Zanmbeel

Friday, October 12, 2007

Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer

INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the primary cause of death in women ages 45 to 55. Each year, 211,000 American women are diagnosed with breast cancer, and 40,000 die from this disease.

Early detection and treatment can often lead to a cure. Cure is most likely in women whose cancers are confined to the breast, while a substantial number of women with spread to the local lymph nodes can also be cured with appropriate therapy.

Breast cancer is a very complex topic. An introduction to breast cancer and an overview of available treatments is available elsewhere. (See "Patient information: Breast cancer guide to diagnosis and treatment"). This topic review will focus on the use of adjuvant chemotherapy and trastuzumab (Herceptin®) after surgery in women with early stage breast cancer.

SURGICAL TREATMENT — Surgery for localized breast cancer consists of either a mastectomy (removal of the entire breast) or breast-conserving surgery (often called lumpectomy because it removes only the cancerous tissue, preserving the unaffected part of the breast) (show figure 1). If breast-conserving surgery is chosen, radiation treatment to the remainder of the breast is needed. Together, breast-conserving surgery and radiation are referred to as breast-conserving treatment. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").

Lymph nodes — Even if a breast cancer is removed completely, there is still a risk that cancer cells have broken away from the tumor and spread to other parts of the body. The most common site of spread is the lymph nodes (glands) located in the armpit (also called the axilla). These nodes are usually removed by the surgeon and examined under the microscope for evidence of cancer spread. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Management of axillary lymph nodes).

If cancer cells are found in the lymph nodes (node-positive breast cancer), there is a higher chance that the cancer has spread elsewhere. Even if no cancer cells are detected (node-negative breast cancer), there is still a chance that the tumor could have spread elsewhere in the body; however the chance of spread is 50 percent lower if the nodes are uninvolved.

DEFINING ADJUVANT THERAPY — The term "adjuvant therapy" refers to any additional anticancer treatment that is given after a cancer is surgically removed. The purpose is to eliminate any remaining tumor cells in the body (often termed micrometastases). Advances in adjuvant therapy have improved the chance of curing localized breast cancer and decreased the risk of dying of breast cancer by 20 to 30 percent. Thus, adjuvant therapy is a very important component of modern breast cancer treatment.

Choice of therapy — There are three different types of systemic (bodywide) adjuvant therapy that are useful in women with breast cancer: hormone therapy, chemotherapy, and trastuzumab (Herceptin®). The choice of which treatment to use is mainly dependent upon whether a woman's breast cancer is hormone-responsive and whether it makes a protein called HER2.

Hormone receptors — About 50 to 70 percent of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce molecules called hormone receptors, which are essential in order for the cell to use estrogen for growth. These hormone receptors can be estrogen receptors (ER), progesterone receptors (PR), or both.

If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen, thus depriving the cancer cells of the material that stimulates their growth. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as "hormone-responsive". In contrast, women whose tumors do not contain ER or PR do not benefit from adjuvant hormone therapy (ie, they are hormone-nonresponsive), and it is not recommended. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").

Hormone-responsive breast cancers appear to benefit less from chemotherapy than do those that are hormone nonresponsive. Nevertheless, chemotherapy may still be recommended, in addition to hormone therapy, for some ER-positive tumors, particularly if there is node-positive disease, a large tumor size, or other features that suggest a higher risk for a cancer recurrence. (See "Indications for chemotherapy" below).

HER2 expression — Breast cancers that make high levels of the protein tumor marker HER2 (ie, those that overexpress HER2) have a poorer prognosis (outcome) as compared to those that either do not make this protein or make lower levels. On the other hand, overexpression of HER2 also identifies those women who may benefit from the targeted drug Herceptin, and those who do better with chemotherapy regimens that contain a drug of the anthracycline class (see below).

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 (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues.

Modern adjuvant chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. Most drugs are given intravenously (IV) rather than by mouth. They are not usually taken daily, but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen is a one hour IV infusion of two different chemotherapy medications given once every three weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three months, four cycles of chemotherapy would be administered.

Types of chemotherapy — There are many different types of adjuvant chemotherapy regimens. They differ with regard to the specific chemotherapy drugs that are given, the number of treatment days within the cycle, and the duration of each cycle.

There are two broad categories of chemotherapy regimens for the adjuvant treatment of breast cancer. These regimens vary based on the drugs they contain, how they are given, and also in the side effects they cause. CMF-type chemotherapy Anthracycline-based chemotherapy (using either doxorubicin [Adriamycin®] or epirubicin [Ellence®]), which may be combined with a taxane (paclitaxel [Taxol®] or docetaxel [Taxotere®])

Anthracycline-based regimens can cause hair loss, vomiting, and mouth soreness (mucositis) and have a long-term risk of heart muscle damage. In contrast, CMF is more likely to cause nausea (especially the oral version, see below), and premature menopause. (See "Side effects of chemotherapy" below).

CMF chemotherapy — The CMF chemotherapy regimen includes a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (abbreviated 5-FU). This combination can be administered entirely IV (called IV CMF), or with oral cyclophosphamide plus IV methotrexate and 5-FU (termed oral or classic CMF). Most doctors consider oral CMF to be more effective than the all-IV version.

Anthracycline-based chemotherapy — There are several different regimens of anthracycline-based chemotherapy: AC chemotherapy — doxorubicin and cyclophosphamide CAF or FAC chemotherapy — cyclophosphamide, doxorubicin, and 5-FU CEF or FEC chemotherapy — cyclophosphamide, epirubicin, and 5-FU

CMF versus anthracycline-based chemotherapy — Several studies have compared the benefits of CMF versus anthracycline-based adjuvant chemotherapy in women with early breast cancer. In general, anthracycline-containing chemotherapy regimens seem to provide modestly better outcomes over CMF chemotherapy, particularly for women with HER2 overexpression, and are preferred in most cases. If an anthracycline-type drug cannot be used (eg, if a woman has underlying heart disease, or if she received prior anthracycline-based therapy for a previous breast cancer), oral CMF or another type of chemotherapy that does not contain an anthracycline may be used.

Taxane-containing chemotherapy — Taxanes (paclitaxel or docetaxel) are usually combined with an anthracycline-based chemotherapy regimen. One active non-anthracycline-containing taxane regimen is TC (docetaxel plus cyclophosphamide).

Taxanes are some of the most effective drugs for women with advanced breast cancer. An increasing amount of data supports their use in women with earlier-stage breast cancer. Taxanes are now routinely included as a component of the adjuvant chemotherapy regimen for women with node-positive breast cancer, and for some high-risk node-negative breast cancers. A popular type of anthracycline- and taxane-containing adjuvant chemotherapy called dose-dense therapy is discussed below. (See "Dose-dense therapy" below).

INDICATIONS FOR CHEMOTHERAPY — Combination chemotherapy is the adjuvant treatment of choice for women with hormone-nonresponsive (ie, ER-negative) breast cancer. It is also appropriate for some women with hormone-responsive breast cancer, in conjunction with hormone therapy, although there is some disagreement as to which of these patients needs chemotherapy. This is due, at least in part, to the more favorable prognosis of these tumors and the more marginal benefits of chemotherapy in this group [1].

Recommendations from expert groups — This disagreement is reflected in the differing recommendations of expert groups.

NCCN guidelines — In the United States, many doctors follow the recommendations of the National Comprehensive Cancer Network (NCCN). [2]. Chemotherapy is recommended for women whose breast cancers are node-positive or 1 centimeter in size, regardless of hormone-responsiveness.

International Consensus Panel — Practice outside the United States is more often guided by recommendations from the International Consensus Panel on the Primary Therapy of Early Breast Cancer [3]. Unlike the NCCN recommendations, these guidelines consider HER2 expression and other pathologic features in addition to node status and tumor size. Their recommendations are presented in Table 1 (show table 1). Recommendations are based upon the estimated risk of cancer recurrence, outlined in the Table (show table 2). For hormone-nonresponsive breast cancer, adjuvant chemotherapy is recommended for those with either intermediate-risk or high-risk disease (show table 2). For hormone-responsive, node-negative breast cancers 2 centimeters in size, and for some node-positive tumors with few (less than four) involved lymph nodes, adjuvant hormone therapy alone is considered sufficient as long as a woman has low-risk disease (defined as tumors that are low-grade [grade 1], no evidence that the cancer has invaded blood or lymph vessels, and no evidence of HER2 overexpression).

The addition of adjuvant chemotherapy to hormone therapy is suggested for women with hormone-responsive, higher-risk disease.

Tools to help in making treatment decisions — Not all women benefit from or need adjuvant chemotherapy. Two tools are available to estimate the likelihood of a breast cancer recurrence and the relative risks and benefits of adjuvant therapy in individual women.

Adjuvant! Online — The Adjuvant! Online program (www.adjuvantonline.com) uses data from a large number of breast cancer patients and a proprietary formula to estimate an individual woman's prognosis and the benefit of adjuvant systemic therapy (hormone therapy, chemotherapy, and Herceptin).

Oncotype DX assay — Some experts feel that the Oncotype DX assay™ may be useful in deciding which women with node-negative hormone-responsive breast cancer require chemotherapy. This test uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence. If the recurrence score indicates that the patient is in a low-risk category, hormone therapy alone (tamoxifen) may be sufficient, while patients in a higher-risk category may have a better outcome with chemotherapy followed by tamoxifen.

Breast cancer experts disagree about whether the results of the Oncotype DX assay should be used for making decisions about the need for adjuvant chemotherapy. An important clinical trial (The TAILORx trial) is underway to determine the validity of the Oncotype DX results; eligible women are encouraged to enroll [4]. In the meantime, the author of this monograph suggests adding chemotherapy to hormone therapy for women with an intermediate or high recurrence score (18), and hormone therapy alone for women with hormone-responsive, node-negative breast cancer and a low recurrence score (<18).

TIMING, DURATION, SCHEDULING, AND DOSE CONSIDERATIONS — Adjuvant chemotherapy is usually started within four to six weeks after surgery for breast cancer. The optimal duration of CMF or anthracycline-based chemotherapy (with or without a taxane) is between 3 and 6 months. Chemotherapy for more than 6 months is not associated with any benefits, and therapy for less than three months is inferior to treatment for a longer duration. These treatment durations are for chemotherapy only, and do not include Herceptin, which is discussed below.

Scheduling chemotherapy and hormone therapy — In general, hormone therapy should not be started until after chemotherapy is completed. There are concerns that giving both at the same time could decrease the effectiveness of the chemotherapy.

Scheduling chemotherapy and postoperative radiation — Most women who undergo breast-conserving treatment will need radiation to their breast after the tumor is removed surgically. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").

Because of the risk of side effects, chemotherapy is usually not given at the same time as radiation. Instead, the entire course of chemotherapy is usually administered after surgery, before the start of radiation. Studies show that delaying the radiation until after chemotherapy is finished does not have a detrimental effect on outcome.

The importance of dose — The "dose intensity" of adjuvant chemotherapy refers to the drug doses that are administered in a given amount of time, such as the dose per week. Reducing the chemotherapy dose may decrease some of the beneficial effects of adjuvant therapy. Because of this, every effort should be made to avoid unnecessary dose reductions or delays. Some patients will need injections of proteins called growth factors during therapy to stimulate the bone marrow to produce blood cells (for example Neupogen® or Neulasta®).

Dose-dense therapy — Dose-dense therapy is a method of giving anthracycline and taxane-containing chemotherapy that increases the intensity of therapy by shortening the interval between cycles of therapy from 21 to 14 days. In one trial, dose-dense treatment with doxorubicin, cyclophosphamide, and paclitaxel every 14 days was associated with a significantly greater chance of being alive and free of a breast cancer recurrence at five years as compared to the same regimen given every 21 days [5]. This approach has become popular, at least in the United States, for the treatment of patients with node-positive breast cancer, as long as they do not require Herceptin (see below). Growth factor support is necessary during treatment, which can increase the cost of therapy and produce additional side effects (such as bone pain).

SIDE EFFECTS OF CHEMOTHERAPY — Chemotherapy can be associated with both short-term and long-term side effects. The type and severity of these side effects depends upon the particular regimen used.

Short-term side effects — Side effects that occur while chemotherapy is given are usually temporary and reversible. These include nausea, vomiting, mouth soreness, temporary lowering of the blood counts, and hair loss.

Hair loss — Temporary hair loss (alopecia) occurs in nearly all women who receive chemotherapy containing an anthracycline like doxorubicin or paclitaxel. Many women receiving CMF therapy do not lose as much of their hair.

Lowered blood counts — A moderate reduction in the white blood cell count often occurs 10 to 14 days after each cycle of therapy. However, the likelihood of a serious complication (eg, fever or life-threatening infection) related to a low blood count is small, 2 percent or less. As noted above, some patients will need injections of proteins called growth factors such as Neupogen® or Neulasta® during therapy to stimulate the bone marrow to produce white blood cells

Other blood components, such as red blood cells and platelets, can also decrease during therapy. If needed, injections of a protein growth factor called erythropoietin (Procrit®, Aranesp®) can stimulate the bone marrow to produce red blood cells, and diminish the need for blood transfusions during treatment. Platelets are rarely low enough during treatment to require platelet transfusions.

Nausea, vomiting, mouth soreness, and diarrhea — The majority of women receiving adjuvant chemotherapy will have some nausea or vomiting, although symptoms are severe in less than 5 percent. Most women can be treated with anti-nausea medications at the time of chemotherapy. Nausea is more common with CMF; vomiting is more common with anthracycline-based regimens. Severe mouth soreness (mucositis) is also more common with anthracycline-based regimens than CMF. In contrast, diarrhea is uncommon with AC, but more likely when 5-FU is added to AC (eg, with the CAF or FAC regimens).

Neurologic toxicity — Paclitaxel (and less commonly docetaxel) can be associated with numbness and tingling of the fingers and toes. In general, symptoms tend to improve with time (over weeks to months); if severe, recovery may not be complete.

In addition, temporary pain and soreness of the muscles and joints can occur within 72 hours of treatment. Muscle and joint aches may be diminished by pretreatment with gabapentin (Neurontin®), which decreases nerve pain.

Weight gain — The majority of women treated with adjuvant chemotherapy gain weight during treatment, on average 5 to 20 pounds with CMF, and less with AC. Since obesity has been associated with poorer outcomes in women with breast cancer, a diet and exercise program are important components of adjuvant therapy.

Fatigue — Moderate to severe fatigue is a common complaint during adjuvant chemotherapy. Factors that cause fatigue include low red blood count, hot flashes that lead to sleep disturbance, and depression. Symptoms usually resolve after treatment is completed.

Impaired memory and concentration — Many women have mildly impaired memory and a decreased ability to concentrate while receiving chemotherapy. Typically, these symptoms resolve with time.

Hot flashes — Hot flashes may occur during adjuvant treatment either because of premature menopause caused by the chemotherapy (see below), or because of the use of tamoxifen. Sweating and sleep disturbance may also occur. Several non-estrogenic treatments (eg, the antidepressant venlafaxine [Effexor®]) may provide relief.

Long-term side effects

Premature menopause — Menopause (ovarian failure) may develop prematurely when women are given adjuvant chemotherapy; the risk is greater with CMF or CEF regimens as compared with AC regimens with or without a taxane. In one study, only 18 percent of women between ages 20 and 45 were still menstruating 36 months after CMF chemotherapy was completed, while approximately 50 percent of women were still menstruating 12 months after completing AC chemotherapy (with or without a taxane).

Age at the time of treatment is a significant factor; women who receive CMF after the age of 40 are more likely to develop premature menopause. Chemotherapy may be more effective in premenopausal women who become menopausal. Women who become menopausal prematurely need to address concerns about the risk of bone loss with their healthcare provider.

Effects on the heart — The anthracycline drugs have been associated with damage to the heart muscle in some women. Heart failure occurs in up to 1 percent of women who receive standard adjuvant doses of doxorubicin (300 mg/m2 or less). Factors that increase this risk include high lifetime doses of doxorubicin, older age, a history of prior heart problems, and radiation therapy directed at the chest wall.

The risk of damage to the heart muscle appears to be higher with regimens that combine anthracyclines with Herceptin (see below).

Leukemia — There is a small risk of leukemia related to the use of alkylating agents (eg, cyclophosphamide) or anthracycline-based chemotherapy. The risk depends upon the dose, duration, type of chemotherapy given, and possibly whether hematopoietic growth factors were used during adjuvant therapy.

TRASTUZUMAB (HERCEPTIN) — Herceptin is a novel type of drug that specifically targets the protein HER2, present on the cells of some breast cancers. About 18 to 20 percent of breast cancers express very high levels of this marker, and Herceptin appears to be effective only in this group of women.

Herceptin was previously used only for the treatment of women with advanced breast cancer. However, several studies now demonstrate a significant benefit for adding adjuvant Herceptin to anthracycline- and taxane-containing chemotherapy in women with early stage, node-positive, HER2-overexpressing breast cancer. The use of Herceptin reduced the risk of breast cancer recurrence by about 50 percent, and the risk of death by about 33 percent [6,7].

Administration — Herceptin is given by IV injection over 30 to 90 minutes once per week, usually for one year. It is generally given after anthracycline administration has been completed.

Risks — Women who receive Herceptin in addition to chemotherapy have a small but serious increase in the risk of developing weakening of the heart muscle. In the early studies, approximately two to three percent of patients (2 to 3 of every 100 treated women) developed heart failure requiring treatment with medication, despite careful monitoring for early signs of heart problems. Furthermore, the long-term risk may be underestimated since initial reports only included short-term follow-up.

Heart failure is a serious, sometimes irreversible, and potentially life-threatening disease. However, the small risk of heart failure must be balanced against the increased risk of dying from breast caner for women with node-positive, HER2 overexpressing breast cancers. Ongoing studies are trying to determine whether combinations of Herceptin with non-anthracycline-containing chemotherapy regimens are as effective as regimens that contain an anthracycline, with less toxic effects on the heart.

SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 3 (show table 3).

SUMMARY AND RECOMMENDATIONS — There are many options for the adjuvant therapy of breast cancer, and deciding which is best can be confusing. General guidelines help clarify which therapies are most appropriate for large groups of women. Because individual factors strongly influence the choice of therapy, each woman should discuss the options for adjuvant therapy with her doctor to determine which therapy is best for her based upon her estimated risk of developing a breast cancer recurrence. The web-based program, Adjuvant! Online (www.adjuvantonline.com), can be used to estimate the risk of recurrence, long-term prognosis, and the expected benefit from different adjuvant therapy strategies. (See "Tools to help in making treatment decisions" above).

The following summarizes our general approach to adjuvant therapy:

HER2-negative breast cancer

ER-negative — In general, chemotherapy is recommended for all women with hormone nonresponsive, lymph node-positive breast cancer, and for women with hormone nonresponsive, lymph node-negative breast cancer who have a tumor size greater than 1 centimeter. Whether chemotherapy should be given to women with smaller, ER-negative tumors is controversial; the author suggests chemotherapy to all such women with tumors size >0.6 centimeters.

ER-positive — The recommendations for chemotherapy in women with ER-positive breast cancer are difficult to define at present. Many clinicians in the United States follow guidelines from the NCCN which suggest the addition of chemotherapy to hormone therapy for all patients with node-positive breast cancer or tumor size 1 centimeter [8].

On the other hand, the International Consensus Group suggests that hormone therapy alone is sufficient for patients with tumor size up to 2 cm, favorable pathologic features, and up to three positive nodes as long as their tumor does not overexpress HER2 [3]. In general, we agree with the International Consensus Group approach, but we discuss the pros and cons of chemotherapy individually with these women, taking personal preference into account as well. Although others disagree, we use the results of the Oncotype DX assay to stratify women with ER-positive, node-negative breast cancer into prognostic groups in order to tailor adjuvant therapy. We suggest chemotherapy for women with an intermediate or high recurrence score. We suggest not administering adjuvant chemotherapy to women with ER-positive, node-negative breast cancer and a low recurrence score (<18). Women with hormone-responsive breast cancer who receive both chemotherapy and hormone therapy should be given hormone therapy after chemotherapy has been completed, and not at the same time. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women"). Anthracycline-containing regimens offer a modest but significant benefit over other regimens (ie, CMF-type regimens), and they are preferred (see "CMF versus anthracycline-based chemotherapy" above and see "Tools to help in making treatment decisions" above). A drug of the taxane class (paclitaxel or docetaxel) should be added to anthracycline-containing adjuvant chemotherapy for women with node-positive breast cancer (see "Taxane-containing chemotherapy" above).

HER2-positive — Women whose tumors make high levels of HER2 derive additional benefits from use of Herceptin for one year. Herceptin should not be started until after the anthracycline portion of chemotherapy treatment is completed. However, combined treatment is associated with a small but real increase in the risk of heart muscle weakness (see "Trastuzumab (Herceptin)" above).

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. National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
Adjuvant! Online

(www.adjuvantonline.com)
Susan G. Komen Breast Cancer Foundation

(www.komen.org)

[3,6,7,9-11]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Berry, DA, Cirrincione, C, Henderson, IC, et al. Estrogen receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006; 295:1658.
2. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls/_english/_breast/contents.asp. (accessed May 19, 2006).
3. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
4. Enrollment information for the TAILORx trial available at www.ctsu.org/data/protocols/ECOG/PACCT-1/pfs.pdf (accessed on May 8, 2006).
5. Citron, ML, Berry, DA, Cirrincione, C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21:1431.
6. Romond, EH, Perez, EA, Bryant, J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673.
7. Piccart-Gebhart, MJ, Procter, M, Leyland-Jones, B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659.
8. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org.
9. Shapiro, CL, Recht, A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344:1997.
10. Bines, J, Oleske, DM, Cobleigh, MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14:1718.
11. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.

Primary low-grade glioma in adults

INTRODUCTION — Malignant brain tumors are cancers that originate either in the brain itself (primary brain tumors) or spread (metastasize) to the brain from a cancer elsewhere in the body (also known as secondary (malignant) brain tumors or brain metastases). Secondary brain tumors are much more common, and their treatment is determined by where the cancer began and by the areas where the cancer has spread elsewhere in the body.

In this topic review, we will discuss the symptoms, diagnosis and treatment of low-grade gliomas, an important category of primary brain tumors.

CLASSIFICATION OF PRIMARY BRAIN TUMORS — Primary brain tumors are classified according to their appearance under the microscope, and what type of brain cell they are thought to have arisen from. Over 80 percent of all malignancies that arise in the brain fall into the general category called a "glioma" [1].

Gliomas (also sometimes called astrocytomas) are the result of uncontrolled growth of glial cells (also called astrocytes). Glial cells provide the structural backbone of the brain and support the function of the neurons, which are directly responsible for thought, sensation, muscle control, and coordination. Thus, a tumor originating in glial cells can disrupt almost any function of the normal brain.

Low-grade versus high-grade gliomas — Examination of gliomas through a microscope shows changes of the glial cells that give information about the aggressiveness of the cancer (ie, the relative degree of malignancy). This tends to correlate with the speed with which the tumor is growing and damaging normal brain cells. Based on this, the World Health Organization (WHO) classifies gliomas into four grades depending on prognosis [2].

The term low-grade glioma refers to those tumors in Grades I and II of this classification. They have fewer aggressive characteristics and therefore are more likely to grow slowly, as opposed to high-grade gliomas, which show more aggressive features of malignancy and are more likely to grow rapidly. This distinction of a glioma as either low-grade or high-grade is an important one, since both the prognosis and the approaches to treatment are different [1]. This topic review will focus on low-grade gliomas. For information about high-grade gliomas, see "Patient information: High-grade glioma in adults".

Types of low-grade glioma — Low-grade gliomas are subdivided into different types based upon the microscopic appearance of the tumor. The more common subtypes are:

Diffuse astrocytomas — Diffuse astrocytomas are the most common low-grade glioma. They are usually diagnosed in individuals in their late thirties. The average survival is approximately seven years, although about 20 percent of patients survive ten years or more.

Juvenile pilocytic astrocytomas — These tumors occur almost exclusively in patients less than 25 years of age. It is important to distinguish juvenile pilocytic astrocytomas from other low-grade gliomas because these tumors tend to progress very slowly. Unlike diffuse astrocytomas, over 80 percent of patients survive ten years or more, generally with a very good functional level.

Oligodendrogliomas — Oligodendrogliomas can be slow-growing tumors. The prognosis of patients with this tumor type depends in part upon the presence or absence of a portion of human Chromosome 1 (1p). Patients with loss of this chromosome tend to survive longer and are more responsive to chemotherapy. Patients who have tumors that have components of both astrocytomas and oligodendrogliomas (tumors called "oligoastrocytomas"), tend to have tumors that behave like diffuse astrocytomas.

Gangliogliomas — These tumors have features of both gliomas and of tumors arising from neurons, the other main type of cell within the brain besides glial cells. These tumors tend to grow very slowly, and many patients do well for a long time.

Mixed gliomas — Some low-grade gliomas consist of mixtures of different tumor subtypes (eg, diffuse astrocytoma and oligodendroglioma). These tend to behave similarly to diffuse astrocytomas.

SYMPTOMS — Low-grade gliomas do not spread outside the brain, but instead grow into the normal brain tissue, creating symptoms as the tumor grows locally. This can disrupt connections between normal brain cells, and can also create pressure on the adjacent brain. The brain cannot expand when there is a tumor growing within it since it is confined within the skull. As a result, even a relatively small, slow-growing tumor can cause severe brain dysfunction and death, particularly if the tumor is in a critical area of the brain.

In many patients, a seizure is the first symptom of a low-grade glioma. Seizures, which can also occur in other conditions such as epilepsy, are caused by disorganized electrical activity in the brain. They can cause loss of consciousness, involuntary movements, and/or loss of muscle control throughout the body.

Seizures can often be completely controlled with medications. In patients with a low-grade glioma who are first diagnosed after a seizure, no neurologic signs or symptoms may be evident once the seizure is controlled with medication.

Other patients have symptoms due to swelling around the tumor (called cerebral edema) or blockage of the normal cerebrospinal fluid that circulates within the brain (called obstructive hydrocephalus). In either case, symptoms can include headache, nausea and vomiting, diminished consciousness, weakness or numbness, and loss of mental sharpness or difficulty concentrating. The area of the brain affected by the tumor and/or the swelling will determine the specific symptoms.

DIAGNOSIS — All of the symptoms described above, including seizures, can be caused by neurologic illnesses other than tumors, and by non-neurologic diseases. A clinician will need to do a careful history and physical examination as well as basic laboratory and x-ray tests to define the cause of symptoms or seizures. The presence of a brain tumor is often established by x-ray or imaging studies.

Imaging studies — If a brain tumor is suspected, the physician will want to obtain a x-ray scan of the brain. This is done using either magnetic resonance imaging (also known as an MRI) or computed tomography (also known as CT or CAT scan). A major difference between an MRI and a CT scan is that the MRI uses a magnet to image the brain, while CT uses x-rays. Both give a detailed image of the brain's structure, and both can show the presence of a tumor and its location.

CT scans are generally more available and less expensive than MRI scans, so often a brain CT is the first test that is ordered when a neurologic condition affecting the brain is being evaluated. However, the MRI provides much more useful information when a brain tumor is suspected. Thus, it is the preferred test in most situations. However, there are a few situations where a CT scan can offer advantages. Although not every tumor can be visualized by MRI or CT, most can be identified.

Sometimes, the findings on the brain CT or MRI are sufficiently characteristic that the diagnosis of a low-grade glioma may be fairly certain. In such cases, a biopsy may not be necessary. However, in most cases, a biopsy is recommended to establish the type of tumor that is present since it may impact on treatment (See "Treatment" below).

It is important to characterize a brain tumor as a low-grade glioma, high-grade glioma, or a different type of tumor altogether. An additional noninvasive x-ray test that may help in this distinction is a positron-emission tomography, PET scan. During this test, glucose (a sugar) with a radioactive tag is injected into the bloodstream, which then circulates to the brain. Differences in the metabolism of glucose between normal cells and various types of cancer cells permit identification of a tumor, and may permit the distinction between low-grade gliomas, high-grade gliomas, and other brain tumors.

Biopsy — A biopsy is usually required to establish the definitive diagnosis and subtype of a brain tumor and plan appropriate treatment. Biopsy involves the removal of at least a small amount of tissue from the brain for microscopic examination.

A brain biopsy may be done in conjunction with surgery to remove the tumor. Alternatively, a small sample may be removed from the tumor by stereotactic needle biopsy, which involves the insertion of a needle through the skull into the precise area of the tumor under x-ray (radiographic) guidance. Although both surgical biopsy and stereotactic needle biopsy are usually safe, neurologic damage is a potential complication.

If the findings on CT, MRI, and PET are characteristic, biopsy of the tumor may be deferred until symptoms worsen or there is evidence of tumor growth or a change in the imaging characteristics that suggest that the tumor is becoming more aggressive. The decision regarding the optimal timing of a biopsy requires the physician and patient to carefully weigh the risks of the biopsy against the benefit of knowing the specific type of tumor that is present.

TREATMENT — Treatment of a low-grade glioma has to take into account both the management of symptoms as well as specific approaches to remove the tumor or reduce its size. The optimal treatment of low grade-glioma (particularly the timing of treatment) is a controversial area, and treatment decisions must balance the benefits of therapy against the potential for treatment-related complications.

Symptom management — Seizures, cerebral edema (swelling in the brain around the tumor), and obstructive hydrocephalus (increased pressure within the brain due to blockage of the flow of cerebrospinal fluid within the brain) can all result in serious symptoms for patients with brain tumors. Each of these requires a different therapeutic approach: The same medications used to treat epilepsy are usually successful in controlling seizures associated with brain tumors, such as low-grade gliomas. However, seizures may be more difficult to control in patients with brain tumors, particularly low-grade gliomas. If medications are not effective, surgery to remove part of the tumor may be recommended in an attempt to reduce seizure activity. Cerebral edema usually can be treated successfully with a class of drugs called corticosteroids (steroids); the most commonly used steroid is dexamethasone (Decadron). Dexamethasone use can be temporary if specific treatment of the tumor is planned, and is expected to decrease edema. Dexamethasone may be used for a more prolonged period of time if treatment is deferred, and may be particularly useful in the late phases of the illness, such as if the tumor recurs and there is no other way to control cerebral edema.

One of the problems with long-term use of dexamethasone (particularly high doses) is the potential for side effects (eg, ulcers, bleeding from the gastrointestinal tract, behavioral changes, thinning of the skin, loss of bone strength, high blood sugar). Thus, the dose of dexamethasone is tapered to achieve the lowest dose that can effectively control symptoms, yet minimize long-term complications. Obstructive hydrocephalus may require surgery to bypass the blockage and lower the pressure within the brain.

Antitumor therapy — Surgery, radiation therapy, and chemotherapy may be used to treat a low-grade glioma, either separately or in combination.

Surgery — The objective of surgery is to remove (resect) as much of the tumor as possible, while minimizing damage to the normal brain. While patients with juvenile pilocytic astrocytomas do particularly well after removal of their tumors, the impact of surgery on the survival of patients with other types of low-grade glioma is less clear [4].

Low-grade gliomas infiltrate into normal brain, and there is often no distinct boundary between the tumor and normal brain. As a result, efforts to remove all tumor cells inevitably removes some of the normal brain and can leave behind tumor cells. The remaining glioma cells continue to grow, eventually causing additional damage to the remaining normal brain, and recurrence of symptoms. Thus, surgery, even when extensive, rarely results in cure of a adults with an infiltrative low-grade glioma.

Whether or not all patients should have surgery after initial diagnosis is an area of controversy [4-7]: Some physicians recommend that resection of as much tumor as possible be attempted in all patients as soon as the diagnosis of a brain tumor is made. This recommendation is based upon studies suggesting that patients who have immediate surgery survive longer, possibly because the tumor is less likely to change into a more aggressive form. Other physicians recommend that carefully selected patients initially be observed without therapy, until there is evidence of tumor growth or an increase in symptoms despite medical therapy. The rationale behind this approach is that low-grade gliomas may progress very slowly, surgery can create more symptoms than are caused by the tumor, and surgery undertaken later may be equally effective [6].

The physician and patient must try to balance the benefits of removing tumor versus the neurologic symptoms that can be expected from damage to normal brain. The extent of surgery and whether it is feasible are influenced heavily by the location of the tumor within the brain: If the tumor is in an area of the brain controlling one or more critical functions, surgery may result in severe damage. In this setting, the physician may recommend against surgery or recommend limiting the amount of tumor removed. If the tumor is in a less critical area of the brain, the physician may recommend trying to remove as much of the tumor as possible.

Other accepted indications for neurosurgery include increased pressure within the brain, a neurological deficit due to the tumor or a bleed (hemorrhage) into the tumor, or seizures that are unresponsive to medical therapy [4].

Radiation therapy — Radiation therapy (also called radiotherapy or x-ray therapy) uses high energy x-rays that are carefully aimed at the area of the brain affected by the tumor. Radiation therapy is generally given in a series of treatments over several weeks. The total radiation dose, which is based upon the number of treatments and the amount of radiation administered per treatment, is carefully calculated to maximize the killing of tumor cells and minimize damage to the normal brain.

Radiation therapy may be recommended in three circumstances in patients with low-grade gliomas: Radiation can be given after surgery, with the objective of eradicating tumor cells that were not removed at the time of surgery. The effectiveness of immediate radiation therapy after surgery is unclear. Because benefit is uncertain [8], and radiation has the potential for long-term neurologic side effects, postoperative radiation is often not recommended (see below). Radiation therapy may be the preferred treatment when a symptomatic low-grade glioma has been diagnosed in a critical area of the brain that cannot be surgically removed, and therapy is felt to be necessary. Radiotherapy can be utilized later in the course of the illness, when there is evidence that the tumor has recurred and is causing symptoms. Use of radiation therapy at this time may be dependent upon how much radiation was given earlier, since radiation therapy can usually not be administered in full doses to the same area of the brain more than once.

A major problem with radiation therapy is treatment-related side effects. Radiation kills both tumor cells and normal cells, although tumor cells are somewhat more sensitive to the effects of radiation. Nevertheless, radiation therapy cannot kill all tumor cells without damaging adjacent normal brain, and this results in treatment-related side effects.

The most serious side effect is radiation necrosis (the death of large numbers of normal brain cells), which may occur many months after the radiation therapy is given, particularly if high doses are used [9]. This is generally not a reversible condition, and may require surgery to remove the area of dead tissue. Fortunately, this complication is uncommon with conventional radiation doses.

More commonly, radiation may damage the surrounding normal brain cells in a more subtle way, resulting in gradually worsening impairment of mental sharpness and ability to think and concentrate (called impaired cognition) [10-12]. This cognitive impairment, which tends to be greater with larger radiation fields, tends to worsen over time, and is more of a problem in patients who survive for several years after undergoing radiation therapy to the brain. It is difficult to know for certain whether impaired cognition results from the radiation or whether it might be due to the disease itself. Nevertheless, although the risk of worsened cognition after radiation is still studied, this possibility remains one of the main reasons why radiation therapy is often deferred until it is absolutely necessary.

Chemotherapy — Regardless of the initial form of therapy, low-grade gliomas generally progress over time; the time frame may be long, sometimes as long as ten years or more after the original diagnosis. They may also develop an aggressive (more malignant) phase after a variable period of time. This aggressive phase is characterized by more rapid tumor growth and progressive neurologic dysfunction.

Therapeutic options are limited in the late phases of the disease, since surgery and radiation therapy are unlikely to be useful or feasible. In such cases, chemotherapy may be considered.

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 (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair roots (follicles), and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment. In general, side effects are more frequent when two or more drugs are administered simultaneously (termed combination chemotherapy, see below), and with higher as compared to lower doses of chemotherapy. Most chemotherapy drugs that are used for the treatment of brain tumors are administered into the vein, although some (temozolomide, for example) are effective when given by mouth.

Chemotherapy is not curative, but it produces short-term benefits (months rather than years) in some patients. Tumor shrinkage (which may be accompanied by an improvement in symptoms) has been seen in selected patients using various drugs or combinations, such as temozolomide (Temodar) or the "PCV" combination (procarbazine, lomustine, and vincristine). Patients with the oligodendroglioma subtype (especially those with the chromosome1p deletion) are most likely to benefit from chemotherapy [13]; response rates in other types of low-grade gliomas have generally been disappointing.

The use of chemotherapy in conjunction with radiation therapy earlier in the course of low-grade glioma has not been adequately studied. Thus, benefit from this approach has not been established, and it should only be used in the setting of a clinical research study.

SUMMARY — Low-grade gliomas are cancers arising in the brain that tend to be slow-growing, and associated with a long natural history. Although patients with these tumors are only rarely cured, most are able to maintain a high level of functioning for a number of years. Careful medical management of seizures, brain swelling, and other complications, combined with the timely use of surgery, radiation therapy, and perhaps chemotherapy, can help preserve a high quality of life and minimize disability.

CLINICAL TRIALS — Progress in treating low-grade glioma requires that better treatments be identified through clinical trials, which are conducted all over the world. Many clinical trials are ongoing. Patients may be eligible for one of these clinical trials, many of which are sponsored by the National Cancer Institute (see below). Patients should ask doctor about participating in a study.

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. National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Brain Tumor Association

(www.abta.org)
National Brain Tumor Foundation

(www.braintumor.org)
National Institute of Neurological Disorders and Stroke

(www.ninds.nih.gov)

[1-13]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. DeAngelis, LM. Brain tumors. N Engl J Med 2001; 344:114.
2. Kleihues, P, Cavenee, WK (eds). Tumours of the Nervous System. Pathology and Genetics, IARC Press, 2000.
3. Claus, EB, Black, PM. Survival rates and patterns of care for patients diagnosed with supratentorial low-grade gliomas: data from the SEER program, 1973-2001. Cancer 2006; 106:1358.
4. Piepmeier, J, Baehring, JM. Surgical resection for patients with benign primary brain tumors and low grade gliomas. J Neurooncol 2004; 69:55.
5. Keles, GE, Lamborn, KR, Berger, MS. Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurg 2001; 95:735.
6. Recht, LD, Lew, R, Smith, TW. Suspected low-grade glioma: Is deferring treatment safe? Ann Neurol 1992; 31:431.
7. Bampoe, J, Bernstein, M. The role of surgery in low grade gliomas. J Neurooncol 1999; 42:259.
8. Karim, AB, Afra, D, Cornu, P, et al. Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 2002; 52:316.
9. Shaw, E, Arusell, R, Scheithauer, B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a north central cancer treatment group/radiation therapy oncology group/eastern cooperative oncology group study. J Clin Oncol 2002; 20:2267.
10. Surma-aho, O, Niemela, M, Vilkki, J, et al. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 2001; 56:1285.
11. Klein, M, Heimans, JJ, Aaronson, NK, et al. Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet 2002; 360:1361.
12. Shaw, EG, Tatter, SB, Lesser, GJ, et al. Current Controversies in the Radiotherapeutic Management of Adult Low-Grade Glioma. Semin Oncol 2004; 31:653.
13. Olson, JD, Riedel, E, DeAngelis, LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology 2000; 54:1442.

Primary low-grade glioma in adults

Brain tumors Patient information: Meningioma

INTRODUCTION — Meningiomas are brain tumors that develop in the tissue that surrounds and protects the outer surface of the brain and spinal cord (the meninges). Meningiomas account for about 15 to 30 percent of all tumors that originate in the brain. They are seen most frequently after age 40, and are more common in women than men [1].

Meningiomas can occur in any part of the lining over the brain or spinal cord (show figure 1). About 90 percent occur within the head: around the cerebral hemispheres (just inside the skull), on the under surface of the brain (at the base of the skull), or in the lower part of the brain (the brainstem, which is located just above the spinal cord). Most of the remaining meningiomas arise in the optic nerve sheath (which protects the nerve connecting the eye to the brain) and around the spinal cord.

CLASSIFICATION OF MENINGIOMA — Meningiomas are classified according to their appearance when examined under the microscope and their position in the brain. Microscopic examination provides information about the cells comprising the meningioma, including how rapidly the cells are dividing (referred to as the "mitotic index") and whether the meningioma cells are growing into or invading the adjacent normal brain. Classification provides valuable information about the likelihood of meningioma returning ("recurring") after treatment.

The most widely used classification system is that of the World Health Organization (WHO), which separates meningiomas into three categories:

Grade I or benign meningiomas — Benign meningiomas are slow-growing tumors that have well-defined borders and do not appear to invade the adjacent normal brain. Few meningioma cells are actively dividing (ie, the tumor has a low mitotic index). Approximately 90 percent of all meningiomas fall into this category.

Grade II or atypical meningiomas — Atypical meningiomas contain more cells that are actively dividing (ie, they have a higher mitotic index) than benign meningiomas. In addition, grade II tumors have other features that suggest that they are growing more rapidly than benign meningiomas. These lesions are more likely to recur than benign tumors. Atypical meningiomas constitute about 5 to 7 percent of all meningiomas.

Grade III or malignant meningiomas — Malignant meningiomas, which are sometimes referred to as anaplastic meningiomas, have the highest mitotic index. Malignant meningiomas are likely to recur after treatment. These comprise 1 to 3 percent of all meningiomas.

A higher grade correlates with a worse prognosis. Patients with benign (grade I) meningiomas generally do well, with 80 percent or more remaining free of progression or recurrence after their initial treatment. In contrast, patients with atypical (grade II) and malignant (grade III) meningiomas are at much higher risk for recurrence. In one report, patients with atypical meningiomas had recurrence within an average of five years, while patients with malignant meningiomas had recurrence within an average of only two years [2].

RISK FACTORS — The cause of meningiomas is not well understood, but may include both genetic (inherited) and environmental factors. Several conditions have been associated with an increased risk for the development of a meningioma [1]: Neurofibromatosis - Neurofibromatosis type 2 is a rare inherited disease that usually appears first during childhood. This disorder affects the skin and the nervous system, and increases the risk of meningiomas as well as other brain tumors. Affected patients may develop multiple meningiomas. Previous radiation therapy treatment - Patients who have had radiation exposure to the head have an increased risk for developing a meningioma, especially 10 to 20 years after treatment. Individuals who underwent irradiation of the brain and spinal cord during treatment for childhood leukemia are at a particularly high risk. History of head trauma — Magnetic resonance imaging (MRI) or computed tomography (CT scan) are frequently performed after a head injury. These tests do not increase the risk of developing meningiomas, but instead increases the chance of finding a meningioma that is not causing any symptoms. Exposure to female hormones and breast cancer — Several observations support a link between exposure to female hormones and the risk of meningioma. Meningiomas are more common in women overall, particularly in those who use postmenopausal hormone replacement therapy [3]. In addition, meningiomas may increase in size during pregnancy, a time when female hormones are at their highest levels. There is also a well-described relationship between breast cancer (a tumor that is dependent upon female hormones for growth) and meningioma.

Women with a history of breast cancer have a higher incidence of meningiomas, and women with a history of a meningioma have a greater likelihood of developing breast cancer [4]. Although not proven, these data suggest a shared underlying cause for both tumors.

SYMPTOMS — As noted above, meningiomas may be identified after the patient has an MRI or CT scan for some other reason, such as a head injury. Meningiomas may also be discovered when a person seeks medical attention because he or she is experiencing neurologic symptoms [5]. A variety of symptoms are possible, depending primarily on the location of the meningioma.

Seizures — Seizures (sometimes called "fits") are the result of disorganized electrical activity in the brain. They can cause a person to pass out, involuntarily move the arms and legs, and/or lose muscle control throughout the body. Seizures are also seen in patients with epilepsy and other neurologic disorders. Among patients with meningioma, seizures are the most common presenting symptom and occur in 30 to 40 percent of patients [6].

Neurologic symptoms — Symptoms of a meningioma develop as a result of abnormal functioning of a specific area of the brain. This usually occurs when the tumor presses on normal brain tissue. The symptoms depend upon the location of the meningioma within the brain and the function of that particular area (eg, movement, vision, hearing, sense of balance).

A wide range of symptoms can be seen in patients with meningiomas. Some examples include: Visual changes - Individuals with a meningioma may experience a variety of visual difficulties such as loss of vision in one eye, blind spots, or blurred or double vision. Visual changes may not be noticed by the patient, and may only be noticed as a result of detailed testing. Hearing loss - Meningiomas can cause hearing loss by damaging or compressing the cochlear nerve, which transmits nerve impulses from the ear to the brain. Mental status changes - Patients with large meningiomas on the undersurface of the brain may have subtle changes in their personality or mental status, causing the person to appear that they are not paying attention or are forgetful. Arm and/or leg weakness - A meningioma can cause different patterns of weakness in the arms and legs, depending upon the location of the tumor. As an example, parasagittal meningiomas (ie, tumors located along the separation of the right and left halves of the brain, show figure 1) may cause weakness in both legs. In contrast, tumors arising at the foramen magnum (ie, the location where the base of the brain connects to the spinal cord) may produce a progressive weakness first in the arm and then progresses to involve the leg on the same side, followed by similar changes on the other side of the body.

Obstructive hydrocephalus — As meningiomas grow, they may block the flow of spinal fluid (referred to as obstructive hydrocephalus). Spinal fluid is a clear liquid that is produced within the brain; it functions to fill and protect spaces within and around the brain and spinal cord. If the flow of spinal fluid is blocked, pressure within the head increases. As the pressure on the brain increases, a person may experience headaches (particularly in the morning), nausea, and vomiting. If the condition is untreated, the person may become unable to respond to those around him or her (called a coma).

DIAGNOSIS — If a meningioma is suspected, the clinician will want to obtain a detailed scan of the brain, using either MRI or CT. The major difference between an MRI and CT is that the MRI uses a magnet to image the brain, while CT uses x-rays. Both give a detailed image of the brain's structure, and both can show a tumor and its location.

CT scans are generally more readily available and less expensive than MRI, so a brain CT is often the first test that is ordered. However, MRI is the preferred test if a brain tumor is suspected because it can define more precisely the location and extent of a tumor in the brain or spinal cord (including the meninges), allowing for better treatment planning. Furthermore, the appearance of meningiomas on MRI scanning is unique, meaning that few other types of tumors have a similar appearance. As a result of this unique appearance, a biopsy to confirm that a tumor is a meningioma may not be needed.

In some cases, other disorders need to be ruled out to make a definite diagnosis. As examples, infections (such as tuberculosis), cancers other than meningiomas, and inflammatory diseases (such as sarcoidosis) can cause similar neurologic signs and/or symptoms and thickening of the meninges, making it difficult to determine if a meningioma or another problem is the cause.

TREATMENT — The initial treatment of a meningioma may include surgery, radiation therapy, or careful observation without treatment (sometimes referred to as "conservative management").

Risks versus benefits of treatment — The best approach requires a balance between the potential benefits of treatment (ie, alleviating symptoms and preventing further tumor growth) and the potential side effects and risks of treatment.

Factors that are considered in choosing among different treatment options include: Location of the meningioma — The location of the meningioma determines whether or not the tumor can be removed completely and whether or not blood vessels, nerves, and the underlying brain are likely to be damaged during surgery. As an example, tumors located on the surface of the brain are easiest to remove without risking potentially serious complications.

In contrast, tumors located on the undersurface of the brain or in the groove between the right and left halves of the brain may be more difficult to remove safely. When a tumor cannot be resected by surgery, radiotherapy may be used in conjunction with partial removal of the meningioma. Size of the meningioma — Large tumors are more likely to compress or damage the brain, either directly or by causing swelling of the surrounding normal brain. In contrast, small tumors may not produce symptoms. Thus, patients with larger tumors are more likely to require surgery, even though the operation may be difficult. Symptoms — Tumors that produce symptoms generally require treatment, both to relieve symptoms and prevent their worsening. If a patient is asymptomatic and has no evidence of neurologic dysfunction, careful observation may be appropriate until it can be determined how fast the tumor is growing. Age — Active treatment may not be recommended for older patients with small meningiomas that do not cause symptoms because of the increased risk of serious medical complications following surgery in this age group. In addition, if an older person's tumor is growing slowly, it may never reach a size where it causes symptoms.

In contrast, surgery is more often recommended for younger patients who are less likely to have serious treatment complications. Furthermore, younger patients have a longer life expectancy, and even a slow growing tumor may have time to reach a size where it could cause symptoms. Overall medical condition — Surgery to remove a brain tumor is complex and can be associated with serious complications; this is more likely to occur in patients who have other serious medical conditions.

Surgery — Surgery is the preferred treatment for most meningiomas.

Extent of surgery — Total removal of a meningioma provides the best chance of avoiding a future recurrence. However, the ability to completely remove the tumor depends upon the size and location of the meningioma. Some tumors cannot be totally removed because the tumor is too close or involved with important parts of the brain or blood vessels. In such cases, the tumor may be only partially removed. For tumors near the optic nerve, a small sample of the tumor may be removed so that it can be examined more closely with a microscope.

To improve the chances of completely removing a meningioma, a procedure called embolization may be recommended before surgery. During this procedure, a catheter is carefully placed into the blood vessels leading to or "feeding" the tumor. A material is injected into the blood vessels, which blocks the blood flow. This helps to decrease the risk of serious bleeding during surgery [7].

For tumors that are incompletely removed, the likelihood of recurrence is relatively high, even for grade I tumors. As an example, of 581 patients treated with surgery alone, 75 percent of those undergoing complete removal of a meningioma were free of recurrence 10 years after surgery compared with 39 percent whose tumors had not been completely resected [8].

Following surgery, the risk of tumor recurrence depends upon how much tumor was removed and whether it was cancerous, noncancerous, or atypical. (see "Outcomes" below). For patients whose tumor cannot be removed completely with surgery, radiation therapy is often recommended after surgery to reduce the risk of recurrence (see "Adjuvant radiotherapy" below).

Complications of surgery — Complications associated with surgery include damage to nearby normal brain and medical complications of major surgery (eg, bleeding, infection). Examples of potentially serious complications include: Accumulation of fluid in the brain (cerebral edema) is common after surgery for meningiomas. A corticosteroid medication such as dexamethasone (Decadron) may be given before and after surgery to minimize the extent of cerebral edema. About 20 percent of patients without seizures prior to surgery will develop them after surgery. Thus antiseizure medication is usually recommended following surgery. The medication can usually be slowly discontinued within one week after surgery if seizures do not occur. Worsened or new neurologic symptoms may develop after surgery. Examples of neurologic symptoms include muscle weakness, speech problems, or difficulty with coordination. These symptoms are a result of damage to the brain or other parts of the nervous system, or they may be due to bleeding, cerebral edema, or infection. Medical complications of brain surgery include pneumonia, heart attack, an irregular heart rhythm, or blood clots. Patients who undergo brain surgery or who have brain tumors have an increased risk of blood clots in the veins (deep venous thrombosis) and movement of blood clots to the lungs (pulmonary embolism). As a result, preventive measures are recommended after surgery. This includes use of anticoagulant medications and compression boots (devices that go around the legs and inflate periodically). (See "Patient information: Venous thrombosis").

Radiation therapy — Radiation therapy uses high energy x-rays to damage tumor cells. The x-rays are carefully aimed at the area of the brain affected by the tumor. Unlike normal cells, tumor cells are less able to repair the damage caused by exposure to x-radiation, particularly when the radiation is administered over several days.

Radiation treatment is given in frequent low doses (usually daily treatment, five days per week for 5 to 6 weeks). The total radiation dose is based upon the number of treatments and the amount of radiation administered per treatment. The area of the area of the brain treated is called the treatment field. The total radiation dose and the treatment field are carefully calculated to maximize radiation exposure of tumor cells and minimize damage to the normal brain tissue.

The standard way to deliver radiation is by 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 as he or she lies on a table underneath the machine. The high energy beams are targeted to the area of the brain where the meningioma is located.

Radiation therapy is used for patients who have had partial removal of their meningioma. In addition, radiation may be recommended when surgery is not possible or if surgery has more risks than benefits. As an example, radiation therapy has become the preferred treatment for optic nerve sheath meningiomas (ie, tumors arising in the lining around the nerve to the eye), since there is a lower risk of vision loss after radiation compared to surgery.

Side effects of radiotherapy — A common concern of patients who undergo radiation therapy is treatment-related side effects. Radiation kills both tumor and normal cells, although tumor cells are somewhat more sensitive to the effects of radiation. Nevertheless, radiation therapy cannot kill all tumor cells without damaging nearby normal brain tissue. Side effects of radiotherapy to the brain can be divided into short term and long term effects. Short term effects — During radiation treatment, hair loss will occur, typically starting around the third or fourth week of therapy. Hair loss is limited to the areas where treatment occurs; this may be temporary or permanent. Regrowth typically begins two to three months after treatment ends. Mild fatigue is common and often does not develop until the last few weeks of radiation treatment. Mild skin redness or irritation may occur and is temporary. Headaches or nausea occur less frequently and can be treated so that they are not persistent. Long term effects — Potential long term effects of RT are more concerning but fortunately less common than short term side effects, especially when modern dosing and treatment plans are used. The most serious long term effect of RT is death of a large number of normal brain cells; this is called radiation necrosis. This may occur many months after the radiation therapy is completed, particularly if high doses are used [6].

Most patients have no symptoms of radiation necrosis. However, patients who have symptoms may have difficulties with short term memory, planning and reaching goals, controlling behavior, paying attention, and organizing thoughts [9]. The risk of these effects depends upon the location and size of the tumor being irradiated and the radiation techniques used; high doses of radiation to a small area are thought to pose a greater risk than lower doses of radiation to larger areas of the brain.

Adjuvant radiotherapy — Use of radiation therapy after partial surgical removal of meningioma is called adjuvant radiotherapy. Adjuvant radiotherapy appears to reduce the risk of recurrence substantially. In one analysis, 77 percent of patients who received adjuvant radiotherapy after a partial surgical removal of a noncancerous meningioma had no recurrence after 10 years [10]. This outcome is similar to that of people who have complete removal of a noncancerous meningioma.

Stereotactic radiosurgery — Stereotactic radiosurgery is an alternative to external beam radiation therapy. This does not actually involve performing surgery, but instead uses narrow beams of radiation that are delivered from multiple angles. This allows a very high dose of radiation to be delivered to a narrow area. This approach may offer substantial advantages to a person with a meningioma because it is able to deliver more radiation to the tumor while minimizing the amount of normal brain that is affected. In contrast to conventional external beam radiation therapy, stereotactic radiosurgery is given as a single treatment.

Stereotactic radiosurgery has been used to deliver adjuvant radiation therapy following partial removal of a meningioma. It has also been used as an alternative to surgery for patients with relatively small meningiomas that cannot be completely removed with surgery. Stereotactic radiosurgery and surgical removal have similar long-term outcomes for patients with small meningiomas [11].

Stereotactic radiotherapy — Stereotactic radiotherapy is slightly different than stereotactic radiosurgery, although both use multiple narrow beams of radiation directed from different angles. However, stereotactic radiotherapy divides the dose into several treatments rather than giving the dose in one single treatment. The intent of stereotactic radiotherapy is to reduce radiation injury to nearby brain structures while maintaining tumor control.

This technique has been particularly useful in meningiomas of the optic nerve sheath, as well as those arising at the base of the skull.

Watchful waiting versus treatment — If a meningioma is small and does not cause symptoms, it may be possible to postpone surgery and/or radiation therapy. The decision to delay treatment is also influenced by the location and size of the tumor, as well as the person's overall medical condition. Treatment is usually considered if there is evidence of tumor growth or if the person develops symptoms.

Watchful waiting requires periodic physical examination along with an imaging test (MRI or CT scan of the head). This is usually recommended every three months for one year, then once per year, assuming that the meningioma does not grow or cause symptoms during this time.

Outcomes do not appear to be worse in patients who are closely monitored. In a review of 60 patients who were diagnosed with small, asymptomatic meningiomas, none developed symptoms during an average of 32 months [12]. Of the 45 patients who had a repeat MRI or CT, 35 had no increase in the size of their tumor, while the remaining 10 showed slow tumor growth, even over the course of up to 15 years.

Systemic therapy — Several treatments, including chemotherapy, hormone therapy, and immunotherapy, have been studied in patients whose tumor recurs after surgery and/or radiation therapy. These treatments are referred to as systemic treatments because they are given by mouth or into a vein and can affect the entire body. The goal of systemic therapy is to slow the growth of the meningioma. The benefits of systemic therapy are usually limited and the treatment is not intended to cure the condition. If possible, re-irradiation or repeat surgery should be considered.

Systemic treatments have been used for patients with malignant meningiomas in an attempt to prevent recurrence. Although initial reports were positive, subsequent studies have not confirmed a benefit. Thus, systemic therapy is usually reserved for treatment of meningiomas that recur after surgery or radiotherapy.

OUTCOMES — The long-term outcome of people with meningioma depends upon several factors. For patients who require treatment of symptomatic or large meningiomas, the outcome depends upon the completeness of surgery and the meningioma type (ie, benign, atypical, or malignant). It is important to remember that discussions of outcomes are based upon averages; these averages do not necessarily predict how long an individual patient will survive. Small meningiomas that cause no symptoms and do not require treatment do not usually shorten a person's life. Complete resection of the tumor is possible in about 80 percent of patients with benign meningiomas, approximately 70 to 80 percent of whom survive at least ten years without a recurrence. For patients whose tumors cannot be completely removed and those with cancerous tumors, the rate of recurrence is markedly increased. However, the use of radiation therapy after surgery has improved outcomes, and the risk of recurrence may be similar to patients whose tumor is completely resected. Cancerous (malignant) meningiomas are much more likely to recur, even after complete surgical removal. Recurrence rates are somewhat lower after removal of atypical meningiomas, although recurrence is more frequent than in people who have surgical removal of a benign meningioma. The benefit of postoperative radiation is controversial in these patients.

CLINICAL TRIALS — Progress in treating meningioma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are conducted in many countries around the world. 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. American Brain Tumor Association

(www.abta.org)
American Cancer Society

(www.cancer.org)
National Cancer Institute

(www.cancer.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
OncoLink

(www.oncolink.com/index.cfm)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Claus, EB, Bondy, ML, Schildkraut, JM, et al. Epidemiology of intracranial meningioma. Neurosurgery 2005; 57:1088.
2. Palma, L, Celli, P, Franco, C, et al. Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. J Neurosurg 1997; 86:793.
3. Jhawar, BS, Fuchs, CS, Colditz, GA, Stampfer, MJ. Sex steroid hormone exposures and risk for meningioma. J Neurosurg 2003; 99:848.
4. Custer, BS, Koepsell, TD, Mueller, BA. The association between breast carcinoma and meningioma in women. Cancer 2002; 94:1626.
5. Nakamura, M, Roser, F, Michel, J, et al. The natural history of incidental meningiomas. Neurosurgery 2003; 53:62.
6. Lieu, AS, Howng, SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res 2000; 38:45.
7. Rosen, CL, Ammerman, JM, Sekhar, LN, Bank, WO. Outcome analysis of preoperative embolization in cranial base surgery. Acta Neurochir (Wien) 2002; 144:1157.
8. Stafford, SL, Perry, A, Suman, VJ, et al. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc 1998; 73:936.
9. Armstrong CL, Gyato K, Awadalla AW, Lustig, R, Tochner, ZA. A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy. Neuropsychol Rev 2004; 14:65.
10. Goldsmith, BJ, Wara, WM, Wilson, CB, Larson, DA. Post-operative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994; 80:195.
11. Pollock, BE, Stafford, SL, Utter, A, et al. Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys 2003; 55:1000.
12. Olivero, WC, Lister, JR, Elwood, PW. The natural history and growth rate of asymptomatic meningiomas: a review of 60 patients. J Neurosurg 1995; 83:222.

Pages

Friday, October 12, 2007

Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer

Primary low-grade glioma in adults

Primary low-grade glioma in adults

Brain tumors Patient information: Meningioma