Chemotherapy and Herceptin (trastuzumab) for metastatic 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 main cause of death in women ages 45 to 55. Every year, approximately 205,000 American women are diagnosed with breast cancer and more than 40,000 die from this disease. Early detection and treatment can improve survival by removing the breast tumor before it has a chance to spread (metastasize).

Despite early diagnosis and treatment, breast cancer can reappear at a later time (a recurrence), even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. Although the vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor, 1 to 5 percent of women with breast cancer already have metastatic disease at the time their cancers are discovered.

Metastatic breast cancer is usually not a curable condition. However, systemic (bodywide) treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life (QOL). Options for systemic treatment in women with metastatic breast cancer include chemotherapy, hormone therapy, and targeted agents such as Herceptin (trastuzumab).

This topic review will discuss the use of chemotherapy and Herceptin in advanced and metastatic breast cancer. General principles that guide the treatment of metastatic breast cancer and the use of hormone therapy in this situation are presented elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").

General principles of treatment — As noted above, the goals of systemic treatment for metastatic breast cancer include symptom control, improved quality of life, and prolonged survival rather than cure. To quantify these benefits, oncologists use certain endpoints to measure a treatment's effectiveness. These include: Response rate — The proportion of persons who have a measurable (50 percent or more) decrease in the amount of cancer Clinical benefit rate — The proportion of patients who have measurable as well as partial or stable responses to treatment Disease progression time — The duration of time that a certain therapy is effective before an alternate treatment is required Survival — Despite the importance of response rate, clinical benefit, and disease progression, the gold standard for deciding whether one therapy is better than another is the impact the treatment has on survival. Even if one treatment has a higher response rate than another, it does not follow that survival is also better.

This is a particularly important concept when considering the sequential use of single drugs versus combination chemotherapy regimens for treatment of metastatic breast cancer. Combinations of drugs typically have a higher response rate than a drug given individually, but also have more side effects; survival benefits are modest, at best. It is possible that similar outcomes may be obtained by giving the individual drugs of the combination regimen one at a time (sequentially), rather than all at the same time (concurrently). This is a controversial area in the treatment of metastatic breast cancer, and is discussed in more detail below.

More detailed explanation about the issues surrounding assessment of treatment benefit is provided elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer").

CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These cytotoxic (toxic to cells) drugs work 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, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.

Most chemotherapy drugs are given into the vein (IV) rather than by mouth; one exception is the drug Xeloda (capecitabine), which is given by mouth. Chemotherapy is usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines.

Many different cytotoxic drugs are effective in the treatment of metastatic breast cancer. The most commonly used include: cyclophosphamide (C), methotrexate (M), doxorubicin (often abbreviated A for its brand name Adriamycin®), epirubicin (Ellence®), 5-fluorouracil (abbreviated 5-FU, or F), capecitabine (Xeloda®), paclitaxel (Taxol®), docetaxel (Taxotere®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®).

Combination versus sequential single agent therapy — Specific combinations of these individual drugs (called regimens) have been developed to improve the likelihood of successfully shrinking tumors. As noted above, one of the most pressing and unanswered questions in chemotherapy treatment of metastatic breast cancer is whether similar outcomes can be achieved, with less toxicity, by the sequential use of active single agents, rather than combination regimens. (See "Selecting optimal therapy" below).

Many oncologists consider single-drug chemotherapy a reasonable treatment option, especially for women who have received several different types of chemotherapy for breast cancer. On the other hand, because combination therapy is often associated with a higher response rate, it may be chosen over single agent therapy if the breast cancer is growing rapidly, causing severe symptoms, or if vital organs (eg, liver, lungs) are involved in the tumor.

In the following sections, we will review the most active agents and drug combinations.

Anthracyclines and related drugs — The anthracyclines and related drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), and mitoxantrone (Novantrone®). When used alone, these drugs have a response rate of 35 to 40 percent. Doxil® is a special form of doxorubicin in which the drug is contained or encapsulated within a fat-containing substance called liposomes. This allows the drug to remain in the body for a longer period of time and may reduce the likelihood of side effects involving the heart.

Anthracyclines are often used in combination with other drugs. Common combinations include AC (doxorubicin plus cyclophosphamide), FAC or CAF (cyclophosphamide plus doxorubicin and 5-FU) and CEF (cyclophosphamide plus epirubicin and 5-FU). A good response to these combinations occurs in 20 to 60 percent of women with metastatic breast cancer who have not been previously treated for advanced disease. Side effects — The possible side effects of anthracyclines include nausea, vomiting, hair loss, and temporary loss of bone marrow function. Bone marrow suppression can lead to infections (which can occur with a low white blood cell count), anemia (which can cause fatigue and low energy) and bleeding (which can occur if the platelet count is very low).

The anthracyclines and related drugs can also damage the heart muscle and cause heart failure. Several measures can reduce the likelihood of this side effect, including limiting the total or cumulative dose of these drugs, administering them gradually (over 6 to 96 hours) or in more frequent smaller doses, simultaneously administering drugs that protect the heart muscle, or by using the liposome-encapsulated form of doxorubicin, Doxil®.

Taxanes — As a group, the taxanes (paclitaxel [Taxol®] and docetaxel [Taxotere®]) are some of the most active drugs available for the treatment of advanced breast cancer. Drugs of this class are often the first drugs chosen to treat breast cancers that do not respond to hormone therapy and those that have responded poorly to other chemotherapy drugs such as anthracyclines.

Paclitaxel (and less commonly docetaxel) can cause serious hypersensitivity (allergic) reactions in some women. Because of this, premedication with steroids and antihistamines is generally recommended prior to each treatment. A newer formulation of paclitaxel is available (Abraxane®) which is associated with significantly fewer allergic reactions. Pretreatment is not necessary, but the drug is quite a bit more expensive than conventional paclitaxel.

More frequent administration of these drugs (ie, weekly rather than every three week treatment) allows a higher total dose of chemotherapy drugs to be given, and also appears to lower the likelihood of some side effects, such as bone marrow suppression, or muscle and joint aches, but not others.

Paclitaxel — Paclitaxel may be given once every three weeks or in lower doses once per week. It produces a response in 35 to 55 percent of women with metastatic breast cancer who have not been previously treated with doxorubicin, and in about 20 percent of women whose breast cancers are resistant to doxorubicin. Side effects — Hair loss is a common side effect of paclitaxel; nausea and vomiting are less common. About 5 to 15 percent of women experience muscle and joint pain after paclitaxel treatment; the symptoms typically begin 24 to 72 hours after treatment and last two to four days. This side effect can be minimized with steroid premedication, and seems to be less common when paclitaxel is administered weekly.

Paclitaxel can also suppress the bone marrow function, temporarily lowering the blood counts. It may be possible to reduce the effects of paclitaxel on the bone marrow and nerves by using more frequent, smaller doses.

It can cause a type of nerve damage that affects the fingers and toes. This is called peripheral neuropathy, and is severe in only 10 to 15 percent of women. However, the effects are cumulative (ie, it is more common and more severe as more drug is given). Paclitaxel may be inappropriate for some women with poor liver function.

Abraxane — Abraxane® is a unique formulation of paclitaxel whose main benefit is that it causes significantly fewer allergic reactions. In addition, at least one study suggests that Abraxane may be associated with a moderately higher response rate and duration of benefit compared to paclitaxel, but it may also cause more neurologic toxicity, and is also significantly more expensive than paclitaxel. As a result, there is controversy as to whether Abraxane® should replace standard paclitaxel for the treatment of metastatic breast cancer.

Docetaxel — Like paclitaxel, docetaxel may be given once every three weeks or in lower doses once per week. Docetaxel has a response rate of 35 to 60 percent in women with metastatic breast cancer, including women with advanced disease who have been previously treated with many other types of chemotherapy. In addition, up to 25 percent of breast cancers that are resistant to paclitaxel respond to docetaxel. Side effects — Docetaxel occasionally causes nausea and vomiting and often causes hair loss. Like paclitaxel, docetaxel can also temporarily suppress bone marrow function and may cause peripheral neuropathy, which may or may not be reversible. Docetaxel may cause fluid retention, which can be prevented if steroids are given prior to docetaxel.

It is possible to reduce the side effects of docetaxel by using more frequent, smaller doses (ie, weekly therapy). However, weekly therapy is more often associated with excess tear production in the eyes and nail changes.

Taxane combinations — Paclitaxel or docetaxel may be used in combination with other chemotherapy drugs. Adding a taxane to other chemotherapy drugs increases the likelihood of response, but also increases the chance of serious side effects. Furthermore, as noted above, the increase in response rate with combination therapy has translated into only minor improvements in survival compared to sequential administration of active single agents [1-3]. As an example, in a single study, women receiving both gemcitabine plus paclitaxel had a higher response rate (41 versus 22 percent) and a slightly longer (two month) survival compared to those receiving paclitaxel alone [1]. Although the side effects were more pronounced in women receiving both gemcitabine and paclitaxel, they were not particularly severe in either group.

Although combinations of paclitaxel and doxorubicin have been associated with very high response rates, they also cause higher than expected rates of heart damage in many but not all [3] studies. While combination of docetaxel and doxorubicin do not appear to increase the risk for heart problems, they have been associated with life-threatening bone marrow suppression and associated infection.

It is not clear that the added toxicities of anthracycline/taxane combinations are justified by a greater therapeutic benefit, or that anthracycline/taxane combinations provide clear benefit over sequential administration of each agent alone [3]. A pooled analysis of seven trials comparing anthracycline/taxane regimens versus other combinations of an anthracycline/cyclophosphamide with or without 5-FU for first-line therapy came to the following conclusions [4]: Use of a taxane/anthracycline combination significantly increased the response rate, and doubled the chance of a complete response Taxane-based regimens were associated with a borderline improvement in time to tumor progression, but survival was not improved Patients treated with a taxane/anthracycline regimen were nearly three times more likely to require hospitalization for fever in the setting of low blood counts

Alkylating drugs — Cyclophosphamide is the alkylating drug most commonly used to treat metastatic breast cancer, usually in combination regimens, as described above. Side effects — Treatment with alkylating drugs carries a slight risk of bladder inflammation and blood in the urine, but this risk can be minimized by drinking plenty of fluids and urinating frequently during treatment. Cyclophosphamide is also associated with an approximately three-fold increased risk of leukemia at a later time, and a loss of fertility, particularly in women over the age of 30 at the time of treatment.

Antimetabolites — The antimetabolites methotrexate and 5-FU are generally used in combination regimens such as CMF (cyclophosphamide, methotrexate, and 5-FU). 5-FU may also be combined with the drug leucovorin. Both of these drugs may be used together in the triple combination NFL (mitoxantrone, 5-FU, and leucovorin).

An oral (tablet form) derivative of 5-FU with activity against breast cancer is available (Xeloda® [capecitabine]). When used alone for the treatment of patients with breast cancer that has progressed in spite of multiple prior therapies, about 20 percent of women have a response, including those whose breast cancers have responded poorly to intravenous 5-FU. Side effects — 5-FU and related drugs are less likely than many other chemotherapy drugs to cause hair loss or suppress bone marrow function. Furthermore, fewer than 10 percent of women experience nausea and vomiting when treated with these drugs. However, 5-FU and related drugs can cause other gastrointestinal symptoms, including diarrhea and inflammation of the mouth (mucositis). The dose of Xeloda may be reduced if a temporary side effect called hand-foot syndrome develops. This causes the skin of the palms and soles of the feet become red and sore, sometimes with peeling.

Gemcitabine — Gemcitabine (Gemzar®) has a low frequency of side effects such as nausea, vomiting, hair loss, and temporary suppression of bone marrow function. It is more often used,in combination with paclitaxel (see above), for treatment of metastatic breast cancer in patients whose disease has progressed while receiving anthracycline-containing regimens.

Vinca drugs — Vinorelbine (Navelbine®) is the most widely used vinca-type drug for advanced breast cancer. Weekly administration results in a response in over 50 percent of women. Side effects — All of these agents can cause damage to the nervous system, which may cause a feeling of numbness and tingling in the fingers and toes (called peripheral neuropathy). This typically develops after several courses of therapy, and is usually reversible when treatment is stopped. Vinorelbine is less likely than vincristine to cause peripheral neuropathy, and the likelihood of bone marrow suppression is low. Occasionally, vinca alkaloids can cause sudden, severe pain around the tumor that begins during or immediately after the drug is administered, and lasts several minutes to hours.

Summary — Among the many chemotherapy drugs available for treatment of metastatic breast cancer, the most active are the anthracyclines and taxanes. Taxanes are often used first in women with metastatic breast cancer whose cancers are unlikely to respond to hormone therapy, and for breast cancers that have recurred after other types of chemotherapy. An anthracycline combination may be used for women who have not previously received anthracycline or those who have had a recurrence more than 12 months since anthracyclines were used. Xeloda, Navelbine, and Gemzar are good second or third-line options, or they may be used as a first line treatment in combination with a taxane.

Due to the small survival difference and more favorable side effect profile, therapy with serial single agents is a reasonable alternative to combination regimens, especially in the second, third, or fourth-line treatment setting (show figure 1). On the other hand, for symptomatic patients or those with rapidly progressive vital organ metastases, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response.

HERCEPTIN — Herceptin (trastuzumab) is an antibody (a type of protein) that specifically targets HER2/neu, a protein present on the cells of some breast cancers. About 30 percent of breast cancers express very high levels of HER2/neu, and Herceptin appears to be effective only in this group of women. The level of HER2/neu within a tumor is determined using a special stain on a microscopic slide containing a sample of the tumor.

Herceptin inhibits the growth of breast cancer cells when given alone or in combination with other chemotherapy drugs. For women with metastatic breast cancer whose breast cancers have not responded to conventional cytotoxic chemotherapy drugs, Herceptin used alone has a response rate of 15 percent.

Herceptin plus other chemotherapy drugs — Adding Herceptin to treatment with other chemotherapy drugs may improve the effectiveness of treatment [5]. Herceptin plus anthracyclines — The use of Herceptin plus an anthracycline-containing drug has been found to cause serious side effects affecting the heart. Thus, despite their high level of activity, combinations of Herceptin and doxorubicin are avoided. Herceptin plus taxanes — The combination of Herceptin plus a taxane may be associated with less toxicity than Herceptin plus an anthracycline, and a better outcome when compared to paclitaxel alone. In one research study, women with breast cancers that produced high levels of the HER2/neu marker and that were resistant to doxorubicin were treated with either paclitaxel alone or paclitaxel plus Herceptin [6]. The women treated with combination therapy had a higher response rate (57 versus 25 percent), a longer time until the cancer progressed, and they also survived for four months longer. Herceptin plus other drugs — High response rates have been reported with combinations of Herceptin plus other cytotoxic drugs such as cisplatin, and vinorelbine, even in women who have used several prior therapies [7]. These combinations may be considered in women with HER2/neu-producing metastatic breast cancer who have failed Herceptin alone or in combination with a taxane.

Side effects — Herceptin occasionally causes a hypersensitivity or allergic reaction, which can be severe. Rarely, severe lung damage can occur. Heart damage develops in about 3 to 5 percent of women treated with Herceptin alone or with paclitaxel; the risk is higher in women who receive Herceptin with an anthracycline drug. Because of this, Herceptin is NOT given with an anthracycline-type drug. When given alone, Herceptin does not cause bone marrow suppression, nausea, vomiting, or hair loss.

Summary — Herceptin alone is a reasonable treatment option for women whose metastatic breast cancers make have high levels of HER2/neu, and that have become resistant to standard hormone therapy and chemotherapy drugs. The combination of Herceptin with paclitaxel is also a reasonable choice.

Herceptin resistance — Lapatinib is an oral medication that targets HER2 in a different way than Herceptin. It can be effective for women whose disease is resistant to Herceptin. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin. It is not yet approved as an initial treatment for women with HER2-positive advanced breast cancer.

AVASTIN (BEVACIZUMAB) — Avastin® (bevacizumab) is an antibody that targets a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the process by which a growing cancer develops its own blood supply, which is essential in order for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.

Early data suggest that selected patients with metastatic breast cancer may benefit from the use of bevacizumab. In one study, bevacizumab was combined with paclitaxel and compared to paclitaxel alone as initial chemotherapy for metastatic breast cancer [8]. Combined therapy was associated with a higher response rate (28 versus 14 percent), and a longer time to progression of the breast cancer; however, the study has not yet determined the impact on survival [8]. Potentially serious side effects with bevacizumab included high blood pressure, bleeding, and loss of protein in the urine.

At present, bevacizumab is not approved for treatment of metastatic breast cancer in the United States; it is only approved for patients with advanced colorectal cancer. Nevertheless, using bevacizumab plus paclitaxel could be considered for a woman who had not received chemotherapy for metastatic breast cancer, and who does not have clotting or bleeding problems, kidney problems, recent surgery, or spread of cancer to the brain (brain metastases). It is not yet known whether the modestly better outcomes from this approach justify the more serious side effect profile and greater expense.

CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of chemotherapy for women with metastatic breast cancer is unknown. Several studies have compared the effectiveness of continuous chemotherapy until it becomes ineffective versus intermittent chemotherapy (approximately six cycles or courses of chemotherapy followed by a discontinuation of chemotherapy until progression of the cancer). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor progression may be delayed a little while longer in women treated with continuous therapy.

Because of the periods of time where chemotherapy is not being given, intermittent chemotherapy may also be associated with a better quality of life. Intermittent chemotherapy may therefore be a reasonable option for women whose cancer-related symptoms are relieved with this therapy.

BONE MARROW TRANSPLANTATION — The improved outcomes with higher as compared to lower doses of chemotherapy drugs raise the possibility that outcomes can be further improved by administering very high doses of chemotherapy. Such doses not only kill more cancer cells, but also destroy young blood cells (stem cells) in the circulating blood and bone marrow. This requires that new stem cells be provided or transplanted into the patient in order to restore the production of blood cells. This entire procedure is referred to as high dose chemotherapy with stem cell transplantation (commonly called a bone marrow transplant). (See "Patient information: Overview of bone marrow transplantation").

Although some women with metastatic breast cancer and few sites of tumor involvement have been offered a bone marrow transplant in the past, this approach has fallen out of favor since studies suggest that it does not provide any benefit over the currently recommended standard dose treatment regimens that do not require stem cell support [1,9]. Because of this, and the substantially greater toxicity of high-dose chemotherapy, this approach should not be considered standard for any women with metastatic breast cancer.

SELECTING OPTIMAL THERAPY

Hormone receptor status — Because hormone therapy generally causes fewer side effects than chemotherapy or biologic therapy, it is usually chosen as initial treatment for women with hormone receptor-positive metastatic breast cancer.

Chemotherapy is initially recommended if the cancer is ER-negative, and in some circumstances for ER-positive tumors. Women with ER-positive breast cancer are most likely to be treated with chemotherapy initially if: The breast cancer is progressing rapidly Metastases are present in vital organs There are many cancer-related symptoms

Chemotherapy is also an appropriate option for treatment of ER-positive breast cancers when hormone therapy is no longer effective.

HER2/neu-negative — Options for initial chemotherapy depend on whether a woman's breast cancer makes the protein HER2/neu. Several options are available for initial treatment in women with HER2/neu-negative metastatic breast cancer: Combination therapy with an anthracycline-containing regimen such as AC (doxorubicin plus cyclophosphamide), FAC (5-FU plus doxorubicin and cyclophosphamide), or FEC (5-FU plus epirubicin and cyclophosphamide) Single agent treatment with an anthracycline or a taxane The combination of a taxane plus either capecitabine or gemcitabine The combination of paclitaxel plus bevacizumab

All of these options have a 30 to 60 percent likelihood of response and relief of cancer-related symptoms. However, questions remain as to whether any of these regimens have a significant survival benefit over another. If there is a survival benefit from combination therapy, it is probably modest (between two and five months); this has been seen with the combinations of paclitaxel plus either gemcitabine or bevacizumab (compared to paclitaxel alone), and docetaxel plus capecitabine (compared to docetaxel alone) [2,3,5].

The decision regarding which regimen to choose, and whether to choose single agent or combination chemotherapy is complex, and depends upon a number of different factors, including what treatments have been used and the length of time since the last treatment. For women considering paclitaxel plus bevacizumab, a history of bleeding problems, blood clots, kidney problems, recent surgery, or poorly controlled high blood pressure are important considerations.

HER2/neu-positive — For women whose breast cancers contain high levels of the HER2/neu protein, Herceptin alone or in combination with a taxane are reasonable choices for initial treatment. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin.

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

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

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

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

(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society

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

(www.nlm.nih.gov/medlineplus/healthtopics.html)
Susan G. Komen Breast Cancer Foundation

(www.komen.org)


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