Epirubicin--docetaxel combination in first-line chemotherapy for patients with metastatic breast cancer: final results of a dose-finding and efficacy study

The aim of the study was to define a regular and tolerable dose of the epirubicin-docetaxel combination in first-line chemotherapy of patients with metastatic breast cancer. Sixty-five women with measurable and/or evaluable disease were treated with epirubicin escalated from 60 to 110 mg/m(2) according to 5 dose levels, in combination with a fixed dose of 75 mg/m(2) docetaxel, every 21 days for 6 cycles, without preventive use of hematopoietic growth factors or antibiotics. Forty-three women received adjuvant chemotherapy, consisting of anthracyline- or anthracenedione-based regimens in 39 cases (60%). Twenty-seven women were treated in the phase I study (3 at epirubicin 60 mg/m(2), and 6 at each subsequent dose level). Dose-limiting toxicity consisted of grade III asthenia and febrile neutropenia (epirubicin 75 mg/m(2)), grade IV thrombopenia and grade III asthenia (epirubicin 90 mg/m(2)), grade IV stomatitis and grade III diarrhea (epirubicin 100 mg/m(2)), and grade III diarrhea (epirubicin 110 mg/m(2)). In the phase II study, an additional 38 women were treated at epirubicin 90 mg/m(2) and epirubicin 100 mg/m(2). During the 349 cycles delivered, grade IV neutropenia occurred in 90%; febrile neutropenia requiring hospitalization occurred in 62 (17.8%) and lasted more than 3 days in 12 (3.4%). Nonhematologic toxicity was acceptable. Three left ventricular ejection fraction depressions occurred and normalized during follow-up. The overall response rate in the 62 evaluable women was 69.4% (range: 58--81%), with a median duration of 7.8 months. After 26 months of follow-up, the median time to progression was 9.1 months and median overall survival was 22.7 months. On the basis of efficacy and toxicity, the recommended dose of the combination is epirubicin 100 mg/m(2) plus docetaxel 75 mg/m(2).     

Capecitabine with weekly paclitaxel for advanced breast cancer: a phase I dose-finding trial

OBJECTIVE: To determine the maximum tolerated dose (MTD), toxicity and activity of combined weekly paclitaxel and capecitabine in patients with metastatic breast cancer. METHODS: Sixteen patients with metastatic breast cancer, of whom 15 were evaluable for toxicity and response, were enrolled in 7 Swiss centers. Paclitaxel 80 mg/m2 was given intravenously on days 1, 8 and 15. Capecitabine was administered orally on days 1 through 14 using five different dose levels. Both drugs were given in a 21-day schedule. RESULTS: Capecitabine could be administered at doses commonly used for the drug as a single agent, i.e. 1,250 mg/m2 twice daily in combination with weekly paclitaxel. Hematological and other toxicities did not appear to be dose-limiting; however, significant skin and nail toxicities were observed. A response or stable disease was observed in 87% of patients [13/15; exact 95% confidence interval (CI) 60-98%], with 2 complete responses, 4 partial responses (overall response rate 40%, exact 95% CI 16-68%) and 7 patients with stable disease for at least 9 weeks. CONCLUSION: The phase I evaluation of capecitabine in combination with fixed-dose weekly paclitaxel did not allow the definition of an MTD of capecitabine based on the predefined criteria. Instead, the dose for the phase II evaluation was determined based on the occurrence of toxicity in later courses and on experience with other regimens containing capecitabine. Capecitabine (1,000 mg/m2 twice daily, days 1-14, every 3 weeks) with paclitaxel (80 mg/m2 weekly) is a promising combination for advanced breast cancer now being investigated in a phase II trial.     

Capecitabine monotherapy in patients with anthracycline-and taxane-pretreated metastatic breast cancer

The selection of chemotherapeutic regimens is challenging for metastatic breast cancer (MBC) patients whose diseases have failed to respond to anthracyline and taxane. Capecitabine has advantages of oral administration and favorable toxicity profiles. This study was conducted to evaluate the efficacy of capecitabine and to identify the subgroup of patients who would potentially have benefit from capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC. Female patients with MBC who had been previously treated with anthracycline and taxane received oral capecitabine 2500 mg/m² divided in two doses daily for 2 wk with 1-wk rest period. Between September, 1999, and December, 2002, a total of 38 patients were enrolled. Among the 36 evaluable patients, one patient achieved a complete response (CR), 9 patients had partial responses (PRs), and 13 patients had stable diseases (SDs). Response rate was 26% [95% confidence interval (CI), 12–40%] and the tumor control rate (TCR, CR+PR+SD) was 61% (95% CI, 45–77%). The median follow-up duration was 27.8 mo. The median duration of response was 8.9 mo, the median time to progression was 4.6 mo, and the median overall survival was 18.1 mo. The major toxicities were hand-foot syndrome, diarrhea, and emesis. There was no treatment-related death. The predictors of better overall survival were positivity of hormone receptor, disease-free survival longer than 1 yr, non-refractoriness to anthracycline, and fewer number (≤3) of involved organs. Capecitabine monotherapy is effective and well tolerated for MBC patients who had previously been treated with anthracycline and taxane. The TCR could predict overall survival as well as the objective respose in this study, suggesting a possible role of TCR as a surrogate marker for survival in MBC patients on salvage chemotherapy. The patients who have relatively slow growing tumor and less tumor burden could have benefit from capecitabine monotherapy following anthracycline- and taxane-based chemotherapy.     

Capecitabine maintenance therapy for XT chemotherapy-sensitive patients with metastatic triple-negative breast cancer

Objective： To investigate the efficacy and safety of capecitabine maintenance therapy（MT） after initial capecitabine plus docetaxel（XT） chemotherapy in patients with metastatic triple-negative breast cancer（m TNBC）.
Methods： Fifty-five m TNBC patients treated with XT chemotherapy between May 2007 and June 2013 were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, capecitabine was continued for 32 patients（MT）, while 23 patients remained without any treatment（nonMT）. We compared progression-free survival（PFS） and safety of both groups.
Results： The median PFS of 55 patients was 8.1 months, overall median PFS time of 32 patients in the capecitabine MT group and 23 in the non-MT group was 10.1 vs. 6.7 months（P=0.032）, respectively. When compared PFS time of maintenance treatment, single-agent capecitabine prolonged PFS by 7.1 months, for non-MT patients, the PFS without any treatment was 3.1 months, and this between-group difference was statistically significant（P=0.003）. Adverse events, including of hematologic toxicity, gastrointestinal toxicities, hand-foot syndrome and abnormal liver function were not significantly different between two groups.
Conclusions： After initial disease control was achieved with the XT combination chemotherapy, capecitabine MT can significantly prolong PFS time with a favorable safety profile in m TNBC patients.     

Capecitabine and vinorelbine in metastatic breast cancer

BackgroundAs anthracyclines and taxanes are frequently used in the adjuvant and first-line metastatic settings, capecitabine and vinorelbine are frequently used as monotherapy and in combination for metastatic breast cancer (MBC). In the absence of comparative, phase III data, retrospective analyses and cross-trial comparisons provide the only indication of the relative efficacy of these options.MethodsWe reviewed studies evaluating the 2 agents alone or in combination in MBC.ResultsWe identified 6 capecitabine and 2 vinorelbine phase III trials, numerous phase II monotherapy studies and 35 phase I/II studies exploring capecitabine–vinorelbine combination therapy (1 with trastuzumab in HER2-positive MBC).ConclusionFor monotherapy, the limited, retrospective comparative evidence supported by consistent prospective data suggests that capecitabine is more effective than vinorelbine. Comorbidities, organ function tolerability, tumour biology and patient characteristics should also inform treatment choice. If combination therapy is deemed clinically appropriate, intravenous vinorelbine with capecitabine may be considered, potentially improving efficacy compared with monotherapy, but at the cost of increased toxicity. Randomised evaluation versus capecitabine monotherapy is ongoing. In contrast, cross-trial comparison suggests that addition of oral vinorelbine to capecitabine adds haematological toxicity without apparently improving efficacy in pretreated MBC. Data from small, single-arm, phase II studies in the first-line setting are more encouraging. In summary, the strongest clinical data support capecitabine monotherapy in the majority of patients. In certain populations, a capecitabine–vinorelbine combination may be appropriate but requires further validation in randomised trials.     

Capecitabine monotherapy: safe and effective treatment for metastatic breast cancer

Optimal management for metastatic breast cancer frequently involves cytotoxic chemotherapy. Over the years, several complex multidrug regimens have been developed that were based upon a rationale of synergistic antitumor activity and nonoverlapping toxicities. However, recently the clinical value of these complex regimens has been called into question as several drugs used alone (monotherapy) or in sequence (serial single agent) have been shown to be both efficacious and better tolerated. Capecitabine (an orally administered fluoropyrimidine carbamate) is one such agent that has been proven to be effective when used alone for metastatic breast cancer, metastatic colorectal cancer, and adjuvant colon cancer. In this review, published (or reported in abstract form) data examining various aspects of clinical response and tolerability with single-agent capecitabine for (primarily) first- and second-line metastatic breast cancer are examined. For the most part, response rates are comparable with those of the more complex regimens. Dose reductions from the labeled dose of 1,250 mg/m(2) twice daily are relatively common. Toxicities (following dose reductions if needed) are generally manageable, even by more frail patients. Elderly patients are more likely to have impaired renal function or be receiving warfarin treatment, and special attention to these factors is warranted. Nonetheless, the drug administered alone is a reasonable choice when single-agent chemotherapy is entertained as a treatment option for metastatic breast cancer, including in the first-line setting.     

Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study

BackgroundBreast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood–tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy.MethodsStudy patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m²) 2–3 h before surgery or 2–5 doses of lapatinib (1250 mg) daily, the last dose 2–3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry.ResultsTwelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19–9.8) was noted for lapatinib BCBM-to-serum ratio.ConclusionsThis is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system.Trial registration ID: {"type":"clinical-trial","attrs":{"text":"NCT00795678","term_id":"NCT00795678"}}NCT00795678.     

Docetaxel in combination with 5-fluorouracil in patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy: a phase I, dose-finding study

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicity and recommended dose of docetaxel in combination with 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy. 32 patients received docetaxel at 60, 75, 85 or 100 mg/m(2) by 1-h intravenous (i.v.) infusion, followed, after a 1-h interval, by 5-FU at 250, 350, 500 or 750 mg/m(2)/day by continuous infusion over 5 days every 3 weeks. Dose-limiting stomatitis defined the maximum tolerated dose at a docetaxel dose of 100 mg/m(2) with 5-FU 750 mg/m(2)/day. None of 5 patients treated at the previous dose level (docetaxel 85 mg/m(2) with 5-FU 750 mg/m(2)/day) had a dose-limiting toxicity in the first cycle, and this was, therefore, considered the recommended dose. The combination was generally well tolerated. Grade 4 neutropenia was common (29 patients; 91%), but no patient experienced febrile neutropenia of duration >3 days requiring i.v. antibiotics. An objective response was achieved by 18 patients overall (56%), and in 4 out of 5 patients treated with the determined recommended dose. No pharmacokinetic interaction between docetaxel and 5-fluorouracil was apparent. The activity of docetaxel 85 mg/m(2) with 5-fluorouracil 750 mg/m(2)/day will be explored more extensively in phase II studies of patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy.     

Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m² on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m² on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m². Forty-six patients were enrolled and 45 received ≥1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.     

Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

Background

Eribulin is a nontaxane microtubule inhibitor with activity in patients with metastatic breast cancer (MBC). We conducted a phase I dose-finding study of eribulin and capecitabine in patients with MBC pretreated with anthracycline and taxane.

Methods

Women with MBC aged ≤70 years were enrolled. A 3 + 3 dose escalation design was used: level 0 dosing, eribulin (1.4 mg/m² intravenously on days 1 and 8) plus capecitabine [825 mg/m² orally twice daily (BID)]; 2-weeks-on, 1-week-off in a 21-day cycle. If there were no dose-limiting toxicities (DLTs), level 1 capecitabine dose was 1000 mg/m² BID. The primary objective was to determine maximum tolerated dose, DLTs, and recommended dose (RD). Secondary objectives included pharmacokinetics, safety, and best overall response rate.

Results

Nine women with MBC were enrolled; six at level 0, three at level 1. One patient had grade 4 DLTs at level 0 (serum creatinine 7.65 mg/dL and uric acid 13.4 mg/dL), considered associated with study drugs. Level 1 dosing was taken as the RD. Neutropenia was the most common ≥grade 3 toxicity. Pharmacokinetic parameters of eribulin were not influenced by co-administration of capecitabine. Of three patients in level 1, one achieved partial response and one had prolonged stable disease.

Conclusion

Eribulin with capecitabine in the level 1 dosing schedule was associated with manageable toxicities and promising clinical activity. This combination is recommended for phase II investigation.

     

Capecitabine plus docetaxel combination chemotherapy for metastatic breast cancer

Doxifluridine(5'-DFUR)is converted to its metabolite 5-FU by the enzyme thymidine phosphorylase(TP). TP is expressed significantly higher in tumor tissue than in normal tissue. Capecitabine(N4-pentoxylcarbonyl -5'-deoxy-5-fluorocytidine)is a pro-drug of 5'-DFUR and a novel fluoropyrimidine carbamate that is converted to 5-FU preferentially in tumor tissue through a three-step enzymatic cascade. Expression of TP in tumor tissue may clinically predict efficacy of capecitabine. Induction of TP activity has brought about enhancement of capecitabine efficacy by taxanes in human cancer xenografts. In addition, a phase III study directly comparison docetaxel monotherapy and docetaxel plus capecitabine has been conducted for metastatic breast cancer patients who had received anthracyclines. The overall response rate of the combination group was 42%(n=255), and that of the monotherapy group was 30%(n=256)(p=0.006). The primary endpoints were time to disease progression, and time to treatment failure, and these parameters were superior in the combination arm than in the single arm, suggesting that capecitabine sensitization by docetaxel might be a new approach to breast cancer treatment.     

Cyclophosphamide, methotrexate,5-fluorouracil, alternating with adriamycin and mitomycin C in metastatic breast cancer: a pilot study

To explore the clinical applicability of the Goldie and Coldman hypothesis, we treated 28 patients with metastatic breast cancer with alternating non-cross-resistant chemotherapy. The patients received cyclophosphamide, 600 mg/m2, 5-fluorouracil, 600 mg/m2, methotrexate, 40 mg/m2, alternated every three weeks with adriamycin, 60 mg/m2, and mitomycin C, 10 mg/m2. Only one patient had previously received palliative chemotherapy. Six patients had received adjuvant CMF, and 17 patients had been pretreated with endocrine therapy (13 for advanced disease, 4 as adjuvant). Fourteen patients had bone involvement, and 10 had visceral metastases. A mean of 12 cycles was given to 24 evaluable patients. The objective response rate was 67%: 11 patients (46%) achieved complete and 5 (21%) partial remission. Response rate in soft tissues was 83.3%, in bone 50%, in liver 100%, and in lung 80%. The median duration of response was 14 months, with 7 patients still in remission. No life-threatening toxicity was observed. Our preliminary results support the validity of this approach and the efficacy of this combination chemotherapy. A large-scale randomized study is warranted.     

Capecitabine and weekly paclitaxel as first-line therapy in Thai patients with metastatic breast cancer

Aim: The combination of a taxane and capecitabine offers synergistic antitumor activity. This study aimed to determine the efficacy and tolerability of a paclitaxel and capecitabine combination in Thai patients with metastatic breast cancer (MBC) not previously treated for metastatic disease. Methods: This open‐label, single‐center, non‐comparative phase II study was conducted between December 2006 and March 2009. In all 40 MBC patients were treated with oral capecitabine 1000 mg/m² twice daily on days 1 to 14, and weekly paclitaxel 80 mg/m² in a 3‐week cycle for a total of six cycles. Results: After a median follow up of 13.4 months, an overall objective response rate of 80%, with a partial response of 74% and a complete response of 5% were achieved. While 8% of patients achieved stable disease, 13% had progressive disease. Median time to progress was 8 months and median overall survival was 24.4 months. One patient discontinued because of hypersensitivity to paclitaxel. There was no grade 4 toxicity. Skin and nail toxicity was found in 75% of patients (with 25% in grade 2 or 3), followed by neutropenia (45% in all with 15% in grades 2 or 3), neuropathy (25% in total with 5% in grade 2) and stomatitis and diarrhea (in both of which 5% experienced grade 1 severity). Conclusion: A first‐line regimen of weekly paclitaxel plus capecitabine is effective and tolerable in Thai MBC patients.     

Intra-arterial chemotherapy in patients with breast cancer: a feasibility study.

The aim of this study was to assess the practicality of treating patients with various stages of breast cancer by means of regional (intra-arterial) chemotherapy. Three groups of patients received a median of four (range 2-4) cycles of combination chemotherapy: group I operable primary (n = 10); group II, locally advanced disease (n = 20); group III, recurrent locoregional disease (n = 22). The response rates (complete response, partial response and mixed response) in these groups of patients were 100% in groups I and II and 86% in group III. Morbidity included drug streaming and dysaesthesia in the hand. Patients in groups I and II had their tumours downstaged, allowing surgery to be performed. Local control was also achieved in group III when other treatment modalities had failed.     

Acupuncture care for breast cancer patients during chemotherapy: a feasibility study

Acupuncture care delivered pragmatically as an adjunct to conventional care may lead to improvements in quality of life and alleviation of conventional treatment-related side effects among breast cancer patients. Patient perceptions and expectations of treatment and the therapeutic relationship inherent to acupuncture care could modify treatment effects. The aim of this study was to design a rigorous feasibility study in preparation for trial to evaluate the effects of acupuncture care (a whole system) on the fatigue experienced by patients undergoing conventional treatment of their breast cancer. Phase 1 included the development of a treatment protocol for a short course of acupuncture care for patients with breast cancer undergoing chemotherapy. Defining best practice in this context will ensure that the intervention tested will have meaning and validity for all professional acupuncturists. Phase 2 will be a randomized feasibility pilot study using the acupuncture treatment protocol for 40 patients with breast cancer undergoing chemotherapy. The study will use a mixed-methods approach involving both qualitative and quantitative assessments. Outcome assessment will include validated measures for fatigue, quality of life, and depression. The proposed study will tell us what effects of acupuncture care are important to the patient and address acupuncture as it is practiced in the real world. Results from thisstudy will enable a definitive randomized controlled trial to evaluate the effectiveness of accupuncture care for fatigue in breast cancer patients undergoing chemotherapy.     

Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study.

PURPOSE: The goal of this multicenter, open-label phase II study was the clinical evaluation of combination therapy with the oral fluoropyrimidine capecitabine and the taxane paclitaxel in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-seven patients with MBC received oral capecitabine at 1650 mg/m(2)/d (825 mg/m(2) twice daily) on days 1 through 14, and intravenous infusion of paclitaxel at 175 mg/m(2) on day 1 of each 21-day treatment cycle. Treatment continued until disease progression, intolerable toxicity, or patient' s decision to discontinue. Patients (35 to 76 years old) had a median Karnofsky performance status of 90%. Forty-four patients (94%) received study treatment as first-line therapy for metastatic disease. RESULTS: Objective responses occurred in 24 (51%) patients; seven (15%) complete responses and 17 (36%) partial responses. Stable disease lasting 180 days or more was observed in nine (19%); the clinical response rate was 70%. Median duration of response was 12.6 months, median time to disease progression was 10.6 months, and median overall survival time was 29.9 months. The most common treatment-related adverse events, regardless of severity, were alopecia, hand-foot syndrome, nausea, and fatigue. Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only grade 3 or 4 treatment-related adverse events that occurred in more than 10% of patients. CONCLUSION: The combination of capecitabine plus paclitaxel is a highly active and generally well-tolerated regimen for first-line treatment of MBC.