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 ( 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 (, 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 ( 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

People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
National Comprehensive Cancer Network

American Cancer Society

Adjuvant! Online

Susan G. Komen Breast Cancer Foundation



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2. National Comprehensive Cancer Network (NCCN) guidelines available online at (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 (accessed on May 8, 2006).
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8. National Comprehensive Cancer Network (NCCN) guidelines available online at
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