Treatment of early stage cervical cancer for women who desire future pregnancy

INTRODUCTION — More than 10,000 American women develop cancer of the uterine cervix (cervical cancer) each year. Cervical cancer is most frequently diagnosed in women between the ages of 45 and 49. A Pap test (also called cervical cytology screening) involves scraping cells from the cervix and examining them under a microscope; this test can detect abnormal changes in the cells of the cervix before they become cancerous. As a result of the widespread use of Pap tests, the number of women diagnosed with cervical cancer has decreased steadily over the past 50 years. Pre-cancerous lesions are detected far more frequently than invasive cervical cancer. (See "Patient information: Screening for cervical cancer").

Cervical cancer is a treatable condition, and there is a good chance of cure if it is found and treated in the early stages. This topic review discusses the diagnosis and treatment of women with the earliest stages of localized cervical cancer who wish to preserve their ability to become pregnant in the future. A separate topic review discusses the standard treatment of all early stage cervical cancers (which usually includes hysterectomy). (See "Patient information: Treatment of early stage cervical cancer").

THE CERVIX — The uterus (womb) opens into the vagina through the cervix (show figure 1). Squamous cells make up the outer layer of the cervix. Squamous cell carcinoma of the cervix is the name for cancer that affects these cells.

The cervix also includes glandular (also called columnar) cells, which line the opening of the cervix and the canal that leads into the uterus (the endocervical canal) (show picture 1). These cells can also become cancerous; when they do, they are called adenocarcinomas of the cervix. Although they arise from different types of cells, squamous cell carcinoma and adenocarcinoma of the cervix are treated similarly in the early stages.

SIGNS AND SYMPTOMS — Typically, cervical cancers develop slowly over a period of several years. The first step is that the cells of the cervix become abnormal in appearance (called dysplasia). These precancerous cells usually cause no signs or symptoms, but can often be detected with a Pap test and treated effectively before they develop into a cancer. Therefore, all women who have a cervix should have regular screening with Pap tests. (See "Patient information: Screening for cervical cancer").

If a cervical cancer does develop, it may initially cause no symptoms or it may cause abnormal vaginal discharge or bleeding. This can include bleeding between menstrual periods, bleeding after sexual intercourse, or bleeding after menopause. This bleeding may be no more than a spot of blood.

Abnormal vaginal bleeding can also be caused by a number of other conditions that may or may not be related to cancer. Any woman who develops abnormal vaginal bleeding should consult a healthcare provider.

RISK FACTORS — The most important risk factor for cervical cancer is infection with a virus called human papillomavirus (HPV). HPV is spread by direct skin-to-skin contact, including sexual intercourse, oral sex, anal sex, or any other contact involving the genital area (eg, hand to genital contact). HPV infection can also cause a noncancerous condition called condyloma (genital warts). (See "Patient information: Condyloma (genital warts) in women").

Most HPV infections are temporary because the body's immune system effectively clears the infection. When certain types of the HPV virus persist in the body, there is a higher likelihood that the viral infection will cause cervical cell abnormalities such as dysplasia or cancer; persistent infections are believed to occur in 10 to 20 percent of women. Evidence of HPV infection can be detected in almost all cervical cancers (squamous cell carcinomas as well as adenocarcinomas). For more information about HPV testing, see "Patient information: Screening for cervical cancer".

Additional risk factors for cervical cancer include cigarette smoking and a weakened immune system (caused by certain diseases, medications, or HIV/AIDS).

DIAGNOSIS AND STAGING — Cervical cancer is diagnosed with a cervical biopsy. A biopsy involves removing a small piece of abnormal appearing tissue. This is done either because the clinician sees an abnormal area on the cervix, or because of an abnormal Pap test. The biopsy is performed during an office visit using a procedure called colposcopy. The colposcope (similar to a large magnifying lens) magnifies the cervix (show picture 2). This allows the clinician to better see the location, extent, and degree of very small abnormalities that may not be visible with the naked eye alone.

The tissue obtained during the biopsy is analyzed under a microscope to determine if cancer cells are present. Sometimes the small, colposcopy-directed biopsies are not sufficient to diagnose cervical cancer and a larger biopsy, called cervical conization, is needed. If a biopsy shows the presence of a cervical cancer, the woman should consult with a doctor who specializes in cancers of the female reproductive system (called a gynecologic oncologist). A gynecologic oncologist has received specialized training in the techniques needed to diagnose and treat cervical as well as other gynecologic cancers.

FIGO staging system — Once a diagnosis of cervical cancer is made, the next step in the evaluation is to assess the "stage" of the cancer. Staging is a system that describes the size of the cancer and any signs of spread. For all cancers, including cervical cancer, treatment and prognosis depend upon the tumor stage. For cervical cancers, the stage is based upon the size of the cancer and how deeply it has invaded into the tissues surrounding the cervix, whether the vagina, side walls of the pelvis, or local lymph nodes are involved, and whether the cancer has spread to other organs (metastasis).

The International Federation of Gynecologists and Obstetricians (FIGO) system is the most commonly used staging system for cervical cancer (show table 1). This system classifies the extent of disease involvement as stage 0 through IV (four), with IV being the most advanced stage [1].

The FIGO staging system is mainly based upon the results of physical examination, which includes a complete pelvic (internal) examination of the cervix, uterus, and ovaries. Other procedures such as cystoscopy (to view the lining of the bladder), proctoscopy (to view the lining of the rectum), and intravenous pyelogram (a radiologic test to evaluate the kidneys, ureters, bladder, and urethra) may also be performed to evaluate how far the cancer has invaded locally. Patients may be asked to undergo an chest x-ray or bone x-rays to detect distant spread to the lungs or bone.

Other imaging tests are often recommended to determine the best treatment approach, but the results do typically not change the FIGO stage. These include computed tomography (CT scan), magnetic resonance imaging (MRI), and/or positron emission tomography (PET scan).

TREATMENT OPTIONS — Early stage cervical cancer refers to stage IA, IB, and some small IIA tumors (show table 1). There are several options for treatment of these women. The optimal choice depends upon the stage, the estimated risk of a cancer recurrence following treatment, the woman's age and plans for future pregnancy, whether underlying medical conditions are present, and the preferences of the patient and her physician.

Radical hysterectomy — For women with early stage cervical cancer who do not plan pregnancy in the future, a radical hysterectomy (surgical removal of the uterus, cervix and upper part of the vagina) is the standard treatment. The alternative is radiation therapy, which is usually given in combination with chemotherapy. Future pregnancies are not possible after radical hysterectomy or radiation therapy. (See "Patient information: Treatment of abnormal Pap smears" for information about conization and see "Patient information: Vaginal hysterectomy" for information about simple hysterectomy and see "Patient information: Treatment of early stage cervical cancer" for information about radiation therapy and chemotherapy).

Fertility-preserving therapy — Some women who wish to preserve the ability to carry a pregnancy after treatment may be eligible for less aggressive forms of treatment. Treatments that allow a woman to preserve her ability to carry a pregnancy include the following: Conization (currently recommended only for the earliest microscopic cervical cancers that do not invade very deeply into the cervix [stage IA1] cancers) Radical trachelectomy (a management option for stage IA tumors that invade the cervix a little more deeply (stage IA2) and small visible tumors that are smaller than 4 cm (2 inches, stage IB1 tumors)

Trials have not been done to directly compare outcomes and risk of cancer recurrence of fertility preserving surgery versus radical hysterectomy or radiation therapy. However, available studies suggest that, for appropriately selected young women with early stage IA and IB cervical cancers, fertility-preserving surgery is an acceptable option.

Cervical conization — Cervical conization is the surgical removal of a cone-shaped portion of cervix, including the cancerous area (show figure 2). Conization is performed through the vagina. In order for conization to be considered a reasonable treatment for early superficial cervical cancer, the following criteria must be met on the cervical biopsy: Invasion of cancer cells is no deeper than 3 mm into the cervix. There is no evidence of cancer in the lymphatic or blood vessels The margins (edges) of the cone biopsy and samples of the endocervical cells (biopsy or scraping of cells from the lining of the endocervical canal) must have no evidence of abnormal cells.

Conization is usually performed in the operating room after the woman receives either general or regional anesthesia. General anesthesia induces sleep and prevents pain while regional anesthesia (eg, spinal or epidural) delivers medication to the space around the spinal cord to prevent pain while the patient remains awake during the procedure. Most women can go home the same day or the morning after the procedure.

Alternately, a loop electrosurgical excision procedure (LEEP) may be performed using local anesthesia in the physician's office (show figure 3). (See "Patient information: Treatment of abnormal Pap smears" for more information about LEEP).

Following conization, most gynecologic oncologists recommend that the woman avoid sexual intercourse, not place anything in the vagina, and not take a bath or swim for a few weeks (showers are fine); these activities could potentially interfere with healing. Some bleeding is expected, although it should not be heavy. If bleeding becomes heavy (eg, soaks a pad in less than an hour) or continues for more than one week, the woman should contact her healthcare provider.

After conization, follow up examinations are recommended to ensure that there is no evidence of cervical cancer (see "Follow up" below).

Radical trachelectomy — Conization is not an acceptable treatment for women with early stage IA or IB cervical cancer who do not meet the above criteria. Women who have more deeply invading microscopic stage IA tumors (stage IA2 disease) or a visible tumor that is smaller than 4 cm in size (stage IB1 disease) who wish to preserve future fertility may be appropriate candidates for a procedure called radical trachelectomy.

Clinical studies show that the rate of cancer recurrence after radical trachelectomy is similar to the rate of recurrence after radical hysterectomy. However, longer follow up and more clinical studies are needed to confirm this. Trachelectomy is still considered by many experts to be a relatively new, non-standard form of treatment for stage IA2 and IB1 disease.

Radical trachelectomy is defined as partial or complete surgical removal of the cervix and parametria (connective tissues next to the uterus and cervix). Radical trachelectomy removes much more of the cervix compared to cervical conization (show figure 4). The procedure is performed in the operating room after the woman receives either general or regional anesthesia. General anesthesia induces sleep and prevents pain while regional anesthesia (eg, spinal or epidural) delivers medication to the space around the spinal cord to prevent pain in a patient who remains awake during the procedure.

Trachelectomy may be done through an incision in the vagina or abdomen, depending upon the surgeon's preference. The cervix and upper portion of the vagina may be completely or partially removed, depending upon the size and depth of the cancer. A permanent purse-string stitch (cerclage) is placed at the lower end of the uterus or remaining cervix (show figure 4).

Before trachelectomy begins, most women undergo surgical removal of lymph nodes within the pelvis to be sure that the cancer has not spread; this is called lymphadenectomy (show figure 5). The nodes may be removed through an incision in the abdomen (if an abdominal incision made for the trachelectomy), which allows the physician to see the nodes directly.

Alternately, the nodes are removed with the assistance of a laparoscope. When the laparoscope is used to perform the procedure, smaller incisions are made in the abdomen to insert instruments, including a laparoscope and camera, which are used to find and remove selected lymph nodes. If laparoscopic lymphadenectomy is performed, the radical trachelectomy is performed through the vagina.

After removal, the lymph nodes are examined under a microscope to preliminarily confirm that cancer cells are absent. If any nodes are found to contain cancer cells, trachelectomy is not performed, and more aggressive therapy (radical hysterectomy or chemoradiotherapy) is usually recommended. (See "Patient information: Treatment of early stage cervical cancer").

Following trachelectomy, most gynecologic oncologists recommend that the woman avoid sexual intercourse, not place anything in the vagina, or take a bath or swim for four to six weeks (showers are fine); these activities could potentially interfere with healing. Some bleeding is expected for approximately one week, although it should not be heavy. If bleeding becomes heavy (eg, soaks a pad in less than an hour) or continues for more than one week, the woman should contact her healthcare provider.

After trachelectomy, follow up examinations and testing are recommended to ensure that there is no evidence of cervical cancer (see "Follow up" below).

Need for further treatment — Further surgery may be required if abnormal or cancerous cells are found at the margins (edges) of the area that is surgically removed during conization or trachelectomy. For a woman who had conization, this could mean a second conization, radical trachelectomy, or hysterectomy. For a woman who had radical trachelectomy, this usually means a radical hysterectomy. (See "Patient information: Treatment of early stage cervical cancer").

PREGNANCY AFTER TREATMENT — Most women are advised to wait six to 12 months after conization or trachelectomy before attempting to become pregnant to allow the tissue to heal fully. Even if a woman waits to attempt pregnancy, there is a risk of pregnancy complications and/or infertility after cervical cancer treatment.

Infertility — There is an increased risk of difficulty in becoming pregnant if the cervix or lower uterus becomes scarred or narrowed as a result of the conization or radical trachelectomy. This could potentially prevent sperm from entering the uterus. This can usually be overcome with an infertility treatment, such as intrauterine insemination (IUI). With IUI, a small catheter is used to deliver sperm directly into the uterus.

Cervical insufficiency and preterm delivery — Cervical insufficiency occurs when the cervix opens or thins earlier than normal during pregnancy. This can lead to preterm (premature) labor or preterm delivery (when delivery occurs before 37 weeks of pregnancy). Studies show that women who undergo trachelectomy or conization as a treatment for early cervical cancer have an increased risk of preterm delivery.

For these reasons, women who undergo treatment for cervical cancer are followed closely during pregnancy. This generally involves regular monitoring of the length and opening (dilation) of the cervix. (See "Patient information: Preterm labor", section on cervical length).

After cervical conization — For women who undergo cervical conization, studies have found an increased risk of preterm delivery. Following cervical conization, the risk of preterm delivery is almost tripled compared to women who have not undergone conization (14 percent vs. 5 percent). After a LEEP conization, the risk is also increased (11 percent vs. 7 percent). There is less data about the risk of infertility following conization (LEEP or cervical conization), although most experts believe there is a low risk of difficulty in becoming pregnant because of the conization.

For women who develop cervical insufficiency following conization, a cerclage (stitch) can be placed if the cervix opens prematurely during pregnancy (show figure 6). This temporarily helps to keep the cervix closed; it is usually removed near a woman's delivery date or if she develops preterm labor.

After radical trachelectomy — In one review of 355 women who had a radical trachelectomy, approximately 70 percent of women who tried to become pregnant were able to do so. Approximately 20 percent of these women had a first trimester pregnancy loss, and 8 percent of women had a second trimester loss. Preterm deliveries occurred in 20 percent of pregnancies [2]. The risk of first trimester pregnancy loss after radical trachelectomy is about the same as that of women who have not had any cervical surgery, but the risk of second trimester loss and preterm delivery appear to be a higher. (See "Patient information: Miscarriage").

A cerclage is not placed during pregnancy in women who had trachelectomy because a permanent cerclage is placed at the time of trachelectomy (show figure 4). Because of this, most women who become pregnant after trachelectomy require a Cesarean section for delivery.

Pregnancy options after radical hysterectomy or radiation — It is not usually possible to become pregnant or carry a pregnancy after treatment with radical hysterectomy and/or chemoradiotherapy. However, advances in assisted reproductive technology may offer a way for women to have a biologically-related child after this type of treatment.

Embryo cryopreservation is a technique that has been available for many years for fertility preservation. To use embryo cryopreservation, a woman must use fertility medications and undergo a surgical procedure to harvest her oocytes (eggs). The oocyte is then combined with a partner's or donor's sperm to create an embryo. The embryo is then frozen for use at a later time. Embryo cryopreservation requires that radical surgery, chemotherapy, or radiotherapy are delayed for several weeks, and that a partner's or donor's sperm is available. Thus, it may not be an option for all women.

Reproductive techniques that are currently in the experimental phase include oocyte cryopreservation (freezing the egg before it is fertilized with sperm) and ovarian cryopreservation (freezing the ovary); further study is needed before these techniques are available to the general public. All of these techniques, including embryo cryopreservation, would require a gestational (surrogate) carrier to carry the pregnancy. (See "Gestational carrier pregnancy").

A young woman who wishes to preserve her fertility may feel that she has to choose between doing what seems best for her own life and what might be best for preserving fertility. Every woman's situation is different, and every decision must be individualized based upon the woman's situation. Advice regarding options for fertility preservation is available from physicians who are experts in reproductive endocrinology and infertility, in conjunction with a gynecologic oncologist.

FERTILITY PRESERVING TREATMENT VERSUS STANDARD TREATMENT — The most common treatment for early stage cervical cancer is radical hysterectomy (surgical removal of the cervix and uterus). The alternative is radiation therapy, which is usually given in combination with chemotherapy. These are the best-studied treatments with the lowest risk of recurrence in clinical trials. Radical hysterectomy, radiation, and chemotherapy are discussed in detail in a separate topic review. (See "Patient information: Treatment of early stage cervical cancer").

FOLLOW UP — After cervical cancer treatment, including fertility-sparing treatments, periodic follow up testing and examination is recommended. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following [3]: Physical examination every three months for one year, every four months for one year, every six months for three years, and then annually. This usually involves a physical examination and Pap test (cervical cytology). Annual chest x-ray; there are few data to support the benefit of annual chest x-rays and many doctors do not recommend them. Other radiographic studies, including CT or PET scan are recommended only if there is a concern about cancer recurrence.

LONG-TERM OUTLOOK

Psychosocial function — The women and families affected by cervical cancer commonly experience distress as they worry about their short and long-term health and risk of recurrence. In some cases, this distress continues for many years after treatment ends.

Communication between the woman, her family, and her healthcare team is a vital part of the treatment process. Many women benefit from bringing a family member or friend to physician visits; this person can help the woman to understand her options, ask important questions, and to feel supported.

A variety of support options are available, both during and following treatment, including individual counseling, support groups, and internet-based discussion groups. A list of reputable groups is available below (see "Where to get more information" below).

Sexual function — Vaginal changes after cervical cancer treatment may include shortening, narrowing, and decreased lubrication. These physical changes impact sexual satisfaction because they may result in pain during intercourse, lack of interest in sex, difficulty having an orgasm, and decreased frequency of sexual activity. If the vagina is severely narrowed, use of vaginal dilators may help.

Using a vaginal moisturizer or lubricant during intercourse can relieve some of these bothersome symptoms. Counseling for sexual and/or psychological difficulties may also be helpful. (See "Patient information: Sexual problems in women").

Cure — Each patient with cancer is different, and it is difficult to predict what an individual woman should expect in the future. The chances that early stage cervical cancer can be cured are good in most cases. When discussing chances of cure, it is important to remember that these numbers represent averages, and do not necessarily predict what will happen to you.

The survival rates for women who have the standard treatment of stage IA1 cervical cancer are excellent. At five years after diagnosis, more than 98 percent of women are alive. This means that 2 percent of women died, althought the cause of death was not necessarily related to the cancer.

For women with stage IA2 cervical cancer, more than 95 percent of women who undergo standard treatment are alive at five years after diagnosis. For stage IB1, approximately 88 percent of women are alive at five years after diagnosis. Again, some of these women died as a result of their cancer while others died of other causes (eg, accidents, heart disease).

CLINICAL TRIALS — Progress in treating cervical cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The Gynecologic Cancer Foundation: The official patient information website of the Society for Gynecologic Oncology

(www.sgo.org/publications/gynecologic_cancer.cfm)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
Gynecologic Oncology Group

(www.gog.org/gynecologiccancerinformation.html)
National Cancer Institute

1-800-4-CANCER
(www.cancer.gov/)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
The National Cervical Cancer Coalition

(www.ncc-online.org)


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3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology available at www.nccn.org/professionals/physician_gls/default.asp (Accessed February 5, 2007).
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8. Abu-Rustum, NR, Sonoda, Y, Black, D, et al. Fertility-sparing radical abdominal trachelectomy for cervical carcinoma: Technique and review of the literature. Gynecol Oncol 2006; 103:807.
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