Patient information: Endometrial cancer treatment

ENDOMETRIAL CANCER OVERVIEW

Endometrial cancer is a type of uterine cancer that involves the lining of the uterus (the endometrium). It is the most common gynecologic cancer in women. Treatments for endometrial cancer usually include surgical removal of the uterus, cervix, ovaries, and fallopian tubes; radiation therapy or chemotherapy may be recommended for some women. In general, treatment will depend upon what is found during surgery and the estimated risk that the cancer will recur after surgery alone. Endometrial cancer is estimated to have a low, intermediate, or high risk of recurrence.

The diagnosis and staging of endometrial cancer is discussed separately. (See "Patient information: Endometrial cancer diagnosis and staging".)

LOW RISK ENDOMETRIAL CANCER

Low-risk endometrial cancer is defined as having all the following criteria:

• Low or intermediate grade cancer that is confined to the top of the uterus (called the fundus) with little or no invasion into the uterine muscle (stage I grade 1 or 2, (table 1 and table 2)

• No evidence of cancer cells in the surrounding lymph nodes or blood vessels

Surgical removal of the uterus, ovaries, cervix, and fallopian tubes is considered to be sufficient treatment for women with low risk endometrial cancer (see "Patient information: Abdominal hysterectomy"; treatment with chemotherapy, radiation therapy, or other medications is NOT recommended.

INTERMEDIATE RISK ENDOMETRIAL CANCER

Intermediate-risk endometrial cancer is defined as having the following criteria:

• A deeply invasive tumor (stage IC) or tumor that has limited cervix involvement (stage IIA) or a high-grade cancer with little or no invasion into the uterine muscle (stage IA/IB grade 3) (table 1 and table 2)

• No evidence of cancer in the surrounding lymph nodes or blood vessels
• No evidence of metastasis outside of the uterus

The treatment of choice for women with intermediate risk endometrial cancer is surgical removal of the uterus, cervix, ovaries, and fallopian tubes. (See "Patient information: Abdominal hysterectomy".) The lymph nodes are evaluated during the surgery, and may be removed if cancer cells are suspected.

The best way to manage women with intermediate risk endometrial cancer is controversial. Whether women with intermediate risk endometrial cancer should be given additional treatment after surgery, typically radiation therapy, is controversial. At some centers, nearly all such women have radiation therapy, while at others, it is rarely given.

Adjuvant radiation therapy (RT) — The term "adjuvant therapy" refers to any additional anti-cancer treatment that is given after a cancer is completely removed with surgery. The purpose of adjuvant therapy is to eliminate any remaining tumor cells in the body. Although it is not clear that adjuvant RT improves a woman's chance of surviving her cancer, it does significantly reduce the risk that the cancer will recur locally (ie, in the pelvis or vagina).

When RT is recommended, controversy exists as to how it should be administered. In general, there are two ways of delivering RT: it may be given as vaginal brachytherapy or as external beam RT (EBRT).

Vaginal brachytherapy — Brachytherapy delivers RT directly to the vaginal tissues from a source that is temporarily placed inside the body. This allows high doses of radiation to be delivered to the area where cancer cells are most likely to be found, hopefully minimizing the effects of radiation on healthy tissues.

Traditionally, the radiation source is left in place for 24 hours and requires that the woman remain in the hospital for two to three nights; this is referred to as low dose rate (LDR) brachytherapy. A newer technique delivers the radiation at a high dose rate (HDR); the radiation source is left in place for a few minutes once a day for five or more days. The main advantage of HDR is that it is completed within several minutes and can be performed as an outpatient.

External beam RT — With external beam radiation therapy (EBRT), the source of the radiation is outside the body. EBRT is typically done with a machine called a linear accelerator, which directs radiation at the pelvis. Exposure to the beam typically takes only a few seconds (similar to having an x-ray), and is performed once daily, five days per week for five to eight weeks. Treatment cannot be given over a shorter period because a higher daily dose would cause too many side effects.

EBRT is an outpatient procedure, and women can usually continue their normal activities during treatment. The areas treated by EBRT are designed carefully to limit the amount of radiation that is directed at healthy tissue, although it is inevitable that at least some healthy tissue will be radiated. The risk of damage to normal surrounding tissues may be lower when newer treatment planning techniques, such as intensity-modulated RT (IMRT), are utilized. A trial to determine the benefits of IMRT compared to conventional RT is underway [1] (see 'Clinical trials' below for information on how to participate in a clinical trial).

Newer RT approaches (eg, intensity-modulated RT [IMRT]) are being used in the treatment of women with gynecologic cancer, and preliminary experience with IMRT in patients with endometrial cancer has been promising with low rates of side effects.

Side effects of RT — Possible short term side effects of RT include fatigue, urinary urgency and/or frequency, diarrhea, and loss of pubic hair; most of these problems resolve when treatment is completed. Longer term side effects may include urinary leakage, bowel urgency, and narrowing or scarring of the vagina, which may cause pain with intercourse. Women who are sexually active are often advised to use a vaginal dilator or have intercourse regularly during and after treatment to limit narrowing of the vagina. (See 'Sexual function' below.)

HIGH RISK ENDOMETRIAL CANCER

High-risk endometrial cancer is defined as having one or more of the following criteria:

• High-grade tumor with deep invasion of the uterine muscle (stage1C grade 3 or involvement of the cervix (stage II) (table 1 and table 2)

• Spread of tumor outside of the uterus
• Evidence of cancer in the surrounding lymph nodes or blood vessels
• The cell type is a clear cell or papillary serous cancer (see "Patient information: Endometrial cancer diagnosis and staging", section on 'Histology')

The first step in treating women with high-risk endometrial cancer is surgical removal of as much cancerous tissue as possible, including the uterus, cervix, ovaries, and fallopian tubes. This is called optimal surgical debulking or optimal cytoreduction. Optimal surgical debulking impacts the woman's prognosis (cancer outcome) as well as the choice of adjuvant treatment. A woman is more likely to have optimal cytoreduction if her initial surgery is performed by a gynecologic oncologist, a specialist in cancers of the female reproductive system.

All women with high-risk endometrial cancer are advised to undergo some form of adjuvant therapy. The choice of treatment (RT or chemotherapy) depends upon the location of the cancer:

• If the tumor is confined to the uterus (called organ-confined disease), RT is often recommended.
• If there is disease outside of the uterus (called extrauterine disease), chemotherapy is more often recommended rather than RT [2].

Extrauterine disease — Women with endometrial cancer that has spread outside the uterus (called extrauterine disease) are usually advised to have adjuvant chemotherapy after surgery.

What is chemotherapy? — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (such as cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not rapidly growing, they are not affected by chemotherapy. Exceptions to this include cells of the bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. These tissues are affected most by chemotherapy, causing the typical side effects (low blood counts, hair loss, etc).

In general, the side effects seen with chemotherapy are more frequent and more severe when two or more drugs are given at the same time (termed combination chemotherapy). However, in most cases, combination therapy is preferred over single agent chemotherapy because it is associated with better outcomes.

Most chemotherapy drugs are given into the vein, although some agents can be given by mouth. In general, regardless of the route by which they are given. Chemotherapy drugs are given in a carefully defined sequence and doses over a period of several months. Chemotherapy drugs are usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the effects. During this time, patients are closely monitored for signs of drug toxicity and side effects.

Which chemotherapy regimen is best? — The best chemotherapy regimen for women with high-risk extrauterine endometrial cancer is controversial. Many clinicians use a combination chemotherapy regimen that includes doxorubicin, cisplatin, and paclitaxel.

The benefit of this regimen as an alternative to adjuvant RT was demonstrated in a study known as Gynecologic Oncology Group 122 [2]. In this study, women with advanced endometrial cancer were randomly assigned to RT or postoperative chemotherapy using doxorubicin, cisplatin, and paclitaxel. After approximately 6 years of follow up, the women treated with chemotherapy had an estimated 13 percent improvement in five-year overall survival compared to the group treated with RT (55 versus 42 percent, respectively).

Chemotherapy is usually given in six 21-day cycles (the treatment is given once every 21 days for a total of 6 treatments). However, the optimal number of cycles is unknown. Side effects are significant with this regimen; some oncologists use only one or two of the agents to reduce the risk of developing severe side effects, which would require stopping or delaying treatment.

Another commonly used chemotherapy regimen is carboplatin and paclitaxel, which may have fewer side effects than doxorubicin, cisplatin, and paclitaxel.

What are the side effects of chemotherapy? — The most common side effects of chemotherapy include fatigue, hair loss, nausea and vomiting, diarrhea, low blood counts, and menopausal symptoms. In addition, both cisplatin and paclitaxel can cause numbness, burning and tingling of the fingers and toes, and cisplatin may be associated with kidney problems and hearing loss.

Radiation therapy — Women with extrauterine disease are sometimes offered radiation therapy rather than chemotherapy. The radiation is usually directed at the sites where cancer is known to have spread or is at high risk for tumor spread. (See 'Adjuvant radiation therapy (RT)' above.)

Interest is increasing in a combined approach of chemotherapy plus RT, although this is not yet a standard approach at most institutions.

Organ confined disease — Women with high risk but organ confined endometrial cancer are usually offered adjuvant RT rather than chemotherapy because they have a high risk of lymph node involvement and recurrence (see 'Adjuvant radiation therapy (RT)' above.

The benefit of chemotherapy versus RT for women with high-risk but organ-confined disease is unclear. Based upon the available data, most women are offered adjuvant RT rather than chemotherapy [2]. However, women should discuss the risks and benefits of each approach with her healthcare provider.

ENDOMETRIAL CANCER TREATMENT OPTIONS FOR WOMEN WHO WANT TO PRESERVE THEIR FERTILITY

A 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 her fertility. Every woman's situation is different, and every decision must be individualized based upon that woman's situation. Advice regarding options for fertility preservation is available from gynecologic oncologists and medical oncologists, in conjunction with physicians who are experts in reproductive endocrinology and infertility.

Low risk — Premenopausal women with a low risk endometrial cancer are sometimes able to postpone surgical treatment of their cancer until after having a child. In this case, the woman must have a thorough evaluation to confirm that the endometrial cancer is low grade and low stage and that there is no evidence of ovarian cancer; up to 29 percent of premenopausal women with endometrial cancer also have a cancer of the ovary [3]. The evaluation usually including a transvaginal ultrasound, MRI, and dilation and curettage (see "Patient information: Dilation and curettage (D and C)".

After the evaluation, treatment with a progestin medication is usually recommended. The most commonly used progestin is called megestrol acetate (Megace®), which is taken by mouth every day for at least three month. Other options include an injection of medroxyprogesterone acetate (Depo Provera®) and an intrauterine device that releases progestin (Mirena®). The progestin works by decreasing estrogen levels and thinning the lining of the uterus (the endometrium), which can temporarily prevent the cancer from growing.

With progestin treatment, there is a significant risk that the cancer will not respond or will initially respond but then recur. For this reason, periodic testing is strongly recommended during and after the progestin treatment to monitor the cancer. This may include an endometrial biopsy and/or transvaginal ultrasound three to four times per year. If the cancer progresses during this time, surgical treatment (removal of the uterus, cervix, ovaries, and fallopian tubes) is usually recommended.

After the woman has completed childbearing, most experts recommend surgical removal of the uterus, cervix, fallopian tubes, and ovaries. The reason for this is that there is a significant risk that the cancer will recur, even in women who initially respond to progestin treatment.

Options for women with higher grade endometrial cancer — Women with greater than stage I grade I endometrial cancer are usually advised to have surgery to remove the uterus, cervix, ovaries, and fallopian tubes, even if childbearing is not complete; radiation treatment and/or chemotherapy may also be recommended. The reason for this recommendation is that less aggressive treatment (eg, using a progestin such as megestrol acetate) could potentially allow the cancer to grow and spread beyond the uterus.

Unfortunately, it is not possible to become pregnant or carry a pregnancy after the uterus and ovaries are removed. 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 or donor's sperm to create an embryo. The embryo is then frozen for use at a later time.

Embryo cryopreservation requires that surgical removal of the uterus and ovaries is delayed for several weeks and that partner or donor sperm is available. In addition, a gestational (surrogate) carrier would be required to carry the pregnancy. Thus, it may not be an option for all women. (See "Gestational carrier pregnancy".)

FOLLOW UP AFTER ENDOMETRIAL CANCER TREATMENT

Risk of recurrence — The risk of recurrent endometrial cancer is greatest within the first three years after diagnosis, with 68 to 100 percent of recurrences occurring during this time. Recurrent disease is most common in women with high-risk disease; women with low-risk disease have a recurrence rate of less than 5 percent (table 3).

Approximately 40 percent of recurrences occur locally (in the vagina or pelvis) and 60 percent occur in distant areas (upper abdomen, lung). The risk of local recurrence is lower in women who have had radiation therapy.

Most women with a recurrence have symptoms of vaginal bleeding, abdominal or pelvic pain, persistent cough, or unexplained weight loss.

Cancer surveillance — Although there is no consensus about the best ways to monitor for recurrence after endometrial cancer treatment, the National Comprehensive Cancer Network (NCCN) guidelines suggest the following schedule for follow up visits [4]:

• Physical examination every three to six months for two years, then annually
• Vaginal cytology (Pap smear) every six months for two years, then annually
• Measurement of CA-125 at each visit in women whose initial level was elevated

A gynecologic oncologist or gynecologist usually provides this follow up care. However, if there is no evidence of recurrence after five years of surveillance, the woman can usually be followed by her primary care provider or gynecologic provider.

Safety of hormone replacement — Premenopausal women whose ovaries are surgically removed usually experience symptoms of menopause. This may includes hot flashes, night sweats, and/or vaginal dryness. The most effective treatment for these symptoms is estrogen replacement therapy (ERT). However, there is a theoretical concern that ERT could stimulate an endometrial cancer to grow or recur.

Most experts consider estrogen replacement therapy a reasonable option if the woman is at low risk of a tumor recurrence; however, the potential risks and benefits of this therapy should be discussed in detail with the gynecologic oncologist. If adjuvant treatment (eg, radiation therapy or chemotherapy) will be needed, some experts recommend waiting 6 to 12 months before hormone replacement therapy is started.

Other treatments for menopausal symptoms are available; these are discussed separately. (See "Patient information: Postmenopausal hormone therapy alternatives".)

LONG TERM OUTLOOK WITH ENDOMETRIAL CANCER

Psychosocial function — The women and families affected by endometrial 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 — Changes in the vagina are common after endometrial cancer treatment, and 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. During and after radiation therapy, vaginal dilators or sexual intercourse are recommended to prevent narrowing of the vagina.

Using a vaginal moisturizer or lubricant during intercourse can relieve some of these bothersome symptoms. Women with low risk disease may be able to use a vaginal estrogen (a cream, vaginal ring, or pill) to improve the health of the vaginal tissues. However, women with high-risk disease are usually counseled to avoid the use of any estrogen preparation (vaginal or oral) because there is not enough information about the safety of estrogen in this group. More information about vaginal estrogen is available in a separate topic review. (See "Patient information: Vaginal dryness".)

Pelvic physical therapy and 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 endometrial 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 IA endometrial cancer are excellent. At five years after diagnosis, approximately 92 percent of women are alive. This means that 8 percent of women died, although not all of the deaths were related to cancer; some women died of other causes (eg, accidents, heart disease). The survival rates for other stages of endometrial cancer are listed in the table (table 4).

CLINICAL TRIALS

Progress in treating 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 people 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.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Endometrial cancer diagnosis and staging
Patient information: Abdominal hysterectomy
Patient information: Dilation and curettage (D and C)
Patient information: Postmenopausal hormone therapy alternatives
Patient information: Vaginal dryness
Patient information: Sexual problems in women

Professional Level Information:
Endometrial cancer: Epidemiology, risk factors, clinical features, diagnosis, and screening
Endometrial cancer: Pretreatment evaluation, staging, and posttreatment surveillance
Endometrial hyperplasia
Evaluation of the endometrium for malignant or premalignant disease
Histopathology and pathogenesis of endometrial cancer
Treatment of locally recurrent or advanced endometrial cancer
Uterine papillary serous and clear cell cancer
Uterine sarcoma: Classification, clinical manifestations, and diagnosis
Uterine sarcoma: Staging and treatment
Gestational carrier pregnancy

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.

• American Society of Clinical Oncology

      (www.cancer.net/portal/site/patient)

• The Women's Cancer Network

      (www.wcn.org)

• National Comprehensive Cancer Network

      (www.nccn.com)

• 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)

Patient Support — There are a number of online forums where patients can find information and support from other people with similar conditions.

• About.com Cancer Forum

      (http://cancer.about.com/forum)

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