The Oncologist, Vol. 7, Suppl 6, 4–12,
December 2002
© 2002 AlphaMed Press
Treatment for Anthracycline-Pretreated Metastatic Breast Cancer
Joyce O’Shaughnessya,
Chris Twelvesb,
Matti Aaproc
a Baylor-Sammons Cancer Center and US Oncology, Dallas, Texas, USA;
b Cancer Research UK, Department of Medical Oncology, University of Glasgow and Beatson Oncology Centre, Glasgow, UK;
c Institut Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier, Switzerland
Correspondence:
Joyce O’Shaughnessy, M.D., US Oncology, 3535 Worth Street, Collins 5, Dallas, Texas 75246, USA. Telephone: 214-370-1795; Fax: 214-370-1850; e-mail: joyce.o\|[rsquo ]\|shaughnessy{at}usoncology.com
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Recognize the chemotherapy options that provide a survival benefit for anthracycline-pretreated metastatic breast cancer.
- Identify some of the validated treatment options for breast cancer patients with recurrent disease following anthracycline-based therapy.
- Explain the rationale for specific salvage treatment regimens in patients with recurrent breast cancer following anthracyline-based therapy.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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As a result of increasing anthracycline use earlier in the course of breast cancer, oncologists are frequently faced with the challenge of treating patients whose disease has progressed during or following anthracycline therapy or who are ineligible for further anthracycline therapy. Many of these women remain candidates for cytotoxic chemotherapy, and several treatment options exist. Until recently, the taxanes, docetaxel in particular, were widely regarded as the most effective therapy for these patients, based on a survival advantage observed with docetaxel. However, a recent phase III study demonstrated that the addition of capecitabine to docetaxel results in superior overall survival (with a 3-month improvement in median survival), superior time to disease progression, and a superior response rate, with a manageable safety profile. Capecitabine/docetaxel is the first cytotoxic combination to improve survival over standard monotherapy in patients with anthracycline-pretreated metastatic breast cancer. Moreover, the survival benefit can be attributed to the addition of capecitabine, as it was achieved despite the lower dose of docetaxel administered in the combination arm. Quality of life was maintained with capecitabine/docetaxel combination therapy, which further supports the use of this regimen in patients with anthracycline-pretreated metastatic breast cancer. Pharmacoeconomic modeling using the data from the phase III trial has shown that the capecitabine/docetaxel combination therapy is highly cost effective when compared with other cancer treatments that improve survival. This review describes several treatment options for patients with anthracycline-pretreated breast cancer, including the phase III data (efficacy, tolerability, quality of life, and pharmacoeconomics) for capecitabine plus docetaxel in this setting.
Key Words. Anthracyclines • Taxanes • Breast cancer • Capecitabine • Docetaxel • Pharmacoeconomics • Quality of life
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INTRODUCTION
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Approximately 40% of all patients treated with curative intent for breast cancer will ultimately develop metastatic disease. The typical life expectancy for these patients is approximately 3 years following the diagnosis of metastatic breast cancer [1]. The aims of chemotherapy in the metastatic setting are to relieve tumor-related symptoms while maintaining or improving the patient’s quality of life and, importantly, to prolong survival.
Choice of treatment is influenced by a wide range of factors related to patient and tumor characteristics such as patient age; performance status; previous therapy; extent and location of metastases; estrogen, progesterone, and HER2 receptor status, and treatment preference. Systemic cytotoxic chemotherapy is the first-line treatment of choice for patients whose breast cancers are resistant to hormonal manipulation, are hormone-receptor negative, or who have rapidly growing visceral disease [2]. In patients who have not been previously exposed to anthracyclines in the adjuvant setting, a first-line treatment option for metastatic disease consists of an anthracycline-containing combination regimen, e.g., AC/EC (doxorubicin/epirubicin plus cyclophosphamide) or CAF/CEF (cyclophosphamide/5-fluorouracil [5-FU] plus doxorubicin or epirubicin) [3]. However, the taxanes are increasingly being used, either as single agents or together with agents such as trastuzumab or capecitabine, as first-line treatment for metastatic breast cancer.
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ANTHRACYCLINE USE IN BREAST CANCER
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Since their introduction in the 1980s, the anthracyclines, doxorubicin and epirubicin, have been considered to be among the most active agents for the treatment of breast cancer and are components of many adjuvant and palliative regimens. The majority of randomized, controlled trials in patients with metastatic disease show that anthracyclinecontaining regimens improve efficacy (response rate and time to disease progression) but generally do not improve survival compared with cyclophosphamide/methotrexate/5-FU (CMF) or similar regimens [4–8]. However, a meta-analysis demonstrated that first-line treatment with an anthracycline-containing regimen confers a marginal survival benefit compared with non-anthracycline-containing regimens [9]. Similarly, in the adjuvant setting, anthracycline-based chemotherapy improves efficacy compared with traditional CMF-based regimens, including a small but meaningful survival gain of approximately 3%-6% [10, 11].
As a result of increasing anthracycline use earlier in the course of the disease, patients with anthracycline-pretreated metastatic breast cancer are frequently encountered in clinical practice. These patients most often remain candidates for cytotoxic chemotherapy if their disease is, or becomes, hormone refractory. Nevertheless, until the development of the taxanes in the 1990s, treatment options were extremely limited, and the use of most agents was supported only by data from small phase II studies.
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THE TAXANES
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Both docetaxel and paclitaxel have been widely evaluated in the treatment of anthracycline-pretreated metastatic breast cancer. Docetaxel is the only single agent for which a survival advantage has been demonstrated in this setting. Docetaxel has demonstrated significant efficacy benefits over other recognized regimens in two large prospective, randomized trials in patients with anthracycline-pretreated metastatic breast cancer (Table 1
). Docetaxel significantly improved overall survival (p = 0.0097), time to disease progression (p = 0.001), and response rate (p < 0.0001) compared with mitomycin C plus vinblastine [12]. Single-agent docetaxel was also more effective than methotrexate plus 5-FU, resulting in a significantly superior response rate (p < 0.001) and time to disease progression (p < 0.001) [13].
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Table 1. Efficacy of docetaxel in patients with anthracycline-pretreated metastatic breast cancer: randomized phase III studies
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Paclitaxel is an effective treatment as first-line therapy for metastatic breast cancer, having demonstrated similar response rates and progression-free survival to CMF plus prednisone (CMFP) (29% and 5.3 months for paclitaxel versus 35% and 6.4 months for CMFP) as well as a nonsignificant trend toward improved overall survival [14]. Importantly, no survival advantage was seen in a large phase III trial of combined paclitaxel and doxorubicin compared with sequential administration of these two agents, in either order [15]. When administered as a 3-hour infusion according to a 21-day schedule, paclitaxel 175 mg/m2 achieved marginally improved outcomes compared with 135 mg/m2 in patients with pretreated metastatic breast cancer, with similar response rates observed in patients with and without prior exposure to anthracyclines [16]. Weekly administration of paclitaxel produced a 53% response rate in 30 patients with metastatic breast cancer, 18 of whom (60%) were anthracycline pretreated [17]. In a phase II study in a mixed population of 212 patients with metastatic breast cancer, a response rate of 22% was obtained [18].
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VINORELBINE AND GEMCITABINE
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Several other cytotoxic agents have been evaluated in patients with anthracycline-pretreated breast cancer. Vinorelbine and gemcitabine are commonly administered, generally on the basis of phase II data that have shown consistent antitumor activity.
The efficacy of vinorelbine, a third generation vinca alkaloid, alone or in combination with other agents, has been extensively investigated in phase II trials in patients with anthracycline-pretreated disease. Reported response rates ranged from 15%-25% [19–21], and the agent was generally well tolerated, with myelosuppression and peripheral neuropathy the primary toxicities.
In the early 1990s, a randomized, phase III trial demonstrated that vinorelbine achieves similar response rates to melphalan (p = 0.415; 16% versus 9%, respectively) [20]. Although superior time to disease progression and overall survival were reported with vinorelbine, interpretation of the data must also take into account the questionable single-agent activity of melphalan in this setting, which is reflected in low median values for time to disease progression (2.8 and 1.8 months, respectively) and overall survival (8.0 and 7.1 months, respectively).
Gemcitabine, a nucleotide analog that inhibits DNA synthesis, has demonstrated single-agent activity in patients with a variety of solid tumors, including breast cancer [22]. Response rates between 20% and 30% have been reported in phase II studies in patients with anthracycline-pretreated metastatic breast cancer [23, 24].
A recently reported randomized phase III study demonstrated that gemcitabine was less active than epirubicin as first-line treatment for metastatic breast cancer. As first-line therapy for metastatic breast cancer in patients aged >60 years, gemcitabine (1,200 mg/m2 on days 1, 8, and 15 every 28 days) achieved a significantly inferior response rate (p < 0.01; 16% versus 40%), time to disease progression (p < 0.01; 3.4 months versus 6.1 months), and overall survival (p < 0.01; 11.8 months versus 19.1 months) compared with single-agent epirubicin (35 mg/m2 on days 1, 8, and 15 every 28 days) [25].
Gemcitabine is currently being investigated as part of several combination regimens, and phase III data comparing paclitaxel alone with paclitaxel plus gemcitabine will be available from the pivotal trial in anthracycline-pretreated patients in 2003.
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TRASTUZUMAB
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Trastuzumab is a humanized anti-HER2 monoclonal antibody. HER2, a transmembrane glycoprotein, is overexpressed in 20%-25% of human breast cancers [26]. Trastuzumab produces significant antitumor activity in patients with HER2-overexpressing metastatic breast cancer, either alone [27] or in combination with chemotherapy [28]. In a randomized, multicenter trial, the addition of trastuzumab to paclitaxel significantly increased time to disease progression (p < 0.001; median 6.9 months versus 3.0 months with paclitaxel alone) and response rate (p < 0.001; 38% versus 16%, respectively), and resulted in improved overall survival (median 22.1 months versus 18.4 months) in anthracycline-pretreated patients [28, 29]. Based on these results, trastuzumab/taxane combination therapy is now considered to be the first-line standard of care for patients with HER2-overexpressing metastatic breast cancer. Combinations of trastuzumab and other cytotoxic agents, including docetaxel and vinorelbine, are also highly active.
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CAPECITABINE/DOCETAXEL COMBINATION THERAPY
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Despite numerous attempts to improve upon the efficacy of taxane-based therapy in patients with anthracycline-pretreated metastatic breast cancer, including combination with other cytotoxic drugs, no cytotoxic regimen has been shown to improve survival compared with single-agent docetaxel. The benefits conferred by the addition of trastuzumab to conventional cytotoxic therapy are available to only 20%-25% of patients, and therefore, novel treatments are needed for patients whose tumors are HER2-negative and for those whose disease is unresponsive or resistant to anthracyclines.
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RATIONALE
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The oral fluoropyrimidine capecitabine (Xeloda®) was rationally designed to generate 5-FU preferentially in tumor tissue and to mimic continuous infusion 5-FU. Tumor activation of capecitabine is achieved by exploiting the significantly higher thymidine phosphorylase (TP) concentrations in many tumor tissues compared with their healthy counterparts [30, 31]. Oral capecitabine is an active monotherapy, achieving response rates of 15%-26% and median survival of approximately 1 year in patients with metastatic breast cancer that has progressed during or following anthracycline and taxane therapy [32–35] (see review by Seidman et al., pp. 20-28 [36]). The activity of capecitabine in heavily pretreated patients provided the rationale for investigating the agent earlier in the course of the disease and in combination with other cytotoxic agents. Furthermore, the low incidence of myelosuppression with capecitabine makes it a highly suitable agent for combination with myelosuppressive agents. Accordingly, several studies have investigated capecitabine in combination with cytotoxic agents that have differing safety profiles and mechanisms of action [37–47].
A further important rationale for combining capecitabine with docetaxel is the preclinical observation that administration of either docetaxel or paclitaxel leads to upregulation of TP, the enzyme that mediates the final conversion step of capecitabine to 5-FU in tumor tissue [48]. This finding has been confirmed in women with primary breast cancer who were treated with preoperative docetaxel [49]. Coadministration of capecitabine with either docetaxel or paclitaxel in xenograft models resulted in synergistic antitumor activity, whereas taxanes in combination with either 5-FU or uracil/tegafur demonstrated only additive efficacy [48]. The combination of capecitabine plus a taxane was therefore anticipated to have particularly high clinical efficacy.
Based on a phase I study [40], a regimen of capecitabine 1,250 mg/m2 twice daily on days 1-14 plus docetaxel 75 mg/m2 on day 1 every 21 days was selected for evaluation in a phase III trial, which is described below.
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PATIENTS AND METHODS
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A large international, phase III trial enrolled 511 patients whose unresectable locally advanced or metastatic breast cancer had progressed during or following anthracycline-based chemotherapy [50]. Patients were stratified according to previous exposure to paclitaxel and randomized to either capecitabine plus docetaxel combination therapy or single-agent docetaxel. Both arms received treatment in 21-day cycles with either capecitabine 1,250 mg/m2 twice daily on days 1-14 plus docetaxel 75 mg/m2 on day 1, or single-agent docetaxel 100 mg/m2 on day 1. Patients achieving a complete or partial response or stable disease after 6 weeks of therapy continued on treatment until disease progression or unacceptable toxicity.
The primary objective of the study was to demonstrate superior time to disease progression (defined as time to disease progression or death in patients without reported disease progression) with the combination regimen compared with docetaxel alone. Secondary objectives included comparison of overall response rates, overall survival, safety profiles, and quality of life between treatment groups. Quality of life was assessed every 6 weeks using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (version 2) and the breast cancer module BR-23, both of which assess a wide range of aspects relating to function and symptoms.
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PATIENT CHARACTERISTICS
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Demographic and disease characteristics were well balanced between the two treatment groups (Table 2). In both treatment arms, the most frequently involved metastatic sites were the lymph nodes, liver, bone, and lung. The treatment histories of the patients were also similar. As defined in the protocol, all patients had previously received anthracycline-based therapy, and the degree of resistance to anthracyclines was well balanced between the two treatment arms. In addition, more than 90% of patients had received previous alkylating agents, and 5-FU had been previously administered to approximately three-quarters of patients in both treatment arms. Approximately two-thirds of patients received study therapy as either second- or third-line treatment.
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EFFICACY RESULTS
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All efficacy data are reported using the intent-to-treat (all randomized) patient population (n = 255 in the combination arm; n = 256 in the single-agent docetaxel arm). The primary end point, time to disease progression, was significantly superior in patients receiving combination therapy compared with those receiving single-agent docetaxel (log-rank p = 0.0001, hazard ratio = 0.652; Fig. 1). The hazard ratio of 0.652 translates into a 35% reduction in the risk of disease progression in patients receiving combination therapy compared with those treated with docetaxel alone. The median time to disease progression was 6.1 months with combination therapy and 4.2 months with single-agent docetaxel. The curves separated early in the trial and maintained their separation.
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Figure 1. Time to disease progression: capecitabine/docetaxel versus docetaxel alone. Reprinted with permission [50].
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The tumor response rate was also significantly superior with the combination regimen compared with single-agent docetaxel (p = 0.006; 42% versus 30%, respectively). The significantly superior response rate with combination therapy was confirmed by the Independent Review Committee (p = 0.025). The percentages of patients without disease progression after 6 months were 41% and 29%, respectively (p = 0.04).
Most importantly, the superior time to disease progression and response rate seen with combination therapy translated into a significant survival benefit (log-rank p = 0.0126, hazard ratio = 0.775; Fig. 2). The hazard ratio of 0.775 indicates that the risk of death is 23% lower in patients receiving capecitabine/docetaxel combination therapy than in those receiving docetaxel alone. The combination regimen provided a 3-month median survival benefit over single-agent docetaxel (median 14.5 months versus 11.5 months, respectively). The 1-year survival rates were 57% and 47%, respectively. As with time to disease progression, the Kaplan-Meier curves separated within 2-3 months and remained separated over the duration of follow-up. Survival was not influenced by the setting in which study therapy was administered. The hazard ratio for survival was 0.774 in patients receiving the combination as first-line therapy, with corresponding hazard ratios of 0.769 and 0.746 in patients receiving the combination as second- and third-line therapy, respectively.
Post-study chemotherapy data indicate that survival was not biased by post-study therapy. Following disease progression on study therapy, a similar proportion of patients in both treatment arms received further chemotherapy (70% versus 63% in the combination and single-agent arms, respectively). Post-study 5-FU, vinorelbine, anthracyclines, trastuzumab, and paclitaxel were administered to similar percentages of patients from the combination and single-agent arms. However, among patients who received post-study chemotherapy, more patients in the single-agent arm (27%) were treated with post-study capecitabine than in the combination arm (4%).
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SAFETY RESULTS
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The safety population included all patients who received at least one dose of study drug (n = 251 in the combination arm; n = 256 in the single-agent arm). The incidence of treatment-related adverse events was similar in the combination and single-agent arms (98% versus 94%, respectively). The predominant treatment-related adverse events in the combination arm were diarrhea, stomatitis, and hand-foot syndrome, whereas in the docetaxel arm, diarrhea, stomatitis, fatigue/ asthenia, and alopecia were the most common (Fig. 3). Patients receiving the combination regimen experienced more gastrointestinal and cutaneous adverse effects, whereas patients treated with docetaxel alone reported more febrile neutropenia, myalgia, arthralgia, and pyrexia, due to the higher dose of docetaxel administered in the single-agent arm.
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Figure 3. Most common treatment-related events: capecitabine/docetaxel versus docetaxel alone. Reprinted with permission [50].
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In both treatment arms, the profile of grade 3/4 adverse events was similar to that described for all grades. The incidence of grade 3/4 adverse events was higher in the combination therapy arm (71% versus 49%), mainly due to a higher incidence of hand-foot syndrome (13% incidence in cycle 2). Grade 4 adverse events were, however, less frequent in the combination arm than in the single-agent arm (25% versus 31%, respectively), primarily due to the higher incidence of neutropenic fever in the single-agent docetaxel arm.
The incidence of treatment-related hospitalizations was similar in the two treatment arms (29% versus 26% in the combination and single-agent arms, respectively). Neutropenia and neutropenic fever were the most frequent causes of hospitalization in both arms but caused more hospitalizations in the single-agent docetaxel arm than in the combination arm. There were no significant differences between treatment arms in the incidence of treatment-related deaths or deaths from any cause during the first 60 days of treatment.
Dose reduction for adverse events was required in 65% of patients in the combination arm and in 36% of patients in the docetaxel arm, and was effective in reducing the recurrence of grade 3/4 treatment-related adverse events in both treatment arms. Planned and received doses over time for capecitabine and docetaxel in the combination arm are shown in Figure 4.
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Figure 4. Received versus planned doses of capecitabine and docetaxel over time in the capecitabine/docetaxel arm. Reprinted with permission [50].
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The impact of dose reduction on efficacy was assessed by including time to the first dose reduction as a time-dependent covariate in a proportional hazards regression model of time to disease progression. This retrospective analysis demonstrated that dose modification did not reduce efficacy in the combination arm. The hazard ratio for time to disease progression in patients with versus without dose reductions (all levels) was 0.84 (p = 0.43) for the combination therapy and 0.99 (p = 0.95) for single-agent docetaxel. To better assess the impact of early dose reductions, time to disease progression was analyzed in the combination arm in patients receiving the second cycle at a full versus a reduced dose (primarily to 75% of the standard starting dose) of capecitabine, which represents the closest approximation to a lower starting dose of capecitabine (Fig. 5). Kaplan-Meier plots for patients with versus without dose reduction were clearly superimposable and superior to the docetaxel monotherapy control arm.
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Figure 5. Impact of capecitabine dose reduction after the first cycle on time to disease progression. Reprinted with permission [50].
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Based on the higher incidence of toxicity-related premature withdrawals and grade 3/4 events in older patients (18% of patients 
60 years discontinued treatment during the first cycle compared with 4% of patients <60 years), this lower capecitabine starting dose (950 mg/m2 twice daily) is recommended for patients 60 years of age, as per the package insert in the European Union. The same dose may also be considered for frail patients. Furthermore, trials of capecitabine plus docetaxel in the adjuvant and neoadjuvant settings will evaluate this lower dose of capecitabine (950 mg/m2 twice daily on days 1-14) plus docetaxel 75 mg/m2 on day 1 of a 21-day cycle as it is anticipated, based on the retrospective analyses detailed above, that the efficacy advantage will be maintained but the safety profile may be improved.
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QUALITY OF LIFE
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In the phase III trial of capecitabine/docetaxel versus docetaxel, there was no difference between treatment arms in the primary quality-of-life end point, global health status at week 18, indicating that the survival benefit provided by the addition of capecitabine to docetaxel was not gained at the expense of quality of life. Interestingly, the global health status showed a trend in favor of the combination arm over time (Fig. 6).
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Figure 6. Quality of life (global health status) over time: capecitabine/docetaxel versus docetaxel alone. Reprinted with permission [50].
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The impact of chemotherapy-induced side effects, as judged by the patients in the systemic therapy side effects symptom scale, was also similar in the two treatment arms. Therefore, the greater incidence of gastrointestinal and cutaneous effects experienced by patients receiving the combination regimen appeared to be no more troublesome to the patients than the adverse events occurring with docetaxel alone. No major differences between treatments were detected for any other of the quality-of-life domains.
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PHARMACOECONOMIC EVALUATION
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In this study, data were collected on drug administration, the incidence and severity of adverse events, medications and consultations required for adverse events, and treatment-related hospitalizations. These data were then incorporated into a pharmacoeconomic model, with measures of clinical effectiveness and economic data combined using the U.S. health care system as the base case. The pharmacoeconomic evaluation of capecitabine/docetaxel combination therapy indicated that the combination is highly cost effective, with a total cost similar to that of docetaxel alone. The additional cost of capecitabine was nearly offset by the lower dose of docetaxel administered in the combination arm, even though treatment duration was longer in the combination arm. Figure 7 shows that the slight additional cost of the combination therapy (mean, U.S. $983 per patient) was offset by lower expenditure on hospitalizations with combination treatment.
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Figure 7. Key medical resource costs for capecitabine/docetaxel and docetaxel alone. Abbreviation: AEs = adverse events.
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With an estimated cost of approximately U.S. $4,500 per life year gained (well below the proposed cut-offs for cost effectiveness of U.S. $50,000 or £20,000 per life year gained), the combination therapy compares very favorably with other agents offering a survival benefit in cancer.
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CONCLUSIONS
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For several years, single-agent docetaxel has been considered a standard treatment for patients with anthracycline-pretreated advanced/metastatic breast cancer because of the overall survival advantage that has been demonstrated with this agent. A recent phase III trial has demonstrated that the addition of capecitabine to docetaxel leads to superior overall survival (with a 3-month median survival advantage), superior time to disease progression, and a superior response rate compared with docetaxel alone, with a manageable safety profile. Capecitabine/docetaxel is the first cytotoxic combination to improve survival over single-agent docetaxel in patients with anthracycline-pretreated metastatic breast cancer.
The maintenance of quality of life with the combination therapy further supports this regimen as the treatment of choice for patients with anthracycline-pretreated metastatic breast cancer. The combination treatment is also highly cost effective when compared with other cancer treatments that prolong survival. The important components contributing to the cost effectiveness of the combination therapy are a lower dose of docetaxel, lower hospitalization costs for adverse events, and superior survival compared with docetaxel alone.
The favorable results of the capecitabine/docetaxel trial support both the combination of capecitabine with other agents that upregulate TP and the use of capecitabine earlier as adjuvant therapy for breast cancer. Future trials evaluating the capecitabine/docetaxel combination will focus on different schedules of the two agents, such as administering weekly docetaxel along with capecitabine 950 mg/m2 twice daily for 14 days, to improve the safety profile of the combination while maintaining high efficacy. In addition, the National Cancer Institute U.S. Cooperative Groups are planning neoadjuvant and adjuvant phase III trials incorporating the combination of capecitabine and docetaxel, to elucidate the role of capecitabine in the treatment of breast cancer in years to come. The US Oncology 0162 trial, comparing AC followed by docetaxel with AC followed by capecitabine/docetaxel in node-positive and high-risk node-negative patients, has recently opened and is accruing rapidly.
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Received September 19, 2002;
accepted for publication October 30, 2002.
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