Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer
Introduction
Anthracyclines are established as first-line chemotherapy for metastatic breast cancer, while in patients whose disease progresses following anthracycline-based therapy, the taxanes paclitaxel and docetaxel (alone or in combination with capecitabine) are the current ‘standard of care’. Recent years have seen a general shift towards the use of more aggressive therapy earlier in the course of breast cancer, including adjuvant anthracyclines in patients with primary, non-metastatic disease 1, 2. Combinations of anthracyclines and taxanes are also under evaluation, both as adjuvant/neoadjuvant therapy and as first-line therapy in metastatic disease 3, 4, 5. As a consequence, the number of patients whose disease is resistant or refractory to anthracyclines and taxanes, or who can no longer tolerate these agents, is increasing.
The treatment of anthracycline- and taxane-pretreated patients presents particular challenges for the oncologist. As cure is unlikely at this stage, treatment is primarily palliative. The goal of therapy is therefore to reduce tumour burden and related symptoms and, ultimately, prolong survival, while maintaining quality of life (QOL) by minimising toxicity. The oral fluoropyrimidine, capecitabine, is the only approved treatment for patients with anthracycline- and taxane-pretreated metastatic breast cancer. Capecitabine was rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumour tissue and enable chronic dosing that mimics continuous infusion 5-FU [6]. Following gastrointestinal absorption, capecitabine is metabolised to 5-FU by a three-step enzymatic process, the final step of which is catalysed by the enzyme thymidine phosphorylase. As thymidine phosphorylase activity is significantly higher in tumour compared with normal tissue, 5-FU is generated preferentially in tumour tissue following capecitabine therapy 6, 7. Furthermore, the oral administration of capecitabine is more convenient and enables home-based therapy, which is associated with a significantly improved QOL compared with hospital-based therapy in patients with advanced cancer [8]. Questionnaire-based studies have demonstrated that most patients, given the choice, prefer to receive oral rather than intravenous (i.v.) chemotherapy, provided efficacy is not sacrificed 9, 10.
Clinical trials show that capecitabine monotherapy is active and well tolerated in patients with taxane-pretreated metastatic breast cancer 11, 12, 13, 14, 15 and a promising first- and second-line therapy for metastatic breast cancer 16, 17. A large, phase Ill trial has demonstrated that capecitabine in combination with docetaxel results in significantly superior efficacy, including superior time to disease progression (TTP), response rates and overall survival, compared with single-agent docetaxel in patients with anthracycline-pretreated metastatic breast cancer [18]. Capecitabine plus docetaxel is the first cytotoxic combination to improve survival over standard docetaxel and the combination is approved for the treatment of anthracycline-pretreated metastatic breast cancer patients in the United States of America (USA) and Europe.
The approval of capecitabine monotherapy for the treatment of patients with anthracycline- and taxane-pretreated metastatic breast cancer was based on the results of a large, multicentre, phase II trial [11]. In this study, capecitabine achieved an overall response rate of 20% in 163 patients with paclitaxel-pretreated metastatic breast cancer, with disease stabilisation in a further 40% of patients. In addition to favourable response rates, median overall survival was 12.6 months. Importantly, overall survival was similar in patients with disease stabilisation or a tumour response (median 15.0 and 16.6 months, respectively), and much longer than in those with disease progression (median 5.3 months) [12]. These data confirm previous studies showing that disease stabilisation is a meaningful clinical outcome [19]. The safety profile of capecitabine was typical of infused 5-FU, with gastrointestinal side-effects and hand–foot syndrome the most commonly occurring adverse events. Grade 4 adverse events, myelosuppression and alopecia were particularly rare.
Subsequent studies have further demonstrated the high efficacy and favourable safety profile of capecitabine in anthracycline- and taxane-pretreated patients 13, 14, 15.
We report here, a phase II study conducted in 17 French centres to evaluate the efficacy and safety of capecitabine in this setting. In addition, this is the first study formally evaluating the impact of oral capecitabine monotherapy on QOL in patients with anthracycline- and taxane-pretreated metastatic breast cancer.
Section snippets
Patients and methods
Women aged 18–75 years with histologically-confirmed locally advanced or metastatic breast cancer and at least one measurable metastatic lesion were eligible for the study. Patients were required to have received either two or three prior chemotherapies, including an anthracycline and a taxane, and to have normal haematological, hepatic, renal and cardiological parameters, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and a life expectancy of at least 3 months. A minimum
Patient demographics
A total of 126 patients were recruited to the study and all received at least one cycle of capecitabine. Of these, only one patient did not have measurable or evaluable disease at the initial assessment. Patient demographics are summarised in Table 1. All but one patient (99%) had previously received at least one prior taxane-containing therapy and 96% had previously received an anthracycline.
Efficacy
Efficacy was evaluated in the intent-to-treat (ITT) population (n=126). The Kaplan–Meier curve for TTP,
Discussion
Prior to the introduction of capecitabine, there was no standard treatment for patients with metastatic breast cancer previously treated with both anthracycline- and taxane-based therapy. In this setting, patients require palliative therapy that offers a good prospect of tumour response and alleviation of tumour-related symptoms as well as prolongation of life, but with minimal toxicity and without substantial adverse impact on QOL.
The current study confirms previous findings that oral
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2022, Clinical Breast CancerCitation Excerpt :However, in a subgroup of patients with HER2-negative disease, OS appeared inferior with capecitabine compared with eribulin (13.5 and 15.9 months, respectively; HR 0.84; P=.03)99. In patients with anthracycline/taxane pretreated HR-positive/HER2-negative MBC, capecitabine monotherapy was primarily evaluated in non-randomized Phase II trials (Table 2)107–110; RRs and PFS were similar and toxicities predictable107,108. Additionally, a limited number of Phase III studies have incorporated capecitabine as the control arm in this patient population, reflecting it as a standard treatment in this setting111–116.
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