Stages III and IV Breast Cancer

April 16, 2009

This chapter addresses the diagnosis and management of locally advanced, locally recurrent, and metastatic breast cancer, ie, stages III and IV disease.

This chapter addresses the diagnosis and management of locally advanced, locally recurrent, and metastatic breast cancer, ie, stages III and IV disease.

Approximately 20% to 25% of patients present with locally advanced breast cancer. Inflammatory breast cancer is a particularly aggressive form of breast cancer that falls under the heading of locally advanced disease and accounts for 1% to 3% of all breast cancers.

Locoregional recurrence of breast cancer remains a major clinical oncologic problem. Rates of locoregional recurrence may vary from < 10% to > 50%, depending on initial disease stage and treatment.

Metastatic disease is found at presentation in 5% to 10% of patients with breast cancer. The most common sites of distant metastasis are the lungs, liver, and bone.

The optimal therapy for stage III breast cancer continues to evolve. Recently, the use of neoadjuvant chemotherapy has been effective in downstaging locally advanced breast cancer prior to surgical intervention. The optimal neoadjuvant chemotherapeutic regimens continue to evolve, and studies are being performed to evaluate new agents and delivery methods.

Diagnosis

Locally advanced disease

Patients with locally advanced breast cancer do not have distant metastatic disease and are in this group based on tumor size and/or nodal status. Such patients often present with a large breast mass or axillary nodal disease, which is easily palpable on physical examination. In some instances, the breast is diffusely infiltrated with disease, and no dominant mass is evident.

Patients with inflammatory breast cancer often present with erythema and edema of the skin of the breast (peau d'orange) and may not have a discrete mass within the breast. These patients often are treated with antibiotics unsuccessfully for presumed mastitis.

Mammography is beneficial in determining the local extent of disease in the ipsilateral breast, as well as in studying the contralateral breast.

Fine-needle aspiration (FNA) or biopsy The diagnosis of breast cancer can be confirmed by either FNA cytology or core biopsy. Core biopsy is preferred to perform the wide variety of marker analyses.

Search for metastasis The presence of distant metastatic disease should be ruled out by physical examination, chest radiography, CT of the liver, bone scan, and CT of the chest. 18Fluorodeoxyglucose-positron emission tomography (FDG-PET) has moderate accuracy for detecting axillary metastasis. It is highly predictive for nodal tumor involvement when multiple intense foci of tracer uptake are identified but fails to detect small nodal metastasis. The addition of FDG-PET to the standard workup of patients with locally advanced breast cancer may lead to the detection of unexpected distant metastases. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.

Locoregional recurrence

Biopsy or FNA Locoregional recurrence of breast cancer can be diagnosed by surgical biopsy or FNA cytology. Whichever modality is appropriate, material should be sent for hormone-receptor studies, since there is only an 80% concordance in hormone-receptor status between the primary tumor and recurrent disease. When the suspected recurrent disease is not extensive, the biopsy procedure of choice is a negative margin excisional biopsy. For an extensive recurrence, an incisional biopsy can be used.

Search for distant metastasis Prior to beginning a treatment regimen for a patient with locoregional recurrence, an evaluation for distant metastasis should be instituted, since the findings may alter the treatment plan.

Distant metastasis from the breasts

Metastatic breast cancer may be manifested by bone pain, shortness of breath secondary to a pleural effusion, parenchymal or pulmonary nodules, or neurologic deficits secondary to spinal cord compression or brain metastases. In some instances, metastatic disease is identified after abnormalities are found on routine laboratory or radiologic studies.

Assessment of disease extent by radiography, CT, and radionuclide scanning is important. Organ functional impairment may be determined by blood tests (liver/renal/hematologic) or may require cardiac and pulmonary function testing. Biopsy may be required to confirm the diagnosis of metastasis; this is especially important when only a single distant lesion is identified.

Metastasis to the breasts

The most common source of metastatic disease to the breasts is a contralateral breast primary. Metastasis from a nonbreast primary is rare, representing < 1.5% of all breast malignancies. Some malignancies that could metastasize to the breast include non-Hodgkin lymphoma, leukemias, melanoma, lung cancer (particularly small-cell lung cancer), gynecologic cancers, soft-tissue sarcomas, and GI adenocarcinomas. Metastasis to the breasts from a nonbreast primary is more common in younger women. The average age at diagnosis ranges from the late 30s to 40s. Treatment depends on the status and location of the primary site.

Mammographic findings Mammography in patients with metastatic disease to the breasts most commonly reveals a single lesion or multiple masses with distinct or semidiscrete borders. Less common mammographic findings include skin thickening or axillary adenopathy.

FNA or biopsy FNA cytology has been extremely useful in establishing the diagnosis when the metastatic disease has cytologic features that are not consistent with a breast primary. When cytology is not helpful, core biopsy or even open biopsy may be necessary to distinguish primary breast cancer from metastatic disease.

Treatment

TREATMENT OF LOCALLY ADVANCED DISEASE

The optimal treatment for patients with locally advanced breast cancer has yet to be defined, due to the heterogeneity of this group. There are approximately 40 different substage possibilities with the different combinations of tumor size and nodal status. Between 66% and 90% of patients with stage III breast cancer will have positive lymph nodes at the time of dissection, and approximately 50% of patients will have four or more positive nodes.

Patients with locally advanced breast cancer have disease-free survival rates ranging from 0% to 60%, depending on the tumor characteristics and nodal status. In general, the most frequent type of treatment failure is due to distant metastases, and the majority of them appear within 2 years of diagnosis.

With the increased utilization of multimodality therapy, including chemotherapy, radiation therapy, and surgery, survival for this patient population has improved significantly.

Neoadjuvant systemic therapy

Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity testing, can downstage locally advanced disease and render it operable, and may allow breast-conservation surgery to be performed. Preoperative chemotherapy requires a coordinated multidisciplinary approach to plan for surgical and radiation therapy. A multimodality treatment approach can provide improved control of locoregional and systemic disease. When neoadjuvant therapy is used, accurate pathologic staging is not possible. The majority of patients receiving neoadjuvant chemotherapy, treated with either breast conservation or mastectomy will require radiation therapy following surgery.


 

Active regimens Preoperative chemotherapy regimens reported to result in high response rates (partial and complete responses) include CAF (cyclophosphamide, doxorubicin [Adriamycin], and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), CMF (cyclophosphamide, methotrexate, and 5-FU), and CMFVP (cyclophosphamide, methotrexate, 5-FU, vincristine, and prednisone). Combination chemotherapy with an anthracycline-based regimen-FAC or AC-is used most often. Recently published data suggest that the AT regimen of Adriamycin and docetaxel (Taxotere) given concomitantly may produce equivalently high response rates. Combination agents for metastastic breast cancer also include paclitaxel plus trastuzumab (Herceptin) with carboplatin, gemcitabine (Gemzar) and paclitaxel, and capecitabine (Xeloda) and docetaxel (Table 1). Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response rate for women with locally advanced disease. The doses of these combination chemotherapy regimens are given in Table 1, chapter 10.

There seems to be no difference in survival in women with locally advanced disease who receive chemotherapy before or after surgery. Neoadjuvant chemotherapy results in complete response rates ranging from 20% to 53% and partial response rates (≥ 50% reduction in bidimensionally measurable disease) ranging from 37% to 50%, with total response rates ranging from 80% to 90%. Patients with large lesions are more likely to have partial responses. Pathologic complete responses (pCRs) do occur and are more likely to be seen in patients with smaller tumors. A pCR in the primary tumor is often predictive of a complete axillary lymph node response. Patients with locally advanced breast cancer who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate compared with those who have less than a pCR. However, a pCR does not entirely eliminate the risk for recurrence.

Patients should be followed carefully while receiving neoadjuvant systemic therapy to determine treatment response. In addition to clinical examination, it may also be helpful to document photographically the response of ulcerated, erythematous, indurated skin lesions. Physical examination, mammography, and breast ultrasonography are best for assessing primary tumor response, whereas physical examination and ultrasonography are used to evaluate regional nodal involvement.

The role of MRI in evaluating response to preoperative chemotherapy is still evolving. Dynamic contrast-enhanced MRI performed at baseline, during chemotherapy, and before surgery has yielded more than 90% diagnostic accuracy in identifying tumors achieving a pCR and can potentially provide functional parameters that may help to optimize neoadjuvant chemotherapy strategies. However, despite its high sensitivity, a large number of patients still may have either false-negative or false-positive results on MRI scanning.

Multimodality approach

A multimodality treatment plan for locally advanced breast cancer (stages IIIA and IIIB, M1 supraclavicular nodes) is shown schematically in Figure 1. This approach has been shown to result in a 5-year survival rate of 84% in patients with stage IIIA disease and a 44% rate in those with stage IIIB disease. The most striking benefit has been seen in patients with inflammatory breast cancer, with 5-year survival rates of 35% to 50% reported for a multimodality treatment approach including primary chemotherapy followed by surgery and radiation therapy and additional adjuvant systemic therapy. The same chemotherapy drugs, doses, and schedules used for single-modality therapy are employed in the multimodality approach.

Surgery Traditionally, the surgical procedure of choice for patients with locally advanced breast cancer has been mastectomy. In recently published studies, some patients with locally advanced breast cancer who responded to treatment with neoadjuvant chemotherapy became candidates for breast-conservation therapy and were treated with limited breast surgery and adjuvant breast irradiation. Patients who have been downstaged using neoadjuvant chemotherapy should be evaluated carefully before proceeding with conservative treatment. It may be helpful to mark the site of the primary tumor with the placement of a clip during the course of percutaneous biopsy prior to beginning adjuvant therapy. There can sometimes be a complete clinical and/or radiographic response after neoadjuvant chemotherapy or hormonal therapy, and this may facilitate a wide local incision.

The role of sentinel node biopsy in the treatment of breast cancer after neoadjuvant chemotherapy has yet to be defined. Studies have shown that pathologically positive axillary lymph nodes can be sterilized when neoadjuvant chemotherapy is utilized. There are other biologic concerns with sentinel node biopsy after neoadjuvant chemotherapy. The lymphatics may undergo fibrosis or may become obstructed by cellular debris, making the mapping procedure unreliable, with false-negative rates of up to 25%. The rate of conversion from positive to negative nodes can be enhanced when 4 cycles of a doxorubicin-based regimen are followed by 4 cycles of docetaxel. Sentinel node biopsy will only be accurate then if all the metastatic deposits within the axilla respond in a similar fashion to chemotherapy. Preliminary data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial demonstrated an 11% false-negative rate in women who underwent sentinel node biopsy after receiving 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of docetaxel. However, patients with clinically positive nodes prior to neoadjuvant chemotherapy should have full node dissection.

Radiation therapy remains an integral component of the management of patients with locally advanced breast cancer. For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 5,000–6,000 cGy) is usually employed, as discussed in chapter 10. Randomized trials suggest that postmastectomy patients with any number of positive nodes derive a disease-free and/or overall survival benefit from postmastectomy irradiation.

In a retrospective review of over 500 patients on six prospective trials treated with neoadjuvant chemotherapy, mastectomy, and radiation were compared with 134 patients treated with the same therapy, mastectomy, but without radiation. Despite the more unfavorable characteristics, the radiated patients had a lower rate of local-regional relapse than the unirradiated group (11% vs 22%). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of locoregional response, which was significantly reduced with radiation (10-year rates: 33% vs 3%; P = .006). Radiation improved cause-specific survival (CSS) in the subsets of patients with stage IIIB disease, clinical T4 tumors, and four or more positive nodes.The authors conclude that radiation should be considered for these patients regardless of their response to initial chemotherapy.

Available data do not suggest a problem in delaying radiation therapy until the completion of systemic chemotherapy. Even in patients undergoing high-dose chemotherapy with autologous bone marrow or stem-cell transplantation, irradiation is generally indicated following mastectomy for patients with locally advanced disease (primary tumors ≥ 5 cm and/or ≥ four positive axillary nodes).

For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery.

High-dose chemotherapy The role of adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation for primary breast cancer at high risk of recurrence (at least four involved axillary lymph nodes) has not been well defined. Individually, the available trials have limited power to determine whether HDC has any benefit for this indication, or for any subgroup of patients. Based on a meta-analysis from 15 known randomized trials 6,210 patients (3,118 HDC, 3092 standard-dose chemotherapy [SDC]) were followed for a median of 6 years. Median age was 46 years. After adjusting for age and trial, HDC significantly prolonged disease-free survival but not breast cancer-specific survival (BCSS) or overall survival. After adjusting as well for hormone receptor status in the subset for which it was available, HDC significantly prolonged disease-free survival and had a modest and marginally significant benefit on BCSS and overall survival. For BCSS and overall survival, neither age nor hormone receptor status had a statistically significant interaction with treatment, yet there was a significant interaction between age and treatment for disease-free survival. The investigators caution that any benefits of HDC in the context of contemporary regimens such as taxanes and targeted therapies are unknown.

To date, the results of available clinical trials have not all shown improved disease-free and overall survival in patients treated with dose-intensive regimens. However, trial design, power, and strategy have all been questioned. Outside the context of a clinical trial, high-dose chemotherapy cannot be recommended for patients with primary or metastatic breast cancer.

TREATMENT OF LOCOREGIONAL RECURRENCE AFTER EARLY INVASIVE CANCER OR DCIS

When a patient develops a local failure after breast-conservation treatment for early invasive cancer or ductal carcinoma in situ (DCIS), it is generally in the region of the initial primary tumor. The risk of ipsilateral breast tumor recurrence after conservative treatment in patients with early invasive cancer ranges from 0.5% to 2.0% per year, with long-term local failure rates plateauing at about 15% to 20%. Local failure rates after wide excision alone for DCIS vary from 10% to 63%, as compared with rates between 7% and 21% after wide excision plus radiation therapy. Most patients whose disease recurs after conservative treatment for DCIS can be treated with salvage mastectomy. In one study, 14% of patients who developed local recurrence had synchronous distant metastatic disease.

The optimal treatment of a local or regional recurrence after mastectomy has yet to be defined. Locoregional recurrences are associated with initial nodal status and primary tumor size. Appropriate treatment may result in long-term control of locoregional disease. In many instances, these patients develop simultaneous distant metastasis, or distant disease develops some time after the locoregional recurrence manifests itself.

Recurrence of invasive cancer after breast conservation

Recurrence after wide excision and breast irradiation For patients with early invasive cancer who have undergone conservative surgery followed by irradiation and whose cancer recurs in the ipsilateral breast, salvage mastectomy is the most common treatment modality. The same is true for ipsilateral recurrence (of invasive or in situ disease) after conservative treatment for DCIS, when there is no evidence of distant metastatic disease.

Some studies with limited follow-up have reported acceptable results with repeated wide local excision for ipsilateral breast tumor relapses following conservative surgery and radiation therapy. Selection criteria for this approach are unclear, however, and use of this salvage procedure remains controversial. Although the use of limited-field reirradiation has been reported, selection criteria for this management option and long-term follow-up data are lacking.

Recurrence after wide excision alone In patients initially treated with wide local excision alone who sustain an ipsilateral breast tumor recurrence, small series with limited follow-up suggest that wide local excision followed by radiation therapy to the intact breast at the time of local recurrence may be a reasonable treatment alternative. In this situation, standard radiation doses would be employed.

Recurrent disease in the chest wall after mastectomy

In general, patients who develop minimal recurrent disease in the chest wall after a long disease-free interval may be treated by excision alone, although this approach is controversial and may not be ideal. Locoregional control obtained by radiation therapy alone is related to the volume of residual disease and may not be durable. When possible, disease recurring in the chest wall or axillary nodes should be resected and radiation therapy should be delivered to aid in local control.

Radiation treatment techniques are generally similar to those employed for patients treated with standard postmastectomy irradiation and consist of photon and/or electron-beam arrangements directed at the chest wall and adjacent lymph node regions. Treatment planning should strive for homogeneous dose distributions to the target areas while minimizing the dose to the underlying cardiac and pulmonary structures.

Radiation dose and protocol Conventional fractionation of 180 to 200 cGy/d to the area of locoregional recurrence and immediately adjacent areas at risk, to a total dose of 4,500 to 5,000 cGy, is indicated. A boost to the area of recurrence or gross residual disease, to a dose of approximately 6,000 cGy, results in acceptable long-term locoregional control.

Radical chest wall resection A select group of patients with local chest wall recurrence secondary to breast cancer may be candidates for a radical chest wall resection, which may include resection of skin, soft tissue, and bone. Flap coverage or prosthetic chest wall reconstruction is required. Appropriate candidates would include patients who do not have distant metastases and who have persistent or recurrent chest wall disease after chest wall irradiation and patients who present with a chest wall recurrence after a long disease-free interval.

ADJUVANT SYSTEMIC THERAPY FOR LOCOREGIONAL RECURRENCE

Ipsilateral breast tumor recurrence

Limited data support the use of adjuvant systemic therapy at the time of ipsilateral breast tumor recurrence. Retrospective studies have suggested a 20% to 50% risk of systemic metastases in patients who sustain an ipsilateral breast tumor recurrence. A study conducted at Yale University found that ipsilateral breast tumor recurrence was a significant predictor of distant metastases, particularly among women who relapsed within 4 years of the original diagnosis; these women had a rate of distant metastasis of approximately 50%. Similar findings were noted by the NSABP investigators.

These data suggest that women whose tumors recur in the ipsilateral breast within the first few years following the original diagnosis may be considered for adjuvant systemic therapy. Given the lack of prospective, randomized data, specific treatment recommendations for these women remain highly individualized.

Regional nodal recurrence and postmastectomy recurrence of disease in the chest wall

Although there are limited data addressing the use of adjuvant systemic therapy at the time of locoregional relapse following mastectomy, given the high rate of systemic metastasis in this population, these patients may be considered for adjuvant systemic therapy. A randomized trial demonstrated a disease-free survival benefit with the use of adjuvant tamoxifen following radiation therapy at the time of postmastectomy recurrence of disease in the chest wall in patients with estrogen receptor-positive tumors. The 5-year disease-free survival rate was increased from 36% to 59%, and the median disease-free survival was prolonged by > 4.5 years.

Patients with estrogen receptor-negative tumors and aggressive locoregional recurrences may also be considered for systemic cytotoxic chemotherapy, given their relatively poor prognosis and the high rate of metastasis.

MEDICAL TREATMENT OF METASTATIC BREAST CANCER

Patients with metastatic cancer can be divided into two groups: those with stage IV disease at presentation and those who develop metastases after primary treatment. The management of stage IV disease depends on the site and extent of metastases, comorbid conditions, and clinical tumor characteristics.

Patients with delayed metastatic disease can be divided into two groups, ie, so-called low risk and intermediate or high risk, basedon the biologic aggressiveness of the disease. As shown schematically in Figure 2, the management approach to these two groups differs.

Low-risk patients

The low-risk group includes patients who develop metastatic disease after a long disease-free interval (ie, a long disease-free interval from primary breast cancer diagnosis to presentation with metastasis), those whose tumors are positive for hormone receptors (estrogen and progesterone), those with bone-only disease, and those without extensive visceral organ involvement.

Hormone therapy Low-risk patients, whose tumor is hormone receptor-positive (ie, estrogen receptor-positive and/or progesterone receptor-positive), may be treated with a trial of hormone therapy.

First-line hormonal therapy consists of an aromatase inhibitor, with careful serial assessment of clinical and disease responses.

Hormone therapy may be associated with a “flare” response, a temporary worsening of signs and symptoms of disease within the first few weeks of treatment. This response generally means clinical benefit will follow.

If the tumor initially responds to first-line hormone therapy and then progresses, a second hormonal manipulation is warranted. Various hormonal agents are available (Table 3). They may be used sequentially and may provide disease palliation for prolonged periods in some patients.

Second-line hormonal agents The choice of second-line endocrine therapy depends on the front-line endocrine agent used. Typically, if tamoxifen was used, the second-line agent includes an aromatase inhibitor or fulvestrant (Faslodex) for postmenopausal women. For premenopausal women, the choice may be megestrol or induction of menopause with an LHRH (luteinizing hormone-releasing hormone) agonist with or without an aromatase inhibitor. If aromatase inhibitors were used as front-line agents for postmenopausal women, second-line options can be to change to another class of aromatase inhibitor, fulvestrant, or tamoxifen.

The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo-controlled, multicenter, trial comparing the efficacy and tolerability of fulvestrant versus exemestane (Aromasin) in postmenopausal women with hormone receptor-positive advanced breast cancer following non-steroidal aromatase inhibitor therapy. A fulvestrant loading-dose regimen was utilized (via intramuscular injection): 500 mg on day 0, followed by 250 mg on days 14, 28, and every 28 ± 3 days, thereafter. Exemestane was given as a 25-mg capsule PO, once daily. Treatment was administered until disease progression or death, or withdrawal for any other reason. EFECT is the first phase III trial to specifically evaluate endocrine treatment options following disease progression/recurrence on a nonsteroidal aromatase inhibitor. This trial includes 693 women, ∼60% of whom have received ≥ two prior endocrine therapies.

In the primary analysis (median follow-up of 13 months), the median time to disease progression was 3.7 months in both the fulvestrant and exemestane groups (HR 0.963; 95% confidence interval [CI] 0.819–1.133; P = .06531). Objective response and clinical benefit rates were also similar between groups, although the median duration of response (n = 38; from randomization: 13.5 months vs 9.8 months) and clinical benefit (n = 172; 9.3 months vs 8.3 months) appeared slightly longer in patients receiving fulvestrant. Overall survival data were immature at the time of the primary analysis. However, in a recent update with a median follow-up of 20.9 months, 209 patients (59.5%) in the fulvestrant group and 197 patients (57.9%) in the exemestane group had died. Median overall survival was not significantly different between treatments (24.3 months vs 23.1 months in the fulvestrant and exemestane groups, respectively [HR 1.012; 95% CI, 0.833–1.229; P = .9072].

The most commonly used second-line hormonal agents had been progestational drugs, such as megestrol. Recent randomized trials have indicated that the aromatase inhibitors, such as anastrozole (Arimidex),letrozole (Femara), fulvestrant, and exemestane, are equally effective for palliation of metastatic disease, have less toxicity, and may provide a survival advantage compared with megestrol. Therefore, they are the drugs of choice for second-line therapy following tamoxifen administration. Tamoxifen may also be considered as second-line therapy for patients initially treated with an aromatase inhibitor.

Hormonal therapy continues until evidence of disease progression, or drug-related toxicity precludes further therapy with the same agent. If a partial or complete response to the first hormonal treatment is documented at the time of disease progression, a second hormonal agent may provide further palliation of symptoms and avoid the initiation of systemic chemotherapy. However, subsequent hormonal responses tend to be of shorter duration, and, ultimately, the disease will become refractory to hormonal treatment.

Cytotoxic agents Hormone-refractory disease can be treated with systemic cytotoxic therapy. FAC, paclitaxel, TAC (Taxotere [docetaxel], Adriamycin [doxorubicin], cyclophosphamide), or docetaxel may be used in this situation. (For a more detailed discussion of these agents, see section on “Intermediate- or high-risk patients.” For doses, see Table 1.)

A prospective, multicenter study assessed the role of circulating tumor cells in predicting survival in 177 metastatic breast cancer patientsbefore the start of a new treatment. Patients with levels of circulating tumor cells > 5/7.5 mL of whole blood had a shorter median progression-free survival (2.7 vs 7.0 months; P < .001) and shorter overall survival (10.1 vs > 18 months; P < .001) than those with < 5/7.5 mL circulating tumor cells. Of all the variables in the statistical model, the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival in this group of patients.

Intermediate- or high-risk patients

Intermediate- or high-risk patients include those with rapidly progressive disease or visceral involvement, as well as those with disease shown to be refractory to hormonal manipulation by a prior therapeutic trial.

Anthracycline-containing combinations, such as FAC (see Table 1), are preferred for these patients. However, newer combinations of doxorubicin and a taxane are gaining favor for use in patients who have not received > 450 mg/m2 of an anthracycline and whose relapse has occurred more than 12 months after the completion of adjuvant therapy.

Single agents Many single cytotoxic drugs have shown some activity in metastatic breast cancer (Table 1). They include vinblastine, mitomycin, thiotepa, capecitabine, vinorelbine, and gemcitabine.

Paclitaxel One of the most active agents is paclitaxel. It has demonstrated antitumor activity in patients with anthracycline-resistant disease, as well as in those who have received three or more prior chemotherapy regimens for metastatic disease.

High-dose paclitaxel (250 mg/m2 over 3 hours) has not been shown to be superior to 175 mg/m2 over 3 hours. The higher dose regimen is associated with greater hematologic and neurologic toxicities.

Docetaxel, approved by the US Food and Drug Administration (FDA) for anthracycline-resistant locally advanced or metastatic breast cancer, has demonstrated overall response rates of 41% in patients with doxorubicin-resistant disease. It has been shown to be superior to mitomycin/vinblastine in patients whose disease progressed after an anthracycline-based chemotherapy regimen.

The recommended starting dose of docetaxel-100 mg/m2 as a 1-hour IV infusion-requires premedication with dexamethasone to avoid fluid retention and the capillary leak syndrome. The usual regimen of dexamethasone is 8 mg twice daily for a total of 3 days, beginning 24 hours prior to the administration of docetaxel.

Although 100 mg/m2 is the dose of docetaxel approved by the FDA, many recent trials have demonstrated a high rate of grade 4 hematologic toxicity at this dose level; a dose of 60 to 70 mg/m2 may achieve equivalent therapeutic benefit with improved safety. As with paclitaxel, the docetaxel dosage must be modified in patients who have hepatic impairment, manifested by elevated transaminase or alkaline phosphatase levels.

To determine whether weekly infusion of paclitaxel improves response rates versus the standard 3-hour infusion, 577 patients with metastatic breast cancer who had received one or two prior regimens were randomized to receive standard (175 mg/m2) or weekly (80 mg/m2) paclitaxel. Weekly paclitaxel was shown to be superior with respect to response rate (40% vs 28%; P = .017), time to disease progression (9 months vs 5 months; P = .0008), and overall survival (24 months vs 16 months). When trastuzumab became standard therapy for HER2-positive tumors, all patients with HER2-positive disease received trastuzumab, whereas patients with HER2-negative disease were randomized to receive either the addition of trastuzumab or not. The addition of trastuzumab did not improve any of these endpoints. Weekly paclitaxel caused more grade 3 sensory/motor neuropathy and less grade 3 granulocytopenia. The authors concluded that weekly is superior to standard paclitaxel in the management of metastatic breast cancer.

Capecitabine, an orally active fluorinated pyrimidine carbonate, has been shown to have a substantial antitumor effect in patients whose disease has recurred or progressed after prior anthracycline or taxane therapy. Prolonged survival, limited toxicity, and response in visceral as well as soft-tissue disease add to the benefit of capecitabine. Toxicities include diarrhea, stomatitis, and hand-foot syndrome.

New approaches Multiple new approaches to treating metastatic breast cancer are being explored. Weekly schedules of docetaxel and paclitaxel have been reported to produce high response rates and lower toxicity than 3-week schedules. Combinations of doxorubicin with paclitaxel or docetaxel have also shown substantial antitumor activity, as have combinations of capecitabine and docetaxel, carboplatin and paclitaxel, and gemcitabine and cisplatin. These newer combinations need to be compared with standard AC or FAC (CAF) regimens in phase III trials. Recent studies also suggest that sequential weekly chemotherapy may be as effective as more intensive combinations with respect to overall survival in patients with metastatic breast cancer.

Monoclonal antibody therapy and other targeted agents

Trastuzumab, a humanized monoclonal antibody to the HER2-neu protein, has been approved for use as a single agent in second and third-line therapy for metastatic breast cancer and in combination with paclitaxel as first-line therapy in this setting. A randomized trial consisting of 469 women showed that the combination of trastuzumab with chemotherapy yielded a 45% overall response rate, as compared with a 29% rate with chemotherapy alone-a 55% increase. The addition of trastuzumab had the greatest impact on response when combined with paclitaxel. Among the study group as a whole, 79% of women treated with trastuzumab chemotherapy were alive at 1 year, as compared with 68% of those given chemotherapy alone.

An update of these data has shown a superior median overall survival with chemotherapy plus trastuzumab compared with chemotherapy alone (25.4 months vs 20.9 months). The survival advantage was seen with both AC plus trastuzumab and paclitaxel plus the monoclonal antibody.

In another single-arm trial involving 222 women who had not responded to prior chemotherapy, trastuzumab shrunk tumors by 50% in 14% of women, with a median duration of response of 9 months. Overall, trastuzumab was well tolerated in both trials. Due to an increased risk of cardiac dysfuntion observed in women treated with trastuzumab plus an anthracycline, trastuzumab should not be used in combination with this drug class.

It is important to point out that trastuzumab also produces cardiac toxicity when administered by itself, particularly in patients who have had extensive prior exposure to an anthracycline. Finally, essentially all of the clinical benefit of trastuzumab (alone or in combination) is confined to patients whose breast cancer expresses high (3+) levels of the HER2-neu oncoprotein.

One study explored the relationship between circulating HER2 extracellular domain (ECD) and tissue HER2 status and examined its predictive value in a cohort of metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel. Retrospective analysis of patients treated on a previous trial evaluated the associations between pretreatment serum HER2 ECD and tissue HER2 status and the change in serum HER2 ECD after 12 weeks of therapy and response. Stored serum samples were available for 55 of 95 patients (58%). A statistically significant association was found between HER2 status and baseline serum HER2 ECD level. Patients whose ECD normalized after 12 weeks of therapy had a higher response proportion thatn did those with persistently high ECD levels (68% vs 15%; P = .005). A relative decline of more than 55% from baseline HER2 ECD predicted response to trastuzumab-based therapy.

Lapatinib (Tykerb) Lapatinib is a tyrosine kinase inhibitor of HER2-neu and epidermal growth factor receptor (EGFR), and is active in combination with capecitabine in women with HER2-positive metastatic breast cancer. Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either lapatinib (at a dose of 1,250 mg/d continuously) plus capecitabine (at a dose of 2,000 mg/m2 of body surface area) on days 1 through 14 of a 21-day cycle or monotherapy with capecitabine alone (at a dose of 2,500 mg/m2 on days 1 through 14 of a 21-day cycle).

The interim analysis of time to disease progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The HR for the independently assessed time to disease progression was 0.49 (95% CI, 0.34–0.71; P < .001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to disease progression was 8.4 months in the combination-therapy group, compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. In March 2007, lapatinib in combination with capecitabine was approved by the FDA for treatment of women with HER2-positive advanced breast cancer that has progressed after treatment with trastuzumab.

Ixebepilone (Ixempra) has recently been approved for the treatment of advanced breast cancer after failure of an anthracycline and a taxane, either as monotherapy or in combination with capecitabine. Its approval was based on two pivotal trials. One is a phase II study evaluating the efficacy and safety of ixabepilone in patients with metastatic breast cancer resistant to anthracycline, taxane, and capecitabine. Patients were heavily pretreated: 88% of the 126 patients had received at least two lines of prior chemotherapy in the metastatic setting. Ixabepilone (40 mg/m2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary endpoint was objective response rate, assessed by an independent radiology facility (IRF). A total of 113 patients were assessable for response: IRF-assessed overall response rate was 11.5% (95% CI, 6.3%–18.9%). Fifty percent of patients achieved stable disease; 14.3% achieved stable disease > 6 months. The median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. The median overall survival was 8.6 months. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median of 5.4 weeks.

The other study was a randomized phase III trial evaluating the efficacy and safety of ixebepilone in combination with capecitabine. This trial included 752 patients who were previously treated with anthracyclines and taxanes and whose tumors had

demonstrated prior resistance to these therapies. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 months vs 4.2 months), with a 25% reduction in the estimated risk of disease progression (HR, 0.75; 95% CI, 0.64–0.88; P = .0003). Objective response rate was also increased (35% vs 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% vs 0%), fatigue (9% vs 3%), and neutropenia (68% vs 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% vs 1%, with patients with liver dysfunction [≥ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.

Bevacizumab (Avastin) is the first antiangiogenic agent to demonstrate benefit in women with breast cancer. The phase III Eastern Cooperative Oncology Group (ECOG) 2100 trial randomized patients to receive either standard doses of weekly paclitaxel or the same chemotherapy with bevacizumab as front-line treatment for metastatic disease. The overall response rate was significantly better with the combination (28.2% vs 14.2%; P < .0001). Noteworthy were the significant increases in progression-free and overall survival for patients treated with the combination, although the survival data are still immature. Toxicities associated with the bevacizumab combination included hypertension, proteinuria, and neuropathy. There was also a trend toward an increase in thrombosis and bleeding, but it was not statistically significant.

Capecitabine combined with bevacizumab in heavily pretreated metastatic breast cancer improved the response rate but not progression-free survival. In untreated metastatic breast cancer, the addition of bevacizumab to chemotherapy significantly improves progression-free survival which suggests that bevacizumab, is most effective in early disease. A single-arm, phase II study to evaluate progression-free survival in metastatic breast cancer patients receiving first-line treatment with capecitabine at (1,000 mg/m2 twice daily) on days 1 to 15 (28 doses) and bevacizumab (15 mg/kg) on day 1 repeated every 21 days until disease progression was recently reported. Results are based on 103 patients (intent-to-treat population), with 84 patientsalive at this time. Tumor response, which is based on 91 patients evaluated, showed a 38.5% (35/91) patients have had a response: complete response, 5.5%; partial response, 33.0%. Stable disease was 42.9%, with a 81.4% clinical benefit. The planned dose received was 77.7% for capecitabine and 99.0% for bevacizumab. The majority of adverse events were mild or moderate. The most common grade 3 toxicities were hand-foot syndrome (13%) and pain (10%); grade 4 pulmonary embolism occurred in 2% in the first phase of the study.

High-dose chemotherapy

Patients who present with or subsequently develop distant metastasis may be candidates for high-dose intensive chemotherapy programs with autologous stem-cell support. Multiple feasibility and phase II studies of this approach have been undertaken. The majority of programs include the use of multiple alkylating agents. The role of high-dose chemotherapy in metastatic disease remains controversial, and analysis and observation of ongoing clinical trials continue to be important.

The results from multiple centers indicate an overall 5-year disease-free survival rate of 25% in patients with metastatic disease treated with high-dose chemotherapy. However, it must be remembered that these results were obtained in a select patient population-generally individuals < 60 years of age with good performance status; chemotherapy-sensitive disease; and normal cardiac, pulmonary, renal, and hepatic function. The use of intensive supportive outpatient care, such as colony-stimulating factors and antibiotics, has significantly reduced the morbidity and mortality associated with the high-dose chemotherapy approach.

In randomized trials of high-dose chemotherapy in patients with metastatic breast cancer (Table 3), it appears that most of the benefit occurs in women with low-bulk disease, especially those in complete clinical remission. A meta-analysis with longer follow-up also demonstrated a benefit for the addition of high-dose therapy to standard, anthracycline-containing chemotherapy for advanced disease in the setting of patients in complete clinical remission. This therapeutic modality remains investigational for patients with stage IV disease, however; women referred for high-dose therapy should be enrolled in a clinical trial.

Adjunctive bisphosphonate therapy

Multiple published reports have now confirmed the benefit of bisphosphonates as an adjunct to treatment of patients with bone metastasis. Use of these agents results in a significant reduction in skeleton-related events, including pathologic fracture, bone pain, and the need for radiation therapy to bone. Pamidronate and zoledronic acid (Zometa), both in IV formulations, are available in the United States. Oral bisphosphonates used for this indication, such ibandronate (Boniva) and clodronate, are not in the US market.

Patients with breast carcinoma who had all types of bone metastases (osteolytic, mixed, or osteoblastic) were randomized to receive treatment with either 4 or 8 mg of zoledronic acid as a 15-minute infusion or 90 mg of pamidronate as a 2-hour infusion every 3 to 4 weeks for 12 months. The proportion of patients who had a skeleton-related event (defined as a pathologic fracture, spinal cord compression, radiotherapy, or surgery to bone) was comparable between treatment groups (approximately 45%). However, among patients who had breast carcinoma with at least one osteolytic lesion, treatment with 4 mg of zoledronic acid was more effective than 90 mg of pamidronate in reducing skeletal complications.

The most commonly reported adverse events for both zoledronic acid and pamidronate were bone pain, nausea, fatigue, emesis, and fever. The 4-mg dose of zoledronic acid results in elevated serum creatinine levels in about 7.7% of patients, versus 6.0% with pamidronate. A larger proportion of patients had elevated serum creatinine levels with 8-mg of zoledronic acid; therefore, this dose is not recommended. Symptomatic hypocalcemia, although relatively rare, requires frequent monitoring of calcium and phosphate levels during treatment.

ROLE OF RADIATION THERAPY IN METASTATIC DISEASE

Irradiation remains an integral component of the management of metastatic breast carcinoma. Although bone metastases are the most commonly treated metastatic sites in patients with breast cancer, brain metastases, spinal cord compression, choroidal metastases, endobronchial lung metastases, and metastatic lesions in other visceral sites can be effectively palliated with irradiation.

Radiation dose and schedule Depending on the disease site and volume of the radiation field, fractionation schedules ranging from 20 Gy in 5 fractions to 30 Gy in 10 fractions are used most commonly. In some situations, more protracted courses using lower daily doses may be indicated.

Bone metastasis For patients with widespread bone metastasis, hemibody irradiation (6–7 Gy in one fraction to the upper body or 8 Gy to the lower body) has been shown to be effective. Strontium-89 chloride (Metastron) and other systemic radionuclides also provide effective palliation for widespread bone disease.

Consolidation after high-dose chemotherapy Since patients with metastatic disease treated with high-dose chemotherapy and autologous bone marrow or stem-cell transplantation often develop progressive disease in previously involved sites, studies have suggested the use of “consolidative radiation therapy” for patients undergoing high-dose chemotherapy. Although this approach appears to be well tolerated and preliminary data are encouraging, whether it will affect survival remains to be determined.

Brain metastasis Patients who develop metastasis to the brain generally have poor outcomes. Nonetheless, radiation therapy can often be helpful in palliating their symptoms and may help control disease for some time. In one randomized trial, patients with one to three newly diagnosed brain metastases (breast as well as other sites) were randomly allocated to receive either whole-brain radiation therapy (WBRT, 164 patients) or WBRT followed by a stereotactic radiosurgery boost (167 patients). Univariate analysis showed that there was a survival advantage in the WBRT and surgery group for patients with a single brain metastasis (median survival, 6.5 months vs 4.9 months; P = .0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky performance status score at 6 months’ follow-up than were patients allocated to WBRT alone (43% vs 27%, respectively; P = .03.

ROLE OF SURGERY IN METASTATIC DISEASE

There are selected indications for surgical intervention in patients with metastatic breast cancer, and the role of surgery at this point is generally palliative. Most commonly, palliative surgery is offered to patients with brain metastases, spinal cord compression, fractures, or symptomatic pleural or pericardial effusions not controlled by other means. It is also used for GI complications stemming from metastatic deposits. The curative benefit of surgery in the treatment of metastatic disease to the lungs or liver is not proven, but, in highly selected cases, surgery may be beneficial.

Spinal cord compression Patients with spinal cord compression who have progressive symptoms during irradiation, disease recurrence after irradiation, or spinal instability or who require diagnosis are candidates for surgery.

Solitary brain metastasis Patients with a long disease-free interval and solitary brain metastasis may be candidates for resection. Evidence suggests an improved disease-free survival, overall survival, and quality of life in this subset of patients when treated with surgery combined with postoperative cranial irradiation, as compared with radiation therapy alone.

Gamma- and cyber-knife radiosurgery is increasingly used to manage brain metastases. In some instances, these modalities have been used in patients who have multiple metastatic brain lesions or in patients who had previously received conventional treatment modalities for brain metastases, including whole-brain irradiation. No radiation-induced dementia and a remarkably low incidence of local failure were reported with these treatments. Although in the past, local control of brain metastasis was an issue, these treatment modalities are shifting the question of survival to that of systemic control.

Chest wall resection It is extremely rare for a patient with distant metastatic disease to be a candidate for chest wall resection; however, patients with symptomatic recurrence of disease in the chest wall who have limited distant disease and a life expectancy of > 12 months may be appropriate candidates.

Solitary liver metastatic disease Although rarely indicated, patients with single metastases or a prolonged disease-free or disease-stable interval may be candidates for resection.

Liver metastasis Patients with metastatic disease to the liver have a poor prognosis. In the past, patients with a single focus of disease in the liver who had no evidence of extrahepatic disease were offered liver resection as a means to control their disease and improve outcome. With advanced surgical techniques, the morbidity and mortality for liver resection have decreased. Hepatic resection was undertaken in patients with breast cancer metastases to the liver and not limited to patients whose disease was solely confined to the liver. A 5-year disease-free survival rate of 21% and an overall 5-year survival rate of 37% were observed. These results suggest an expanded role for hepatic resection in patients with breast cancer metastases to the liver.

Follow-up of long-term survivors

For recommendations on the type and timing of follow-up evaluations, see chapter 10.

SUGGESTED READING

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