Original StudyVisceral Disease in Patients With Metastatic Breast Cancer: Efficacy and Safety of Treatment With Ixabepilone and Other Chemotherapeutic Agents
Introduction
Significant progress has been made in the treatment of patients with breast cancer during the past 3 decades. Technologic advances have permitted diagnosis of disease at earlier stages as a result of implementation and acceptance of improved screening procedures. Despite aggressive first-line surgery and chemotherapy, a significant proportion of patients still experience disease relapse. In these patients, the introduction of novel therapies, including hormonal agents, targeted agents, anthracyclines, and taxanes, has resulted in the prolongation of survival and improved quality of life. In addition, an improved understanding of the biologic and biochemical processes underlying the development and progression of breast cancer have led to a better understanding of the heterogeneity of the disease and the various patient subgroups that might benefit most from specific forms of therapy. These advances have led to the identification of a number of factors that are predictive of patient prognoses.1, 2, 3 The major prognostic factors in breast cancer are listed in Table 1.
Nearly 50% of patients treated with hormonal and/or chemotherapeutic agents develop distant metastatic disease.4, 5, 6, 7 Patients who develop metastatic breast cancer (MBC) have a poor prognosis, with a median survival of 1-2 years and a 5-year survival rate of approximately 20%.8, 9 The clinical outcomes of patients with MBC can be highly variable owing to multiple factors that determine the progression of disease.3, 4, 7 Various studies have identified prognostic factors that have important implications for the management of patients with MBC. Among these, axillary lymph node status at diagnosis, relapse-free interval, previous adjuvant chemotherapy, hormone receptor [estrogen receptor (ER) and progesterone receptor (PgR)] status, number of metastatic disease sites, site(s) of recurrence, and visceral involvement have demonstrated correlation with overall patient survival by univariate and multivariate analyses.9, 10, 11, 12, 13
Various studies also demonstrate that the sites of recurrent disease have a strong association with survival of patients with MBC (Figure 1).5, 8, 12, 14, 15 A retrospective analysis of 3-year breast cancer–specific survival (BCSS) rates in 294 patients treated for operable breast cancer revealed that prognosis was highly dependent on the site of first metastatic recurrence. Patients with local recurrence had a BCSS rate of 83%. By contrast, the BCSS rate was 33% for patients with nodal recurrence, 23% for those with bone recurrence, and 13% for patients with visceral recurrence.15
The observed differences in clinical outcomes of patients with MBC might be related to the inherent properties of the tumor as well as the microenvironment of the host organ. For example, clinically apparent breast cancer metastases to the brain develop in approximately 5%–15% of patients, with the reported incidence in autopsy studies ranging between 18% and 30%.16 Recent studies demonstrate a higher incidence of brain metastases in patients with MBC expressing high levels of HER2, reflecting more aggressive nature of HER2+ disease.17, 18, 19 The increased incidence of brain metastases in patients with HER2+ disease persists even after treatment with trastuzumab because the drug cannot penetrate the blood-brain barrier. Higher incidence of brain metastases has also been reported in patients with MBC lacking expression of ER, PgR, and HER2 (triple-negative) MBC.20 Because of restricted penetration of drugs through the blood-brain barrier, chemotherapy is of limited value in patients with brain metastases.16 Lung is the first site of metastasis in approximately 15%–25% of patients with MBC, the second highest frequency of any organ after bone.21 Standard treatment for lung metastases includes chemotherapy and/or radiation therapy.21, 22 Patients with solitary lung nodules (approximately 3% of patients) might benefit from surgery with or without chemotherapy.21, 22, 23
Approximately 50% of patients with advanced breast cancer develop hepatic metastases.5, 22, 23 Patients with breast cancer who develop visceral metastases to the liver generally have much poorer prognoses than patients with metastases to bone or soft tissues, with median survival of < 6 months.5, 14, 15 However, recent improvements in diagnostic techniques and therapeutic regimens have led to improved clinical outcomes in these patients with poor prognoses.5, 22, 23 Zinser et al retrospectively examined the survival of 233 patients with MBC with liver metastases treated with doxorubicin-containing chemotherapy regimens between 1973 and 1980 and compared it with survival of a cohort of 58 patients with MBC with liver metastases treated with hormonal therapy or single-agent chemotherapy (fluorouracil or thiotepa) between 1955 and 1957.24 A marked improvement in median survival was observed for patients with MBC treated with combination chemotherapy in the 1970s (14 months) compared with patients treated in the 1950s (5 months). For patients treated in the 1970s, the number of organs involved had a strong association with overall survival (OS) in response to chemotherapy. The longest median survival, 26 months, was observed in responding patients with metastases restricted to the liver versus 18.5 months and 17 months, respectively, in responding patients with metastases to the liver plus bone and responding patients with metastases to liver plus ≥ 3 organ sites. The median survival for all responding patients was 19.5 months versus 6 months for nonresponding patients.
Pentheroudakis et al examined the outcomes of 500 patients with MBC with liver metastases treated with first-line chemotherapy from 1988 through 2004.14 An objective response rate (ORR; RR) of 34% was observed in these patients treated with first-line chemotherapy. In addition, nearly 80% of the patients received second-line chemotherapy, with an ORR of 16%. Multivariate analyses demonstrated that previous adjuvant chemotherapy, performance status (PS), and degree of metastatic dissemination were independent predictors of survival.
In addition to organ involvement, an important consideration in the selection of chemotherapy for MBC is adequate liver function. This is particularly important for patients with a high burden of hepatic involvement, who could experience decreased clearance of chemotherapeutic agents such as anthracyclines and taxanes.5, 25 Hepatic impairment results in an increased risk of severe toxicity from these agents and limits the ability to deliver adequate and effective treatment doses.25 For example, Alexandre et al demonstrated that in patients with a high burden of visceral metastases (73.5% of the patients), liver dysfunction was associated with a lower RR, shorter time to treatment failure, shorter OS, and increased incidence of adverse events with single-agent docetaxel.26 By contrast, Twelves et al reported that there was no significant change in the absorption or metabolism of capecitabine in patients with MBC with mild to moderate hepatic impairment caused by liver metastases.27 These results suggest that there might be minimal impact on the therapeutic activity of capecitabine in this patient population.
Many studies have evaluated the efficacy of conventional chemotherapeutic agents (anthracyclines, taxanes, and newer agents) as monotherapy and combination therapy in MBC.28, 29, 30, 31 As previously noted, criteria such as location/extent of metastatic disease, patient PS, and extent of previous treatment as well as criteria used to define drug resistance can have a profound influence on responses to therapy. Unfortunately, a significant number of studies in MBC have not reported the proportion of patients with visceral metastases, and for obvious reasons, reported outcomes are difficult to extrapolate to the patient with significant visceral tumor burden. Therefore, it is difficult to assess, across trials, the clinical benefit provided by a specific chemotherapeutic regimen in this population of patients with a poor prognosis. Herein, we discuss the results of clinical trials that have evaluated the efficacy of chemotherapeutic agents (microtubule inhibitors and other agents) as monotherapy and in combination with capecitabine, with an emphasis on MBC trials in patient populations with documented visceral disease by virtue of metastases to liver and/or lung. In addition, we discuss current recommendations for dosing of standard chemotherapeutic agents in patients with hepatic dysfunction.
Section snippets
Monotherapy Options for Patients With Metastatic Breast Cancer With Visceral Disease
A substantial number of trials have evaluated microtubule inhibitors such as the taxanes as monotherapy in patients with MBC with documented visceral disease, generally when administered during earlier lines of treatment. Additional classes of agents have been evaluated as monotherapy, predominantly within the context of previous treatment failure (progressive and/or resistant disease). The results of clinical trials evaluating various chemotherapeutic agents in patients with MBC with
Safety of Monotherapy in Patients With Metastatic Breast Cancer With Visceral Disease
The safety profiles of microtubule inhibitors, capecitabine, and gemcitabine administered as monotherapy in patients with MBC with visceral disease were not significantly different from those observed in the general patient populations and were consistent with the known toxicities of the individual agents. Caution should be exercised when treating patients with MBC with a high burden of liver metastases to minimize the potential for severe toxicities associated with hepatic impairment.
Microtubule Inhibitors
Paclitaxel-Based Combination Regimens With Capecitabine. Although various trials have evaluated paclitaxel- and albumin-bound paclitaxel–based combination regimens with capecitabine in patients with MBC, the regimens were used primarily in the first-line setting, with ORRs ranging between 42% and 63%.122, 123, 124, 125, 126, 127 A 53% ORR was reported in one phase II trial evaluating combination albumin-bound paclitaxel plus capecitabine as first-line therapy for MBC.127 Little information is
Discussion
A significant clinical benefit has been observed for patients with MBC with a high burden of visceral metastases treated with chemotherapy. Similar responses (ORRs ranging approximately between approximately 10% and 60%) have been reported in patients with MBC treated with the single-agent microtubule inhibitors paclitaxel, docetaxel, albumin-bound paclitaxel, vinorelbine, and ixabepilone (Table 2A, Table 2B). Lower responses (ORRs ranging approximately between 0 and 45%) were observed in
Disclosures
The author's sources of support include grants, equipment, and drugs. Sarah Cannon Research Institute has received research funding from Bristol-Myers Squibb Company. Dr. Yardley has participated as an investigator on studies funded by Bristol-Myers Squibb Company. Dr. Yardley does not receive direct research funding from Bristol-Myers Squibb Company.
Acknowledgments
The authors wish to acknowledge the editorial assistance of Roy Garcia, PhD, Inexel.
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