Treatment of early stage cervical cancer

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 early stage cervical cancer. A separate topic review discusses the treatment of early stage cervical cancer in women who want to become pregnant in the future. (See "Patient information: Treatment of early stage cervical cancer for women who desire future pregnancy").

THE CERVIX — The uterus (womb) opens into the vagina through the cervix (show figure 1). The cells on the outermost surface of the cervix are called squamous cells. "Squamous cell carcinoma of the cervix" is the name for cancer that affects these cells. More than 80 percent of cervical cancers are squamous cell carcinomas.

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 cancer. Therefore, all women who have a cervix should undergo regular screening with Pap tests. (See "Patient information: Screening for cervical cancer").

If a cervical cancer does develop, it may initially not cause any 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 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 the 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 can also cause a noncancerous condition called genital warts (condyloma). (See "Patient information: Condyloma (genital warts) in women").

Most HPV infections are temporary because the body's immune system clears the infection. When certain types of HPV virus persist (in 10 to 20 percent of cases), there is a higher likelihood of developing cervical cell abnormalities and cancer. HPV can be detected in almost all cervical cancers (squamous cell carcinomas as well as adenocarcinomas). (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, and 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 (show figure 2). If a biopsy shows the presence of a cervical cancer, a doctor who specializes in cancers of the female reproductive system (called a gynecologic oncologist) should be consulted. 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 (metastasized).

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 a 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 — There are several options for treatment of early stage (stage IA, IB, and some small IIA tumors) cervical cancer. The optimal treatment depends upon the woman's age and her childbearing plans, the stage of the cancer, whether underlying medical conditions are present, and the physician's and patient's preferences.

The most common treatment for early stage cervical cancers is radical hysterectomy (surgical removal of the cervix and uterus). The alternative is radiation therapy, which is usually given in combination with chemotherapy. Patients with the earliest stage cervical cancers (stage IA1) may also be treated by cervical conization or simple hysterectomy alone. (See "Patient information: Treatment of abnormal Pap smears" for information about conization and see "Patient information: Abdominal hysterectomy" for information about simple hysterectomy).

Future pregnancies are not possible after radical hysterectomy or radiation therapy. Some women who wish to preserve their ability to carry a pregnancy after treatment may be eligible for less aggressive forms of treatment (fertility preserving therapies). These involve partial or complete removal of the cervix, while leaving the uterus in place. Women who are not eligible for less aggressive treatment may have options that allow them to have a biologically related child. These issues are discussed separately. (See "Patient information: Treatment of early stage cervical cancer for women who desire future pregnancy").

Radical hysterectomy — Radical hysterectomy is a surgical procedure that removes the uterus and cervix with adjacent tissues and some portion of the vagina (show figure 3). The surgery is done in the operating room after the woman receives anesthesia. Removal of the ovaries is not a necessary part of a radical hysterectomy. A woman's preference to leave or remove the ovaries is usually discussed before surgery. (See "Patient information: Abdominal hysterectomy", section on "Removal of ovaries" for more information about removal of the ovaries).

The surgery is usually performed by removing the uterus and cervix through a vertical or horizontal incision in the abdomen (show figure 3). Alternately, surgery may be done laparoscopically using a small telescope and several small incisions in the abdomen. With laparoscopic surgery, the uterus and cervix are removed through the vagina. The surgical approach depends upon the surgeon's preference and experience and the woman's anatomy. Most women will also undergo a lymphadenectomy (removal of the pelvic and para-aortic lymph nodes, show figure 4), depending upon the stage of the cancer and what is found during surgery.

The time required for radical hysterectomy and pelvic lymphadenectomy is approximately 2.5 to four hours; more time may be required if lymph nodes in other areas are removed or if complications such as bleeding or injury to surrounding organs occurs. Most women remain in the hospital for two to three days after surgery.

If abnormal or cancerous cells are found at the margins (edges) of the tissue or in the lymph nodes that are removed, or if the tumor has other features that increase the risk that the cancer will recur, further (adjuvant) treatment is recommended. This generally includes both radiation therapy and chemotherapy.

Radiation therapy — Radiation therapy (RT) refers to the exposure of a tumor to high-energy x-rays in order to slow or stop its growth. Exposure to x-rays damages cells. Unlike normal cells, cancer cells cannot repair the damage caused by exposure to x-rays, particularly when it is administered over several days. This prevents the cells from further growth, and causes them to eventually die.

There are two ways to deliver RT for cervical cancer: brachytherapy or external beam radiation therapy (EBRT).

Brachytherapy — Brachytherapy is a form of localized RT in which the source of the radiation is within the patient (internal irradiation). This allows the delivery of high doses of radiation to the area where cancer cells are most likely to be found, hopefully minimizing the effects of radiation on healthy tissues.

In most cases, a radiation applicator is temporarily inserted through the vagina into the cervix and uterus. Then, the radiation source is placed (or "afterloaded") into the applicator and left in place internally for a period of time. The treatment is traditionally accomplished using a radiation source that delivers the radiation at a low dose rate (LDR), which requires that the woman remain in the hospital for two to three nights. A newer technique delivers the radiation at a high dose rate (HDR). The main advantage of HDR is that it is completed within several minutes, and can be performed as an outpatient. Studies that compare HDR to LDR therapy are ongoing.

External beam radiation therapy (EBRT) — During EBRT, the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient, who is usually lying on a table underneath or in front of the machine. The high energy beams are targeted to the pelvic area.

Exposure to the beam typically takes only a few seconds (similar to having an x-ray). In general, treatment is repeated five days per week for approximately five to six weeks. Treatment cannot be given over a shorter period because the higher daily doses would cause too many side effects. Unless medically indicated, treatment should not be interrupted or extended beyond the projected time frame because changing the schedule or stopping temporarily could reduce the chance of curing the cancer.

Brachytherapy alone is adequate treatment for the earliest stage IA tumors, but EBRT is generally added to brachytherapy to improve the outcomes in women who have with more advanced disease [2].

Chemotherapy — Most women who undergo EBRT for cervical cancer also receive chemotherapy during the radiation therapy (an approach termed chemoradiotherapy). Chemotherapy drugs are medicines that stop or slow the growth of cancer cells. In general, these drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Chemotherapy also has the ability to enhance the damaging effect of radiation therapy on cancer cells; when chemotherapy drugs are used in this manner, they are referred to as "radiation sensitizers". The chemotherapy is usually given once per week through a vein during the course of EBRT.

It is not clear if there is a benefit of chemoradiotherapy (compared to radiotherapy alone) for all women with early stage disease. Studies of women with predominantly locally advanced cervical cancer have demonstrated that there is a lower risk of recurrence and a better survival when RT is given along with chemotherapy compared to when RT is given alone [3]. That benefit was greater in trials that included a higher proportion of patients with stage I and II disease [4]. It has not been proven that these results apply to women with smaller early stage tumors, although most gynecologic oncologists recommend that chemotherapy be administered when EBRT is used for definitive therapy, regardless of the stage.

FOLLOW UP — After cervical cancer treatment, periodic follow-up testing and examination are recommended. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following [6]: 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 as clinically indicated

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, take notes, and 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 can expect in the future. The chance of cure is high for most early stage cervical cancers. 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 undergo standard treatment for 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, although the cause of death was not necessarily related to the cancer.

For stage IA2, more than 95 percent of women who undergo standard treatment are alive at five years after diagnosis. For stage IB1 disease, 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

(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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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Benedet, JL, Bender, H, Jones H, 3rd, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2000; 70:209.
2. 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 2002; 52:33.
3. Green, J, Kirwan, J, Tierney, J, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005; :CD002225.
4. 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 1999; 340:1154.
5. Rotman, M, Sedlis, A, Piedmonte, MR, et al. A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2006; 65:169.
6. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology available at www.nccn.org/professionals/physician_gls/default.asp (Accessed February 5, 2007).
7. ACOG practice bulletin. Diagnosis and treatment of cervical carcinomas. Number 35, May 2002. American College of Obstetricians and Gynecologists. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002; 78:79.