clinical trials of new anticancer drugs or drug combinations.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent cervical 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. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

To Learn More About Cervical Cancer

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

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


This information is provided by the National Cancer Institute.

This information was last updated on March 14, 2014.


General Information About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide, and it has the fourth highest mortality rate among cancers in women.[1] Most cases of cervical cancer are preventable by routine screening and by treatment of precancerous lesions. As a result, most of the cervical cancer cases are diagnosed in women who live in regions with inadequate screening protocols.

Incidence and Mortality

Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2014:[2]

  • New cases: 12,360.
  • Deaths: 4,020.

Anatomy

The uterine cervix is contiguous with the uterine body, and it acts as the opening to the body of the uterus. The uterine cervix is a cylindrical, fibrous organ that is an average of 3 to 4 cm in length. The portio of the cervix is the part of the cervix that is visible on vaginal inspection. The opening of the cervix is termed the external os. The os is the beginning of the endocervical canal, which forms the inner aspect of the cervix. At the upper aspect of the endocervical canal is the internal os, a narrowing of the endocervical canal. The narrowing marks the transition from the cervix to the uterine body. The endocervical canal beyond the internal os is termed the endometrial canal.

The cervix is lined by two types of epithelial cells: squamous cells at the outer aspect, and columnar, glandular cells along the inner canal. The transition between squamous cells and columnar cells is an area termed the squamo-columnar junction. Most of precancerous and cancerous changes arise in this zone.

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.

Pathogenesis

Cervical carcinoma has its origins at the squamous-columnar junction; it can involve the outer squamous cells, the inner glandular cells, or both. The precursor lesion is dysplasia: cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ, which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in patients with untreated in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.

Risk Factors

Human papillomavirus (HPV) infection

HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.

More than 6 million women in the United States are estimated to be infected with HPV. Transient HPV infection is common, particularly in young women,[3] while cervical cancer is rare. The persistence of an HPV infection leads to increased risk of developing precancerous and cancerous lesions.[4][5]

The strain of HPV infection is also important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN.[6][7][8] Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytologic screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.[9][10][11]

There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed towards HPV-naïve girls and young women, and although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented.[12] (Refer to the PDQ summary on Cervical Cancer Prevention for more information.)

Other risk factors

Other risk factors for cervical cancer include the following:[6]

  • High parity.[13]
  • Increased number of sexual partners.
  • Young age at time of first sexual intercourse.
  • Low socioeconomic status.
  • History of smoking.
  • Long-term use of oral contraceptives.[14]

Given the relevance of HPV status in assessing risk, studies limited to HPV-positive women in cases and the control groups provide the most information on the additional cofactors that may promote progression of HPV infection to precancerous and cancerous lesions.

(Refer to the PDQ summary on Cervical Cancer Prevention for more information.)

Clinical Features

Early cervical cancer may not cause noticeable signs or symptoms.

Possible signs and symptoms of cervical cancer include the following:

  • Vaginal bleeding.
  • Unusual vaginal discharge.
  • Pelvic pain.
  • Dyspareunia.
  • Postcoital bleeding.

Diagnosis

The following procedures may be used to diagnose cervical cancer:

  • History and physical exam.
  • Pelvic exam.
  • Cervical cytology (Pap smear).
  • HPV test.
  • Endocervical curettage.
  • Colposcopy.
  • Biopsy.

HPV testing

Cervical cytology (Pap smear) has been the mainstay of cervical cancer screening since its introduction. However, molecular techniques for the identification of HPV DNA are highly sensitive and specific. Current screening options include the following:

  • Cytology alone.
  • Cytology and HPV testing.

HPV testing is suggested when it is likely to successfully triage patients into low- and high-risk groups for a high-grade dysplasia or greater lesion.

HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique.[15] The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost.[15]

HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines.[15][16][17]

Other studies show that patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have CIN or microinvasive histopathology on biopsy.[6][18][19][20] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer.[21]

For women older than 30 years who are more likely to have persistent HPV infection, HPV typing can successfully triage women into high- and low-risk groups for CIN 3 or worse disease. In this age group, HPV DNA testing is more effective than cytology alone in predicting the risk of developing CIN 3 or worse.[22] Other studies have shown the effectiveness of a primary HPV DNA-screening strategy with cytology triage over the previously used cytology-based screening algorithms.[23][24]

Prognostic Factors

The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. More than 90% of cervical cancer cases can be detected early through the use of the Pap test and HPV testing.[25] Pap and HPV testing are not performed on approximately 33% of eligible women, which results in a higher-than-expected death rate.

Clinical stage

Clinical stage as a prognostic factor is supplemented by several gross and microscopic pathologic findings in surgically treated patients.

Evidence (clinical stage and other findings):

In a large, surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that most prominently predicted for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being the most important and reproducible.[26][27]

In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than with clinical or histologic stage.[28]

A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:[29]

  • Periaortic and pelvic lymph node status.
  • Tumor size.
  • Patient age.
  • Performance status.
  • Bilateral disease.
  • Clinical stage.

The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.

It is controversial whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[30] Several population-based and retrospective studies show a worse outcome for patients with adenocarcinoma, with an increase in distant metastasis noted, when compared with those with squamous histology.[31][32][33][34] Reports conflict about the effect of adenosquamous cell type on outcome.[35][36] One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis.[37]

In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to the lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA.[38] A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[38]

GOG studies have indicated that prognostic factors vary depending on whether clinical or surgical staging are utilized and with different treatments. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. To-date, stage, tumor grade, race, and age are uncertain prognostic factors in studies utilizing chemoradiation.[39]

Other prognostic factors

Other prognostic factors that may affect outcome include the following:

  • Human immunodeficiency virus (HIV) status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.[40]
  • C-myc overexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis.[41]
  • Number of cells in S phase: The number of cells in S phase may also have prognostic significance in early cervical carcinoma.[42]
  • HPV-18 DNA: HPV-18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.[43][44]
  • A polymorphism in the Gamma-glutamyl hydrolase enzyme, which is related to folate metabolism, has been shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.[45]

Follow-up After Treatment

High-quality studies are lacking, and the optimal treatment follow-up for patients after treatment for cervical cancer is unknown. Retrospective studies have shown that patients who recur are most likely to do so within the first 2 years.[46] As a result, most guidelines suggest routine follow-up every 3 to 4 months for the first 2 years, followed by evaluations every 6 months. Most recurrences are diagnosed secondary to new patient symptoms and signs,[47][48] and the usefulness of routine testing including a Pap smear and chest x-ray is unclear.

Follow-up should be centered around a thorough history and physical examination with a careful review of symptoms; imaging should be reserved for evaluation of a positive finding. Patients should be asked about possible warning signs, including the following:

  • Abdominal pain.
  • Back pain.
  • Painful or swollen leg.
  • Problems with urination.
  • Cough.
  • Fatigue.

The follow-up examination should also screen for possible complications of previous treatment because of the multiple modalities (surgery, chemotherapy, and radiation) that patients often undergo during their treatment.

Related Summaries

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

  • Cervical Cancer Prevention
  • Cervical Cancer Screening
  • Unusual Cancers of Childhood (childhood cancer of the cervix)

References:

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  4. Rodríguez AC, Schiffman M, Herrero R, et al.: Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 100 (7): 513-7, 2008.

  5. Jaisamrarn U, Castellsagué X, Garland SM, et al.: Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study. PLoS One 8 (11): e79260, 2013.

  6. Brisson J, Morin C, Fortier M, et al.: Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions. Am J Epidemiol 140 (8): 700-10, 1994.

  7. Koutsky LA, Holmes KK, Critchlow CW, et al.: A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 327 (18): 1272-8, 1992.

  8. Schiffman MH, Bauer HM, Hoover RN, et al.: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85 (12): 958-64, 1993.

  9. Castle PE, Glass AG, Rush BB, et al.: Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up. J Clin Oncol 30 (25): 3044-50, 2012.

  10. Khan MJ, Castle PE, Lorincz AT, et al.: The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 97 (14): 1072-9, 2005.

  11. Schlecht NF, Kulaga S, Robitaille J, et al.: Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 286 (24): 3106-14, 2001.

  12. Muñoz N, Kjaer SK, Sigurdsson K, et al.: Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst 102 (5): 325-39, 2010.

  13. Muñoz N, Franceschi S, Bosetti C, et al.: Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 359 (9312): 1093-101, 2002.

  14. Moreno V, Bosch FX, Muñoz N, et al.: Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 359 (9312): 1085-92, 2002.

  15. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 92 (5): 397-402, 2000.

  16. Wright TC Jr, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197 (4): 346-55, 2007.

  17. Wright TC Jr, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 197 (4): 340-5, 2007.

  18. Tabbara S, Saleh AD, Andersen WA, et al.: The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates. Obstet Gynecol 79 (3): 338-46, 1992.

  19. Cuzick J, Terry G, Ho L, et al.: Human papillomavirus type 16 in cervical smears as predictor of high-grade cervical intraepithelial neoplasia [corrected] Lancet 339 (8799): 959-60, 1992.

  20. Richart RM, Wright TC Jr: Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 71 (4 Suppl): 1413-21, 1993.

  21. Klaes R, Woerner SM, Ridder R, et al.: Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59 (24): 6132-6, 1999.

  22. Katki HA, Kinney WK, Fetterman B, et al.: Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 12 (7): 663-72, 2011.

  23. Naucler P, Ryd W, Törnberg S, et al.: Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 101 (2): 88-99, 2009.

  24. Castle PE, Stoler MH, Wright TC Jr, et al.: Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 12 (9): 880-90, 2011.

  25. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 262 (7): 931-4, 1989.

  26. Delgado G, Bundy B, Zaino R, et al.: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 38 (3): 352-7, 1990.

  27. Zaino RJ, Ward S, Delgado G, et al.: Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Cancer 69 (7): 1750-8, 1992.

  28. Burghardt E, Baltzer J, Tulusan AH, et al.: Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer 70 (3): 648-55, 1992.

  29. Stehman FB, Bundy BN, DiSaia PJ, et al.: Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67 (11): 2776-85, 1991.

  30. Steren A, Nguyen HN, Averette HE, et al.: Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience. Gynecol Oncol 48 (3): 355-9, 1993.

  31. Park JY, Kim DY, Kim JH, et al.: Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix. Br J Cancer 102 (12): 1692-8, 2010.

  32. Eifel PJ, Burke TW, Morris M, et al.: Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol 59 (1): 38-44, 1995.

  33. Lee YY, Choi CH, Kim TJ, et al.: A comparison of pure adenocarcinoma and squamous cell carcinoma of the cervix after radical hysterectomy in stage IB-IIA. Gynecol Oncol 120 (3): 439-43, 2011.

  34. Galic V, Herzog TJ, Lewin SN, et al.: Prognostic significance of adenocarcinoma histology in women with cervical cancer. Gynecol Oncol 125 (2): 287-91, 2012.

  35. Gallup DG, Harper RH, Stock RJ: Poor prognosis in patients with adenosquamous cell carcinoma of the cervix. Obstet Gynecol 65 (3): 416-22, 1985.

  36. Yazigi R, Sandstad J, Munoz AK, et al.: Adenosquamous carcinoma of the cervix: prognosis in stage IB. Obstet Gynecol 75 (6): 1012-5, 1990.

  37. Bethwaite P, Yeong ML, Holloway L, et al.: The prognosis of adenosquamous carcinomas of the uterine cervix. Br J Obstet Gynaecol 99 (9): 745-50, 1992.

  38. Fagundes H, Perez CA, Grigsby PW, et al.: Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 24 (2): 197-204, 1992.

  39. Monk BJ, Tian C, Rose PG, et al.: Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma? Analysis of two Gynecologic Oncology Group (GOG) trials. Gynecol Oncol 105 (2): 427-33, 2007.

  40. Maiman M, Fruchter RG, Guy L, et al.: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71 (2): 402-6, 1993.

  41. Bourhis J, Le MG, Barrois M, et al.: Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix. J Clin Oncol 8 (11): 1789-96, 1990.

  42. Strang P, Eklund G, Stendahl U, et al.: S-phase rate as a predictor of early recurrences in carcinoma of the uterine cervix. Anticancer Res 7 (4B): 807-10, 1987 Jul-Aug.

  43. Burger RA, Monk BJ, Kurosaki T, et al.: Human papillomavirus type 18: association with poor prognosis in early stage cervical cancer. J Natl Cancer Inst 88 (19): 1361-8, 1996.

  44. Lai CH, Chang CJ, Huang HJ, et al.: Role of human papillomavirus genotype in prognosis of early-stage cervical cancer undergoing primary surgery. J Clin Oncol 25 (24): 3628-34, 2007.

  45. Silva IH, Nogueira-Silva C, Figueiredo T, et al.: The impact of GGH -401C>T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer. Gene 512 (2): 247-50, 2013.

  46. Ansink A, de Barros Lopes A, Naik R, et al.: Recurrent stage IB cervical carcinoma: evaluation of the effectiveness of routine follow up surveillance. Br J Obstet Gynaecol 103 (11): 1156-8, 1996.

  47. Duyn A, Van Eijkeren M, Kenter G, et al.: Recurrent cervical cancer: detection and prognosis. Acta Obstet Gynecol Scand 81 (4): 351-5, 2002.

  48. Morice P, Deyrolle C, Rey A, et al.: Value of routine follow-up procedures for patients with stage I/II cervical cancer treated with combined surgery-radiation therapy. Ann Oncol 15 (2): 218-23, 2004.

Cellular Classification of Cervical Cancer

Squamous cell (epidermoid) carcinoma comprises approximately 90% of cervical cancers, and adenocarcinoma comprises approximately 10% of cervical cancers. Adenosquamous and small cell carcinomas are relatively rare. Primary sarcomas of the cervix and primary and secondary malignant lymphomas of the cervix have also been reported.

Stage Information for Cervical Cancer

Carcinoma of the cervix can spread via local invasion, the regional lymphatics, or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.

Pretreatment surgical staging is the most accurate method to determine the extent of disease,[1] but there is little evidence to demonstrate overall improved survival with routine surgical staging; the staging is usually performed only as part of a clinical trial. Pretreatment surgical staging in bulky but locally curable disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by computed tomography (CT) scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.

Tests and procedures to evaluate the extent of the disease include the following:

  • CT scan.
  • Positron emission tomography scan.
  • Cystoscopy.
  • Laparoscopy.
  • Chest x-ray.
  • Ultrasound.[2]
  • Magnetic resonance imaging.[2]

FIGO Stage Groupings and Definitions

The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer have designated staging to define cervical cancer; the FIGO system is most commonly used.[3][4]

Table 1. Definitions of FIGO Stage I
Stage Description
I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded).
IA Invasive carcinoma, which can be diagnosed only by microscopy with deepest invasion ≤5 mm and largest extension ≥7 mm.
IA1 Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm.
IA2 Measured stromal invasion of >3.0 mm and ≤5.0 mm with an extension of ≤7.0 mm.
IB Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IAb.
IB1 Clinically visible lesion ≤4.0 cm in greatest dimension.
IB2 Clinically visible lesion >4.0 cm in greatest dimension.
Stage IA1 and IA2 cervical cancer; drawing shows a cross-section of the cervix and vagina. An inset shows cancer in the cervix that is up to 5 mm deep, but not more than 7 mm wide.
Stage IA1 and IA2 cervical cancer; drawing shows a cross-section of the cervix and vagina. An inset shows cancer in the cervix that is up to 5 mm deep, but not more than 7 mm wide.
Stage IB1 and IB2 cervical cancer shown in three cross-section drawings of the cervix and vagina. An inset on the left shows stage IB1 cancer that is 7 mm wide and more than 5 mm deep. Drawing in the middle shows stage IB1 cancer that is smaller than 4 cm. Drawing on the right shows stage IB2 cancer that is larger than 4 cm.
Stage IB1 and IB2 cervical cancer shown in three cross-section drawings of the cervix and vagina. An inset on the left shows stage IB1 cancer that is 7 mm wide and more than 5 mm deep. Drawing in the middle shows stage IB1 cancer that is smaller than 4 cm. Drawing on the right shows stage IB2 cancer that is larger than 4 cm.
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO committee on gynecologic oncology.[3]
bAll macroscopically visible lesions - even with superficial invasion - are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of ≤7.00 mm. Depth of invasion should be ≤5.00 mm taken from the base of the epithelium of the original tissue - superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with "early (minimal) stromal invasion" (~1 mm). The involvement of vascular/lymphatic spaces should not change the stage allotment.
Table 2. Definitions of FIGO Stage II
Stage Description
II Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina.
IIA Without parametrial invasion.
IIA1 Clinically visible lesion ≤4.0 cm in greatest dimension.
IIA2 Clinically visible lesion >4.0 cm in greatest dimension.
IIB With obvious parametrial invasion.
Stage II cervical cancer; drawing shows a cross-section of the uterus, cervix and vagina. In stages IIA1 and IIA2, cancer that is 4 cm is shown in the cervix and in the upper third of the vagina. In stage IIB, cancer is shown in the cervix, the upper two thirds of the vagina, and in the tissues around the uterus.
Stage II cervical cancer; drawing shows a cross-section of the uterus, cervix and vagina. In stages IIA1 and IIA2, cancer that is 4 cm is shown in the cervix and in the upper third of the vagina. In stage IIB, cancer is shown in the cervix, the upper two thirds of the vagina, and in the tissues around the uterus.
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO committee on gynecologic oncology.[3]
Table 3. Definitions of FIGO Stage III
Stage Description
III The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney.b
IIIA Tumor involves lower third of the vagina with no extension to the pelvic wall.
IIIB Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney.
Stage IIIA cervical cancer; drawing shows a cross-section of the cervix and vagina. Cancer is shown in the cervix and in the full length of the vagina.
Stage IIIA cervical cancer; drawing shows a cross-section of the cervix and vagina. Cancer is shown in the cervix and in the full length of the vagina.
Stage IIIB cervical cancer; drawing shows cancer in the cervix, the vagina, and  the pelvic wall, blocking the ureter on the right. The uterus and kidneys are also shown.
Stage IIIB cervical cancer; drawing shows cancer in the cervix, the vagina, and the pelvic wall, blocking the ureter on the right. The uterus and kidneys are also shown.
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO committee on gynecologic oncology.[3]
bOn rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are known to be the result of another cause.
Table 4. Definitions of FIGO Stage IV
Stage Description
IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.
IVA Spread of the growth to adjacent organs.
IVB Spread to distant organs.
Stage IVA cervical cancer; drawing and inset show that cancer has spread from the cervix to the bladder and rectal wall.
Stage IVA cervical cancer; drawing and inset show that cancer has spread from the cervix to the bladder and rectal wall.
Stage IVB cervical cancer; drawing shows the places in the body where stage IV cervical cancer may spread, including the lymph nodes, lung, liver, intestinal tract, cervix, abdominal wall, and bone. Also shown is an inset of cancer that has spread to a lymph node and through the blood to other parts of the body.
Stage IVB cervical cancer; drawing shows the places in the body where stage IV cervical cancer may spread, including the lymph nodes, lung, liver, intestinal tract, cervix, abdominal wall, and bone. Also shown is an inset of cancer that has spread to a lymph node and through the blood to other parts of the body.
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO committee on gynecologic oncology.[3]

References:

  1. Gold MA, Tian C, Whitney CW, et al.: Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study. Cancer 112 (9): 1954-63, 2008.

  2. Epstein E, Testa A, Gaurilcikas A, et al.: Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial. Gynecol Oncol 128 (3): 449-53, 2013.

  3. Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105 (2): 103-4, 2009.

  4. Cervix uteri. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 395-402.

Treatment Option Overview for Cervical Cancer

Patterns-of-care studies clearly demonstrate the negative prognostic effect of increasing tumor volume and spread pattern.[1] Treatment, therefore, may vary within each stage as the individual stages are currently defined by Féderation Internationale de Gynécologie et d'Obstétrique (FIGO).

Table 5. Standard Treatment Options for Cervical Cancer

Stage ( FIGO Staging Criteria)

Standard Treatment Options

In situ carcinoma of the cervix (this stage is not recognized by FIGO)

Conization

Hysterectomy for postreproductive patients

Internal radiation therapy for medically inoperable patients

Stage IA cervical cancer

Conization

Total hysterectomy

Modified radical hysterectomy with lymphadenectomy

Radical trachelectomy

Intracavitary radiation therapy

Stages IB, IIA cervical cancer

Radiation therapy with concomitant chemotherapy

Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy

Radical trachelectomy

Neoadjuvant chemotherapy

Radiation therapy alone

Intensity Modulated Radiation Therapy (IMRT)

Stages IIB, III, and IVA cervical cancer

Radiation therapy with concomitant chemotherapy

Interstitial brachytherapy

Neoadjuvant chemotherapy

Stage IVB cervical cancer

Palliative radiation therapy

Palliative chemotherapy

Recurrent cervical cancer

Radiation therapy and chemotherapy

Palliative chemotherapy

Pelvic exenteration

FIGO = Féderation Internationale de Gynécologie et d'Obstétrique.

Chemoradiation Therapy

Five randomized, phase III trials (GOG-85, RTOG-9001, GOG-120, GOG-123, and SWOG-8797) have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[2][3][4][5][6] while one trial examining this regimen demonstrated no benefit.[7] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease who were found to have poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery.

  • Although the positive trials vary in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.
  • Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[2][3][4][5][6]

Other studies have validated these results.[8][9][10]

Surgery and Radiation Therapy

Surgery and radiation therapy are equally effective for early stage, small-volume disease.[11] Younger patients may benefit from surgery to preserve the ovaries and avoid vaginal atrophy and stenosis.

Therapy for patients with cancer of the cervical stump is effective and yields results that are comparable with those seen in patients with an intact uterus.[12]

References:

  1. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer. A study of patterns of care. Cancer 69 (2): 482-7, 1992.

  2. Whitney CW, Sause W, Bundy BN, et al.: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17 (5): 1339-48, 1999.

  3. Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999.

  4. Rose PG, Bundy BN, Watkins EB, et al.: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340 (15): 1144-53, 1999.

  5. Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999.

  6. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000.

  7. Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002.

  8. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.

  9. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.

  10. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008.

  11. Eifel PJ, Burke TW, Delclos L, et al.: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter. Gynecol Oncol 41 (3): 199-205, 1991.

  12. Kovalic JJ, Grigsby PW, Perez CA, et al.: Cervical stump carcinoma. Int J Radiat Oncol Biol Phys 20 (5): 933-8, 1991.

In Situ Cervical Cancer Treatment

Consensus guidelines have been issued for managing women with cervical intraepithelial neoplasia or adenocarcinoma in situ.[1] Properly treated, tumor control of in situ cervical carcinoma should be nearly 100%. Either expert colposcopic-directed biopsy or cone biopsy is required to exclude invasive disease before therapy is undertaken. A correlation between cytology and colposcopic-directed biopsy is also necessary before local ablative therapy is done. Unrecognized invasive disease treated with inadequate ablative therapy may be the most common cause of failure.[2] Failure to identify the disease, lack of correlation between the Pap smear and colposcopic findings, adenocarcinoma in situ, or extension of disease into the endocervical canal makes a laser, loop, or cold-knife conization mandatory.

The choice of treatment depends on the extent of disease and several patient factors, including age, cell type, desire to preserve fertility, and medical condition.

Standard Treatment Options for In Situ Cervical Cancer

Standard treatment options for in situ cervical cancer include the following:

  1. Conization.
    • Cold-knife conization (scalpel).
    • Loop electrosurgical excision procedure (LEEP).[3][4]
    • Laser therapy.[5]
  2. Hysterectomy for postreproductive patients.
  3. Internal radiation therapy for medically inoperable patients.

Hysterectomy is the standard treatment for patients with adenocarcinoma in situ. The disease, which originates in the endocervical canal, may be more difficult to completely excise with a conization procedure. Conization may be offered to select patients with adenocarcinoma in situ who desire future fertility.

Conization

When the endocervical canal is involved, laser or cold-knife conization may be used for selected patients to preserve the uterus, avoid radiation therapy, and more extensive surgery.[6]

In selected cases, the outpatient LEEP may be an acceptable alternative to cold-knife conization. This procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization.[7][8][9] However, controversy exists about the adequacy of LEEP as a replacement for conization; LEEP is unlikely to be sufficient for patients with adenocarcinoma in situ.[10]

Evidence (conization using LEEP):

  1. A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia.[6]
  2. Two case reports suggested that the use of LEEP in patients with occult invasive cancer led to an inability to accurately determine depth of invasion when a focus of the cancer was transected.[11]

Hysterectomy for postreproductive patients

Hysterectomy is standard therapy for women with cervical adenocarcinoma in situ, because of the location of the disease in the endocervical canal and the possibility for skip lesions in this region, making margin status a less reliable prognostic factor. However, the effect of hysterectomy compared with conservative surgical measures on mortality has not been studied. Hysterectomy may be performed for squamous cell carcinoma in situ if conization is not possible because of previous surgery, or if positive margins are noted after conization therapy. Hysterectomy is not an acceptable front-line therapy for squamous carcinoma in situ.[12]

Internal radiation therapy for medically inoperable patients

For medically inoperable patients, a single intracavitary insertion with tandem and ovoids for 5,000 mg hours (80 Gy vaginal surface dose) may be used.[13]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 cervical 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. Wright TC Jr, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 197 (4): 340-5, 2007.

  2. Shumsky AG, Stuart GC, Nation J: Carcinoma of the cervix following conservative management of cervical intraepithelial neoplasia. Gynecol Oncol 53 (1): 50-4, 1994.

  3. Wright VC, Chapman W: Intraepithelial neoplasia of the lower female genital tract: etiology, investigation, and management. Semin Surg Oncol 8 (4): 180-90, 1992 Jul-Aug.

  4. Bloss JD: The use of electrosurgical techniques in the management of premalignant diseases of the vulva, vagina, and cervix: an excisional rather than an ablative approach. Am J Obstet Gynecol 169 (5): 1081-5, 1993.

  5. Tsukamoto N: Treatment of cervical intraepithelial neoplasia with the carbon dioxide laser. Gynecol Oncol 21 (3): 331-6, 1985.

  6. Girardi F, Heydarfadai M, Koroschetz F, et al.: Cold-knife conization versus loop excision: histopathologic and clinical results of a randomized trial. Gynecol Oncol 55 (3 Pt 1): 368-70, 1994.

  7. Wright TC Jr, Gagnon S, Richart RM, et al.: Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol 79 (2): 173-8, 1992.

  8. Naumann RW, Bell MC, Alvarez RD, et al.: LLETZ is an acceptable alternative to diagnostic cold-knife conization. Gynecol Oncol 55 (2): 224-8, 1994.

  9. Duesing N, Schwarz J, Choschzick M, et al.: Assessment of cervical intraepithelial neoplasia (CIN) with colposcopic biopsy and efficacy of loop electrosurgical excision procedure (LEEP). Arch Gynecol Obstet 286 (6): 1549-54, 2012.

  10. Widrich T, Kennedy AW, Myers TM, et al.: Adenocarcinoma in situ of the uterine cervix: management and outcome. Gynecol Oncol 61 (3): 304-8, 1996.

  11. Eddy GL, Spiegel GW, Creasman WT: Adverse effect of electrosurgical loop excision on assignment of FIGO stage in cervical cancer: report of two cases. Gynecol Oncol 55 (2): 313-7, 1994.

  12. Massad LS: New guidelines on cervical cancer screening: more than just the end of annual Pap testing. J Low Genit Tract Dis 16 (3): 172-4, 2012.

  13. Grigsby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys 21 (2): 375-8, 1991.

Stage IA Cervical Cancer Treatment

Standard Treatment Options for Stage IA1 Cervical Cancer

Standard treatment options for stage IA1 cervical cancer include the following:

  1. Conization.
  2. Total hysterectomy.

Conization

If the depth of invasion is less than 3 mm, no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients who wish to preserve fertility.[1]

Total hysterectomy

If the depth of invasion is less than 3 mm, which is proven by cone biopsy with clear margins,[2] no vascular or lymphatic channel invasion is noted, and the frequency of lymph-node involvement is sufficiently low, lymph-node dissection at the time of hysterectomy is not required. Oophorectomy is optional and should be deferred for younger women.

Standard Treatment Options for Stage IA2 Cervical Cancer

Standard treatment options for stage IA2 cervical cancer include the following:

  1. Modified radical hysterectomy with lymphadenectomy.

Modified radical hysterectomy with lymphadenectomy

For patients with tumor invasion between 3 mm and 5 mm, modified radical hysterectomy with pelvic-node dissection has been recommended because of a reported risk of lymph-node metastasis of as much as 10%.[2] Radical hysterectomy with node dissection may also be considered for patients for whom the depth of tumor invasion was uncertain because of invasive tumor at the cone margins.

Other Treatment Options

  1. Radical trachelectomy.
  2. Intracavitary radiation therapy.

Radical trachelectomy

Patients with stages IA2 to IB disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. Most centers utilize the following criteria for patient selection:

  • Desire for future pregnancy.
  • Age younger than 40 years.
  • Presumed stage IA2 to IB1 disease and a lesion size no greater than 2 cm.
  • Preoperative magnetic resonance imaging that shows a margin from the most distal edge of the tumor to the lower uterine segment.
  • Squamous, adenosquamous, or adenocarcinoma cell types.

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[3][4][5][6][7]

Intracavitary radiation therapy

Intracavitary radiation therapy is a treatment option when palliative treatment is appropriate because of other medical conditions and for women who are not surgical candidates.

If the depth of invasion is less than 3 mm and no capillary lymphatic space invasion is noted, and the frequency of lymph-node involvement is sufficiently low, external-beam radiation therapy is not required. One or two insertions with tandem and ovoids for 6,500 mg to 8,000 mg hours (100-125 Gy vaginal surface dose) are recommended.[8]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IA cervical 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. Sevin BU, Nadji M, Averette HE, et al.: Microinvasive carcinoma of the cervix. Cancer 70 (8): 2121-8, 1992.

  2. Jones WB, Mercer GO, Lewis JL Jr, et al.: Early invasive carcinoma of the cervix. Gynecol Oncol 51 (1): 26-32, 1993.

  3. Covens A, Shaw P, Murphy J, et al.: Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer 86 (11): 2273-9, 1999.

  4. Dargent D, Martin X, Sacchetoni A, et al.: Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer 88 (8): 1877-82, 2000.

  5. Plante M, Renaud MC, Hoskins IA, et al.: Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol 98 (1): 3-10, 2005.

  6. Shepherd JH, Spencer C, Herod J, et al.: Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG 113 (6): 719-24, 2006.

  7. Wethington SL, Cibula D, Duska LR, et al.: An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer 22 (7): 1251-7, 2012.

  8. Grigsby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys 21 (2): 375-8, 1991.

Stages IB and IIA Cervical Cancer Treatment

Standard Treatment Options for Stages IB and IIA Cervical Cancer

Standard treatment options for stage IB and stage IIA cervical cancer include the following:

  1. Radiation therapy with concomitant chemotherapy.
  2. Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy.

The size of the tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1]

Either radiation therapy or radical hysterectomy and bilateral lymph-node dissection results in cure rates of 85% to 90% for women with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) stages IA2 and IB1 small-volume disease. The choice of either treatment depends on patient factors and available local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival rates when comparing radiation therapy with radical hysterectomy.[2]

In stage IB2, for tumors that expand the cervix more than 4 cm, the primary treatment should be concomitant chemotherapy and radiation therapy.[3]

Radiation therapy with concomitant chemotherapy

Concurrent, cisplatin-based chemotherapy with radiation therapy is the standard of care for women who require radiation therapy for treatment of cervical cancer.[4][5][6][7][8][9][10] Radiation therapy protocols for patients with cervical cancer have historically used dosing at two anatomical points, termed point A and point B, to standardize the doses received. Point A is defined as 2 cm from the external os, and 2 cm lateral, relative to the endocervical canal. Point B is also 2 cm from the external os, and 5 cm lateral from the patient midline, relative to the bony pelvis. In general, for smaller tumors, the curative-intent dose for point A is around 70 Gy, whereas for larger tumors, the point A dose may approach 90 Gy.

Evidence (radiation with concomitant chemotherapy):

  1. Three randomized, phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy,[4][5][6][7] while one trial that examined this regimen demonstrated no benefit.[8] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.
    • Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.
    • The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.
    • Other trials have confirmed these findings.[9][10]

Brachytherapy

Standard radiation therapy for cervical cancer includes brachytherapy after external-beam radiation therapy (EBRT). Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as components of cervical cancer treatment.[11][12]

Evidence (brachytherapy):

  1. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[13][14][15][Level of evidence: 1iiDii]

    Surgery after radiation therapy may be indicated for some patients with tumors confined to the cervix that respond incompletely to radiation therapy or for patients whose vaginal anatomy precludes optimal brachytherapy.[16]

Pelvic node disease

The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[17] Patients who underwent extraperitoneal lymph-node sampling had fewer bowel complications than those who had transperitoneal lymph-node sampling.[18][19][20] Patients with close vaginal margins (<0.5 cm) may also benefit from pelvic radiation therapy.[21]

Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy

Radical hysterectomy and bilateral pelvic lymphadenectomy may be considered for women with stages IB to IIA disease.

Evidence (radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy):

  1. An Italian group randomly assigned 343 women with stage IB and IIA cervical cancer to surgery or radiation therapy. The radiation therapy included EBRT and one Cs-137 LDR insertion, with a total dose to point A from 70 to 90 Gy (median 76 Gy). Patients in the surgery arm underwent a class III radical hysterectomy, pelvic lymphadenectomy, and selective, para-aortic lymph-node dissection. Adjuvant radiation therapy was given to patients with high-risk pathologic features in the uterine specimen or positive lymph nodes. Adjuvant radiation therapy was EBRT to a total dose of 50.4 Gy over 5 to 6 weeks.[2][Level of evidence: 1iiA]
    • The primary outcome was OS at 5 years, with secondary measures of rate of recurrence and complications. With a median follow-up of 87 months, OS was the same in both groups at 83% (hazard ratio [HR], 1.2; confidence interval [CI], 0.7-2.3; P = .8).
    • Complications were highest among the patients who received adjuvant radiation after surgery.
    • In general, radical hysterectomy should be avoided in patients who are likely to require adjuvant therapy.

Adjuvant radiation therapy post surgery

Based on recurrence rates in previous clinical trials, two classes of recurrence risk have been defined. Patients with a combination of large tumor size, lymph vascular space invasion, and deep stromal invasion in the hysterectomy specimen are deemed to have intermediate-risk disease. These patients are candidates for adjuvant EBRT.[22] Patients whose pathology shows positive margins, positive parametria, or positive lymph nodes are high-risk candidates for recurrence.

Evidence (adjuvant radiation therapy post surgery):

  1. The Gynecologic Oncology Group (GOG) compared adjuvant radiation therapy alone with radiation therapy plus cisplatin plus fluorouracil (5-FU) after radical hysterectomy for patients in the high-risk group. Postoperative patients were eligible if their pathology showed any one of the following: positive parametria, positive margins, or positive lymph nodes. Patients in both arms received 49 Gy to the pelvis. Patients in the experimental arm also received cisplatin (70 mg/m2) and a 96-hour infusion of 5-FU (1000 mg/m2/d every 3 weeks for four cycles); the first two cycles were concurrent with the radiation therapy.[6][Level of evidence: 1iiA]
    • There were 268 patients evaluated with a primary endpoint of OS. The study results were reported early because of the positive results in other trials of concomitant cisplatin and radiation therapy.
    • Estimated 4-year survival was 81% for chemotherapy plus radiation therapy and 71% for radiation therapy alone (HR, 1.96; P = .007).
    • As expected, grade 4 toxicity was more common in the chemotherapy plus radiation therapy group, with hematologic toxicity predominating.

Radical surgery has been performed for small lesions, but the high incidence of pathologic factors leading to postoperative radiation with or without chemotherapy make primary concomitant chemotherapy and radiation a more common approach in patients with larger tumors. Radiation in the range of 50 Gy administered for 5 weeks plus chemotherapy with cisplatin with or without 5-FU should be considered in patients with a high risk of recurrence.

Para-aortic nodal disease

After surgical staging, patients found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[23] Treatment of patients with unresected para-aortic nodes with extended-field radiation therapy and chemotherapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3.[18] A single study (RTOG-7920) showed a survival advantage in patients with tumors larger than 4 cm who received radiation therapy to para-aortic nodes without histologic evidence of disease.[24] Toxic effects were greater with para-aortic radiation therapy than with pelvic radiation therapy alone but were mostly confined to patients with previous abdominopelvic surgery.[24] The use of intensity-modulated radiation therapy (IMRT) may minimize the effects to the small bowel usually associated with this treatment.[25]

Other Treatment Options

  1. Radical trachelectomy.
  2. Neoadjuvant chemotherapy.
  3. Radiation therapy alone.
  4. IMRT.

Radical trachelectomy

Patients with presumed early-stage disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. The patient selection differs somewhat between groups, however, general criteria include the following:

  • Desire for future pregnancy.
  • Age younger than 40 years.
  • Presumed stage IA2 to IB1 disease and a lesion size no greater than 2 cm.
  • Preoperative magnetic resonance imaging that shows a margin from the most distal edge of the tumor to the lower uterine segment.
  • Squamous, adenosquamous, or adenocarcinoma cell types.

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[26][27][28][29][30]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[31][32][33][34][35] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[36] As a result, the control arm utilized radiation therapy alone. Although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) is currently randomly assigning patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. OS is the primary endpoint, and the hope is that this trial will delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Radiation therapy alone

External-beam pelvic radiation therapy combined with two or more intracavitary brachytherapy applications is appropriate therapy for patients with stage IA2 and IB1 lesions. For patients with stage IB2 and larger lesions, radiosensitizing chemotherapy is indicated. The role of radiosensitizing chemotherapy in patients with stage IA2 and IB1 lesions is untested. However, it may prove beneficial in certain cases.

IMRT

IMRT is a radiation therapy technique that allows for conformal dosing of target anatomy while sparing neighboring tissue. Theoretically, this technique should decrease radiation therapy-related toxicity, but this could come at the cost of decreased efficacy if tissue is inappropriately excluded from the treatment field. Several institutions have reported their experience with IMRT for postoperative adjuvant therapy in patients with intermediate-risk and high-risk disease after radical surgery.[37][38][39] The Radiation Therapy Oncology Group (RTOG) has closed accrual for a phase II trial (RTOG-0418 [NCT00331760]) that is evaluating the use of IMRT in patients with both cervical and endometrial cancers who require adjuvant radiation therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IB cervical 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. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69 (11): 2796-806, 1992.

  2. Landoni F, Maneo A, Colombo A, et al.: Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 350 (9077): 535-40, 1997.

  3. Eifel PJ, Burke TW, Delclos L, et al.: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter. Gynecol Oncol 41 (3): 199-205, 1991.

  4. Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999.

  5. Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999.

  6. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000.

  7. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.

  8. Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002.

  9. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.

  10. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008.

  11. Nag S, Chao C, Erickson B, et al.: The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52 (1): 33-48, 2002.

  12. Nag S, Erickson B, Thomadsen B, et al.: The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 48 (1): 201-11, 2000.

  13. Patel FD, Sharma SC, Negi PS, et al.: Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 28 (2): 335-41, 1994.

  14. Hareyama M, Sakata K, Oouchi A, et al.: High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 94 (1): 117-24, 2002.

  15. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, et al.: Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys 59 (5): 1424-31, 2004.

  16. Thoms WW Jr, Eifel PJ, Smith TL, et al.: Bulky endocervical carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 23 (3): 491-9, 1992.

  17. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 160 (5 Pt 1): 1055-61, 1989.

  18. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. Int J Radiat Oncol Biol Phys 23 (3): 501-9, 1992.

  19. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecol Oncol 33 (3): 283-9, 1989.

  20. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. Int J Radiat Oncol Biol Phys 31 (4): 717-23, 1995.

  21. Estape RE, Angioli R, Madrigal M, et al.: Close vaginal margins as a prognostic factor after radical hysterectomy. Gynecol Oncol 68 (3): 229-32, 1998.

  22. Sedlis A, Bundy BN, Rotman MZ, et al.: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol 73 (2): 177-83, 1999.

  23. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecol Oncol 43 (1): 51-4, 1991.

  24. Rotman M, Pajak TF, Choi K, et al.: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA 274 (5): 387-93, 1995.

  25. Poorvu PD, Sadow CA, Townamchai K, et al.: Duodenal and other gastrointestinal toxicity in cervical and endometrial cancer treated with extended-field intensity modulated radiation therapy to paraaortic lymph nodes. Int J Radiat Oncol Biol Phys 85 (5): 1262-8, 2013.

  26. Covens A, Shaw P, Murphy J, et al.: Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer 86 (11): 2273-9, 1999.

  27. Dargent D, Martin X, Sacchetoni A, et al.: Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer 88 (8): 1877-82, 2000.

  28. Plante M, Renaud MC, Hoskins IA, et al.: Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol 98 (1): 3-10, 2005.

  29. Shepherd JH, Spencer C, Herod J, et al.: Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG 113 (6): 719-24, 2006.

  30. Wethington SL, Cibula D, Duska LR, et al.: An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer 22 (7): 1251-7, 2012.

  31. Ferrandina G, Margariti PA, Smaniotto D, et al.: Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery. Gynecol Oncol 119 (3): 404-10, 2010.

  32. Ferrandina G, Distefano MG, De Vincenzo R, et al.: Paclitaxel, epirubicin, and cisplatin (TEP) regimen as neoadjuvant treatment in locally advanced cervical cancer: long-term results. Gynecol Oncol 128 (3): 518-23, 2013.

  33. Zanaboni F, Grijuela B, Giudici S, et al.: Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study. Eur J Cancer 49 (5): 1065-72, 2013.

  34. Manci N, Marchetti C, Di Tucci C, et al.: A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol 122 (2): 285-90, 2011.

  35. Gong L, Lou JY, Wang P, et al.: Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet 117 (1): 23-6, 2012.

  36. Benedetti-Panici P, Greggi S, Colombo A, et al.: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20 (1): 179-88, 2002.

  37. Chen MF, Tseng CJ, Tseng CC, et al.: Adjuvant concurrent chemoradiotherapy with intensity-modulated pelvic radiotherapy after surgery for high-risk, early stage cervical cancer patients. Cancer J 14 (3): 200-6, 2008 May-Jun.

  38. Hasselle MD, Rose BS, Kochanski JD, et al.: Clinical outcomes of intensity-modulated pelvic radiation therapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 80 (5): 1436-45, 2011.

  39. Folkert MR, Shih KK, Abu-Rustum NR, et al.: Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer. Gynecol Oncol 128 (2): 288-93, 2013.

Stages IIB, III, and IVA Cervical Cancer Treatment

Standard Treatment Options for Stages IIB, III, and IVA Cervical Cancer

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] Survival and local control are better with unilateral rather than bilateral parametrial involvement.[2] Patterns-of-care studies in stages IIIA and IIIB patients indicate that survival is dependent on the extent of the disease, with unilateral pelvic wall involvement predicting a better outcome than bilateral involvement, which in turn predicts a better outcome than involvement of the lower third of the vaginal wall.[2] These studies also reveal a progressive increase in local control and survival paralleling a progressive increase in paracentral (point A) dose and use of intracavitary treatment. The highest rate of central control was seen with paracentral (point A) doses of more than 85 Gy.[3]

Standard treatment options for stage IIB, stage III, and stage IVA cervical cancer include the following:

  1. Radiation therapy with concomitant chemotherapy.[4]

Radiation therapy with concomitant chemotherapy

Strong consideration should be given to the use of intracavitary radiation therapy and external-beam radiation therapy (EBRT) to the pelvis combined with cisplatin or cisplatin/fluorouracil (5FU).[5][6][7][8][9][10][11][12]

Evidence (radiation therapy with concomitant chemotherapy):

  1. Five randomized, phase III trials have shown an overall survival (OS) advantage for cisplatin-based therapy given concurrently with radiation therapy,[5][6][7][8][9][10] but one trial that examined this regimen demonstrated no benefit.[13] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.
    • Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.
    • The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.

Evidence (low-dose rate vs. high-dose rate intracavitary radiation therapy):

  1. Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[14][15]
  2. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[16][17][18][Level of evidence: 1iiDii]
  3. In an attempt to improve upon standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stages IIB to IVA cervical cancer.[19][Level of evidence: 1iiA] A total of 515 patients from nine countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks with concurrent EBRT (50.4 Gy in 28 fractions) followed by brachytherapy (30-35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent EBRT and brachytherapy as described for the experimental arm.
    • The primary endpoint was progression-free survival (PFS) at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4%; 95% confidence interval [CI], 68%-79.8% vs. 65.0%; 95% CI, 58.5%-70.7%); overall PFS (hazard ratio [HR], 0.68; 95% CI, 0.49-0.95); and OS (HR, 0.68; 95% CI, 0.49-0.95). Patients in the experimental arm had increased hematologic and nonhematologic grade 3 or 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment.

    A subgroup analysis showed an increased benefit in patients with a higher stage of disease (stages III-IVA vs. stage IIB), which suggested that the increased toxic effects of the experimental protocol may be justified for these patients.[20] Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and to determine quality of life during and after treatment, a condition that was omitted from the protocol.

The addition of adjuvant chemotherapy following chemoradiation therapy is currently being evaluated as part of a large multinational clinical trial. The OUTBACK trial (NCT01414608) is randomly assigning women to receive cisplatin (40 mg/m2 weekly for 5 doses) with whole-pelvic radiation therapy (standard chemoradiation therapy) with or without standard chemoradiation therapy plus adjuvant carboplatin (AUC 5 + paclitaxel 155 mg/m2).

Lymph Node Management

Patients who are surgically staged as part of a clinical trial and are found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[21] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3.[22] A single study (RTOG-7920) showed a survival advantage in patients who received radiation therapy to para-aortic nodes without histologic evidence of disease.[23] Toxic effects are greater with para-aortic radiation than with pelvic radiation alone but were mostly confined to patients with previous abdominopelvic surgery.[23]

If postoperative EBRT is planned following surgery, extraperitoneal lymph-node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[24] Patients who underwent extraperitoneal lymph-node sampling had fewer bowel complications than those who had transperitoneal lymph-node sampling.[22][24][25]

The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[26] In addition, prospective data points to improvement in outcomes for patients who undergo resection of positive para-aortic lymph nodes before curative intent chemoradiation therapy; however, only patients with minimal nodal involvement (<5mm) benefited.[27]

Other Treatment Options

  1. Interstitial brachytherapy.
  2. Neoadjuvant chemotherapy.

Interstitial brachytherapy

For patients who complete EBRT and have bulky cervical disease such that standard brachytherapy cannot be placed anatomically, interstitial brachytherapy has been used to deliver adequate tumoricidal doses with an acceptable toxicity profile.[28]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[29][30][31][32][33] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[34] As a result, although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) is currently randomly assigning patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. OS is the primary endpoint, and the hope is that this trial will delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIB cervical 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. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69 (11): 2796-806, 1992.

  2. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer. A study of patterns of care. Cancer 69 (2): 482-7, 1992.

  3. Lanciano RM, Martz K, Coia LR, et al.: Tumor and treatment factors improving outcome in stage III-B cervix cancer. Int J Radiat Oncol Biol Phys 20 (1): 95-100, 1991.

  4. Monk BJ, Tewari KS, Koh WJ: Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol 25 (20): 2952-65, 2007.

  5. Whitney CW, Sause W, Bundy BN, et al.: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17 (5): 1339-48, 1999.

  6. Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999.

  7. Rose PG, Bundy BN, Watkins EB, et al.: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340 (15): 1144-53, 1999.

  8. Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999.

  9. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000.

  10. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.

  11. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.

  12. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008.

  13. Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002.

  14. Nag S, Chao C, Erickson B, et al.: The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52 (1): 33-48, 2002.

  15. Nag S, Erickson B, Thomadsen B, et al.: The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 48 (1): 201-11, 2000.

  16. Patel FD, Sharma SC, Negi PS, et al.: Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 28 (2): 335-41, 1994.

  17. Hareyama M, Sakata K, Oouchi A, et al.: High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 94 (1): 117-24, 2002.

  18. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, et al.: Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys 59 (5): 1424-31, 2004.

  19. Dueñas-González A, Zarbá JJ, Patel F, et al.: Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 29 (13): 1678-85, 2011.

  20. Dueňas-González A, Orlando M, Zhou Y, et al.: Efficacy in high burden locally advanced cervical cancer with concurrent gemcitabine and cisplatin chemoradiotherapy plus adjuvant gemcitabine and cisplatin: prognostic and predictive factors and the impact of disease stage on outcomes from a prospective randomized phase III trial. Gynecol Oncol 126 (3): 334-40, 2012.

  21. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecol Oncol 43 (1): 51-4, 1991.

  22. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. Int J Radiat Oncol Biol Phys 23 (3): 501-9, 1992.

  23. Rotman M, Pajak TF, Choi K, et al.: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA 274 (5): 387-93, 1995.

  24. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecol Oncol 33 (3): 283-9, 1989.

  25. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. Int J Radiat Oncol Biol Phys 31 (4): 717-23, 1995.

  26. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 160 (5 Pt 1): 1055-61, 1989.

  27. Gouy S, Morice P, Narducci F, et al.: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 31 (24): 3026-33, 2013.

  28. Pinn-Bingham M, Puthawala AA, Syed AM, et al.: Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results. Int J Radiat Oncol Biol Phys 85 (3): 714-20, 2013.

  29. Ferrandina G, Margariti PA, Smaniotto D, et al.: Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery. Gynecol Oncol 119 (3): 404-10, 2010.

  30. Ferrandina G, Distefano MG, De Vincenzo R, et al.: Paclitaxel, epirubicin, and cisplatin (TEP) regimen as neoadjuvant treatment in locally advanced cervical cancer: long-term results. Gynecol Oncol 128 (3): 518-23, 2013.

  31. Zanaboni F, Grijuela B, Giudici S, et al.: Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study. Eur J Cancer 49 (5): 1065-72, 2013.

  32. Manci N, Marchetti C, Di Tucci C, et al.: A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol 122 (2): 285-90, 2011.

  33. Gong L, Lou JY, Wang P, et al.: Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet 117 (1): 23-6, 2012.

  34. Benedetti-Panici P, Greggi S, Colombo A, et al.: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20 (1): 179-88, 2002.

Stage IVB Cervical Cancer Treatment

Standard Treatment Options for Stage IVB Cervical Cancer

Standard treatment options for stage IVB cervical cancer include the following:

  1. Palliative radiation therapy.
  2. Palliative chemotherapy.

Palliative radiation therapy

Radiation therapy may be used to palliate central disease or distant metastases.

Palliative chemotherapy

Multiple agents are associated with objective response rates, however, durable responses are rare.

Drugs used in stage IVB cervical cancer treatment are shown in Table 6.

Table 6. Drugs Used to Treat Stage IVB Cervical Cancer

Drug Name

Response Rate

Cisplatin [1][2]

15%-25%

Ifosfamide [3]

31%

Paclitaxel [4][5][6]

17%

Ifosfamide/cisplatin [7][8]

31%

Irinotecan [9]

21% in patients previously treated with chemotherapy

Paclitaxel/cisplatin [10]

46%

Cisplatin/gemcitabine [11]

41%

Cisplatin/topotecan [12]

27%

Cisplatin in combination with other drugs

Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks has been the regimen most often used to treat recurrent cervical cancer since the drug was initially introduced in the 1970's.[2] More recently, the GOG has reported on sequential randomized trials dealing with combination chemotherapy for stages IVB, recurrent, or persistent cervical cancer.[8][12][13][14][15][16]

Evidence (cisplatin in combination with other drugs):

  1. GOG-110, GOG-0179, GOG-0169:
    • GOG 110: The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary endpoint of response rates, but at the cost of increased toxicity.
    • GOG 0179: The cisplatin + topotecan (CT) doublet combination had a significant advantage in overall survival (OS) compared with cisplatin alone, leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.[12]
    • GOG 0169: The paclitaxel + cisplatin (PC) combination, similarly, was superior in response rates and progression-free survival (PFS), and its toxicity was similar to that of the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic-4, totally bedridden). Therefore, PC was chosen as the reference arm in GOG-0204 (NCT00064077).
  2. GOG-0204 enrolled 513 patients and compared four cisplatin-based doublet regimens. The trial was closed early because no one experimental arm was likely to significantly lower the hazard ratio of death relative to PC:[16]
    • 1.15 (95% confidence interval [CI], 0.79-1.67) for vinorelbine + cisplatin (VC).
    • 1.32 (95% CI, 0.91-1.92) for gemcitabine plus cisplatin.
    • 1.27 (95% CI, 0.90-1.78) for CT. Trend in response rates, PFS, and OS favored CT.
    • The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced,[16] but none of the patients in the study arms differed in health-related quality of life during treatment.[17] However, there were more neurologic side effects for PC.
  3. GOG-0240 (NCT00803062) was designed to answer the following two questions:[18]
    • Can a nonplatinum combination show improvement over the standard of cisplatin-paclitaxel in this population that was previously treated with cisplatin during radiation therapy?
    • Can the addition of bevacizumab improve combination chemotherapy in patients with stages IVB, persistent, or recurrent cervical cancer?

    Patients were randomly assigned to the following four treatment arms:

    • Cisplatin (50 mg/m2) + paclitaxel (135 mg/m2 or 175 mg/m2) on day 1 (PC).
    • PC + bevacizumab (15mg/kg) on day 1.
    • Topotecan (0.75 mg/m2) d1-d3 + paclitaxel (175 mg/m2) day 1 (PT).
    • PT + bevacizumab (15mg/kg) on day 1.

    Additional study methods and results included the following:

    • The primary endpoint was OS, and 452 patients were evaluable.
    • The combination PT was not superior to PC and had a hazard ratio (HR) for death of 1.2 (99% CI, 0.82-1.76). Previous exposure to platinum did not affect this result.
    • The addition of bevacizumab to combination chemotherapy led to an improvement in OS: 17 months for chemotherapy plus bevacizumab versus 13.3 months for chemotherapy alone (HR, 0.71; 98% CI, 0.54-0.95), and extended PFS: 8.2 months for chemotherapy plus bevacizumab versus 5.9 months for chemotherapy alone, (HR, 0.67; CI, 0.54-0.82).
    • The addition of bevacizumab was well tolerated and showed no difference in quality of life between the two groups.
    • Patients on bevacizumab were more likely to have grade 3 or higher fistulae (6% vs. 0%), and grade 3 or higher thromboembolic events (8% vs. 1%) compared with patients on chemotherapy alone.
    • As a result, the addition of bevacizumab may be considered for this patient population.

Treatment Options Under Clinical Evaluation for Stage IVB Cervical Cancer

Treatment options under clinical evaluation for stage IVB cervical cancer include the following:

  1. New anticancer drugs in phase I and phase II clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVB cervical 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. Alberts DS, Kronmal R, Baker LH, et al.: Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J Clin Oncol 5 (11): 1791-5, 1987.

  2. Thigpen JT, Blessing JA, DiSaia PJ, et al.: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol 32 (2): 198-202, 1989.

  3. Coleman RE, Harper PG, Gallagher C, et al.: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 18 (3): 280-3, 1986.

  4. Kudelka AP, Winn R, Edwards CL, et al.: Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Clin Cancer Res 2 (8): 1285-8, 1996.

  5. Thigpen T, Vance RB, Khansur T: The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Semin Oncol 22 (5 Suppl 12): 67-75, 1995.

  6. McGuire WP, Blessing JA, Moore D, et al.: Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 14 (3): 792-5, 1996.

  7. Buxton EJ, Meanwell CA, Hilton C, et al.: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81 (5): 359-61, 1989.

  8. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15 (1): 165-71, 1997.

  9. Verschraegen CF, Levy T, Kudelka AP, et al.: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 15 (2): 625-31, 1997.

  10. Rose PG, Blessing JA, Gershenson DM, et al.: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 17 (9): 2676-80, 1999.

  11. Burnett AF, Roman LD, Garcia AA, et al.: A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 76 (1): 63-6, 2000.

  12. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al.: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23 (21): 4626-33, 2005.

  13. Tewari KS, Monk BJ: Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer. Curr Oncol Rep 7 (6): 419-34, 2005.

  14. Moore DH, Blessing JA, McQuellon RP, et al.: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (15): 3113-9, 2004.

  15. Tewari KS, Monk BJ: Recent achievements and future developments in advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group. Semin Oncol 36 (2): 170-80, 2009.

  16. Monk BJ, Sill MW, McMeekin DS, et al.: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 27 (28): 4649-55, 2009.

  17. Cella D, Huang HQ, Monk BJ, et al.: Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 119 (3): 531-7, 2010.

  18. Tewari KS, Sill MW, Long HJ 3rd, et al.: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370 (8): 734-43, 2014.

Recurrent Cervical Cancer Treatment

Treatment Options for Recurrent Cervical Cancer

Treatment options for recurrent cervical cancer include the following:

  1. Radiation therapy and chemotherapy.
  2. Palliative chemotherapy.
  3. Pelvic exenteration.

Radiation therapy and chemotherapy

For recurrence in the pelvis after initial radical surgery, radiation therapy and chemotherapy (fluorouracil with or without mitomycin) may cure 40% to 50% of patients.[1]

Palliative chemotherapy

Chemotherapy can be used for palliation. Drugs used for palliative chemotherapy are shown in Table 7.

Table 7. Drugs Used to Treat Recurrent Cervical Cancer

Drug name

Response rate

Cisplatin [2]

15%-25%

Ifosfamide [3][4]

15%-30%

Paclitaxel [5]

17%

Irinotecan [6]

21% in patients previously treated with chemotherapy

Bevacizumab [7]

11%; 24% survived progression free for at least 6 months, as seen in GOG-0227C (NCT00025233)

Ifosfamide/cisplatin [8][9]

31%

Paclitaxel/cisplatin [10]

46%

Cisplatin/gemcitabine [11]

41%

Cisplatin/topotecan [12]

27%

Cisplatin/vinorelbine [13]

30%

Cisplatin in combination with other drugs

Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks has been the regimen most often used to treat recurrent cervical cancer since the drug was initially introduced in the 1970's.[2] More recently, the GOG has reported on sequential randomized trials dealing with combination chemotherapy for stage IVB, recurrent, or persistent cervical cancer.[9][12][14][15][16][17]

Evidence (cisplatin in combination with other drugs):

  1. GOG-110, GOG-0179, GOG-0169 (NCT00803062)
    • GOG 110: The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary endpoint of response rates, but at the cost of increased toxicity.
    • GOG 0179: The cisplatin + topotecan (CT) doublet combination had a significant advantage in overall survival (OS) compared with cisplatin alone, leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.[12]
    • GOG 0169: The paclitaxel + cisplatin (PC) combination, similarly, was superior in response rates and progression-free survival (PFS), and its toxicity was similar to that of the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic-4, totally bedridden). Therefore, paclitaxel plus cisplatin (PC) was chosen as the reference arm in GOG-0204 (NCT00064077).
  2. GOG-0204 enrolled 513 patients and compared four cisplatin-based doublet regimens. The trial was closed early because no one experimental arm was likely to significantly lower the hazard ratio of death relative to PC:[17]
    • 1.15 (95% confidence interval [CI], 0.79-1.67) for vinorelbine + cisplatin (VC).
    • 1.32 (95% CI, 0.91-1.92) for gemcitabine plus cisplatin.
    • 1.27 (95% CI, 0.90-1.78) for CT. Trend in RR, PFS, and OS favored CT.
    • The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced,[17] but none of the patients in the study arms differed in health-related quality of life during treatment.[18] However, there were more neurologic side effects for PC.
  3. GOG-0240 (NCT00803062) was designed to answer the following two questions:[19]
    • Can a nonplatinum combination show improvement over the standard of cisplatin-paclitaxel in this population previously treated with cisplatin during radiation therapy?
    • Can the addition of bevacizumab improve upon combination chemotherapy in patients with stage IVB, persistent or recurrent cervical cancer?

    Patients were randomly assigned to the following four treatment arms:

    • Cisplatin (50 mg/m2) + paclitaxel (135 mg/m2 or 175 mg/m2) on day 1 (PC).
    • PC + bevacizumab (15mg/kg) on day 1.
    • Topotecan (0.75 mg/m2) d1-d3 + paclitaxel (175 mg/m2) on day 1 (PT).
    • PT + bevacizumab (15mg/kg) on day 1.

    Additional study methods and results included the following:

    • The primary endpoint was OS, and 452 patients were evaluable.
    • The combination PT was not superior to PC and had a hazard ratio (HR) for death of 1.2 (99% CI, 0.82-1.76). Previous exposure to platinum did not affect this result.
    • The addition of bevacizumab to combination chemotherapy led to an improvement in OS: 17 months for chemotherapy plus bevacizumab versus 13.3 months for chemotherapy alone (HR, 0.71; 98% CI, 0.54-0.95), and extended PFS: 8.2 months for chemotherapy plus bevacizumab versus 5.9 months for chemotherapy alone, HR, 0.67; (CI, 0.54-0.82).
    • The addition of bevacizumab was well tolerated and showed no difference in quality of life between the two groups.
    • Patients on bevacizumab were more likely to have grade 3 or higher fistulae (6% vs. 0%), and grade 3 or higher thromboembolic events (8% vs. 1%) compared with patients on chemotherapy alone.
    • As a result, the addition of bevacizumab may be considered for this patient population.

Pelvic exenteration

No standard treatment is available for patients with recurrent cervical cancer that has spread beyond the confines of a radiation or surgical field. For locally recurrent disease, pelvic exenteration can lead to a 5-year survival rate of 32% to 62% in selected patients.[20][21] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.

Treatment Options Under Clinical Evaluation for Recurrent Cervical Cancer

Treatment options under clinical evaluation for recurrent cervical cancer include the following:

  1. New anticancer drugs in phase I and phase II clinical 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 cervical 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. Thomas GM, Dembo AJ, Black B, et al.: Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery. Gynecol Oncol 27 (3): 254-63, 1987.

  2. Thigpen JT, Blessing JA, DiSaia PJ, et al.: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol 32 (2): 198-202, 1989.

  3. Coleman RE, Harper PG, Gallagher C, et al.: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 18 (3): 280-3, 1986.

  4. Sutton GP, Blessing JA, McGuire WP, et al.: Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group study. Am J Obstet Gynecol 168 (3 Pt 1): 805-7, 1993.

  5. McGuire WP, Blessing JA, Moore D, et al.: Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 14 (3): 792-5, 1996.

  6. Verschraegen CF, Levy T, Kudelka AP, et al.: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 15 (2): 625-31, 1997.

  7. Monk BJ, Sill MW, Burger RA, et al.: Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 27 (7): 1069-74, 2009.

  8. Buxton EJ, Meanwell CA, Hilton C, et al.: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81 (5): 359-61, 1989.

  9. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15 (1): 165-71, 1997.

  10. Rose PG, Blessing JA, Gershenson DM, et al.: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 17 (9): 2676-80, 1999.

  11. Burnett AF, Roman LD, Garcia AA, et al.: A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 76 (1): 63-6, 2000.

  12. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al.: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23 (21): 4626-33, 2005.

  13. Morris M, Blessing JA, Monk BJ, et al.: Phase II study of cisplatin and vinorelbine in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (16): 3340-4, 2004.

  14. Tewari KS, Monk BJ: Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer. Curr Oncol Rep 7 (6): 419-34, 2005.

  15. Moore DH, Blessing JA, McQuellon RP, et al.: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (15): 3113-9, 2004.

  16. Tewari KS, Monk BJ: Recent achievements and future developments in advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group. Semin Oncol 36 (2): 170-80, 2009.

  17. Monk BJ, Sill MW, McMeekin DS, et al.: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 27 (28): 4649-55, 2009.

  18. Cella D, Huang HQ, Monk BJ, et al.: Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 119 (3): 531-7, 2010.

  19. Tewari KS, Sill MW, Long HJ 3rd, et al.: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370 (8): 734-43, 2014.

  20. Alberts DS, Kronmal R, Baker LH, et al.: Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J Clin Oncol 5 (11): 1791-5, 1987.

  21. Tumors of the cervix. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. New York, NY: Churchill Livingstone, 1998, pp 107-151.

Cervical Cancer During Pregnancy

During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, although expert colposcopy is recommended to exclude invasive cancer.

Diagnosis

Treatment of cervical cancer in pregnancy is predicated on the extent of disease and the gestational age at diagnosis. Patients should undergo biopsy as needed and imaging to establish the extent of disease to make the most informed choices. The most appropriate imaging modality in pregnancy is magnetic resonance imaging, when indicated.

Treatment for Stage I Disease

Pregnancy does not alter the course of cervical cancer. As a result, in certain cases, patients may elect to postpone treatment until its effects on the pregnancy are minimized. This may be considered for patients with the more common, and less aggressive histologic subtypes: squamous, adenocarcinoma, and adenosquamous. Patients with high-risk subtypes, such as small cell or neuroendocrine tumors, should be counseled toward immediate treatment despite the effects on the fetus, given their risk of progression.

Patients with early stage (IA) disease may safely undergo fertility-sparing treatments including cervical conization or radical trachelectomy, as indicated. The optimal timing for this procedure is in the second trimester, before viability. Some authors have suggested waiting until the completion of a pregnancy to initiate treatment.[1] For patients with IA2 and IB disease such a delay may also be safe, but because of a risk of lymphatic spread, assessment of lymph-node status should first be ascertained. The status is best determined surgically via a laparoscopic or open lymph-node dissection, which can be safely performed up to approximately 20 weeks of pregnancy.[2][3] In patients without lymphatic spread, waiting for fetal viability to initiate treatment is an option. Patients with positive lymph nodes should be counseled toward immediate treatment.

Treatment for Stages II, III, and IV Disease

For patients with stage II or greater disease, waiting for viability is generally not acceptable.[4] The standard of care is curative intent chemotherapy and radiation therapy. This treatment is toxic to the fetus and without ovarian transposition will render the ovaries nonfunctional after treatment. Evacuation of the fetus should be performed before the initiation of radiation. When this is not possible, the radiation will generally cause a spontaneous abortion 3 to 5 weeks after initiating treatment.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy has been offered to patients with locally advanced disease as a way to initiate treatment while maintaining the pregnancy.[1] Most chemotherapy agents can be initiated safely in the second trimester of pregnancy and beyond; mild growth restriction of the fetus is the most common side effect. Restriction of growth has been reported in a relatively small number of patients, and data is lacking on long-term outcomes for these women; as a result, this strategy should be considered with caution. Most of the patients in the reports underwent standard treatment (either surgery or radiation) after completion of the pregnancy.

References:

  1. Morice P, Uzan C, Gouy S, et al.: Gynaecological cancers in pregnancy. Lancet 379 (9815): 558-69, 2012.

  2. Alouini S, Rida K, Mathevet P: Cervical cancer complicating pregnancy: implications of laparoscopic lymphadenectomy. Gynecol Oncol 108 (3): 472-7, 2008.

  3. Favero G, Chiantera V, Oleszczuk A, et al.: Invasive cervical cancer during pregnancy: laparoscopic nodal evaluation before oncologic treatment delay. Gynecol Oncol 118 (2): 123-7, 2010.

  4. Hunter MI, Tewari K, Monk BJ: Cervical neoplasia in pregnancy. Part 2: current treatment of invasive disease. Am J Obstet Gynecol 199 (1): 10-8, 2008.


This information is provided by the National Cancer Institute.

This information was last updated on August 15, 2014.


 
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