Pegylated liposomal doxorubicin (Caelyx®) and oral vinorelbine in first-line metastatic breast cancer patients previously treated with anthracyclines

Doxorubicin is highly effective and widely used in breast cancer; however, its use is limited by cardiotoxicity related to its cumulative dose. In previous studies, pegylated liposomal doxorubicin (PLD) has shown an acceptable toxicity profile with minimal cardiotoxicity. Between June 2006 and October 2009, 27 metastatic breast cancer patients were treated with first-line PLD and vinorelbine at the University of Florence, Radiotherapy Unit. PLD (30 mg/m2) was administered on day 1, and oral vinorelbine (60 mg/m2) was administered on days 1 and 8 of a 4-week cycle. All patients were previously treated with anthracycline-based adjuvant chemotherapy. Median age was 52 years (range 38-69) and median time to metastasis was 78.5 months. There were no treatment interruptions or discontinuation for cardiac toxicity and no treatment-related deaths. Grade 3 hematological toxicity was observed in 18.6% of patients, and 3.7% had grade 3 non-hematological adverse events. With a median follow-up of 13.2 months (range 3-33), median response duration was 6.1 months, and median PFS was 5.3 months. The overall clinical benefit rate was 55.5%. Our experience adds to evidence supporting the activity and cardiac safety of PLD and vinorelbine in metastatic breast cancer patients previously treated with anthracycline-based adjuvant chemotherapy.     

‘Tablet burden’ in patients with metastatic breast cancer

The implications for patients with cancer, of the ‘tablet burden’ resulting from increasing use of oral anticancer drugs and medication for co-morbidities have not previously been well explored.AimWe sought to (i) quantify tablet burden in women with metastatic breast cancer (MBC), (ii) establish which groups of drug contribute most to this burden and (iii) gain insight into patients' attitudes towards oral anti-cancer treatment.MethodsOne hundred patients with MBC anonymously completed a questionnaire describing their medication histories and attitudes towards their tablets.ResultsThe patients (mean age 60, range 31–95) were all female and taking a median of six tablets (range 0–31) daily; 37 patients were taking >10 tablets. Oral anticancer treatment constituted the category of treatment taken by the highest proportion of patients, followed by symptomatic cancer treatments, proton pump inhibitors and cardiovascular medication. Numerically, however, symptomatic drugs accounted for 44% of all tablets and specific anti-cancer treatment for 15%; medication not directly related to the cancer accounted for the remaining 40% of tablets. A quarter of patients reported inconvenience in taking their tablets, the main reason being tablet size and one third reported forgetting their tablets at least once a week. Nearly two thirds of patients expressing a preference favoured oral anticancer treatment, the commonest reason being greater convenience.ConclusionTablet burden is considerable for many patients with MBC and can be problematic. A significant proportion of tablets represent treatment for co-morbidities, the significance of which may be questionable in women with MBC.     

Weekly docetaxel (Taxotere?) in patients with metastatic breast cancer

Background:Docetaxel (Taxotere®) has demonstrated highantitumour activity in first- and second-line treatment of metastaticbreast cancer. This study analysed the efficacy and toxicity ofdocetaxel given weekly. Patients and methods:Thirty-five patients with metastatic breast cancer receiveddocetaxel, 35 mg/m² weekly for six weeks, followed by twoweeks without treatment. Additional cycles (three weekstreatment, two weeks rest) were given until disease progression.All patients had received prior chemotherapy: 32 and 5 patients hadreceived prior anthracycline-containing and taxane-containing regimens,respectively. Docetaxel was administered for a total of 359 doses(median 9, range 6–22). Results:There was onecomplete response (3%), 11 partial responses (31%), 17patients with stable disease (49%) and six with diseaseprogression (17%). Overall response rate was 34%(95% confidential interval (95% CI):18%–51%). Median survival was 307 days; medianprogression-free survival was 2.6 months (range 1.5 to 5.5 months).Three patients showed grade 3 neutropenia, 14 showed grade 3 alopecia,and various grade 1–2 non-haematological toxicities were observed.Treatment was delayed in two patients due to haematotoxicity, andstopped in one patient due to painful nail toxicity. Conclusion:Weekly administration of docetaxel at a dose of35 mg/m² is effective and of low toxicity in patients withmetastatic breast cancer.     

Biweekly vinorelbine and tegafur/uracil in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: GEICAM 2000–02 phase II study

Introduction

To assess the efficacy and safety profile of biweekly vinorelbine and tegafur/uracil (UFT) as treatment in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

Patients and methods

Patients with histologically confirmed breast cancer, measurable disease, no more than one prior chemotherapy regimen for metastatic disease, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate bone marrow, renal and liver function were eligible. Patients received vinorelbine (30 mg/m² on day 1) and UFT (250 mg/m² daily) every two weeks for 12 cycles unless progression or unacceptable toxicity was observed.

Results

Thirty-seven patients were included and received 311 cycles of chemotherapy. Efficacy and toxicity analyses were carried out on an intention-to-treat basis. The overall response rate was 35% (95% CI: 20–53). With a median follow-up of 18.6 months (95% CI: 1.0–74.3), the median time to progression was 7.0 months (96% CI: 5.2–8.9) and the median overall survival was 19.4 months (95% CI: 11.1–27.8). The most common severe toxicities were neutropenia (38% of patients) and asthenia (11% of patients).

Conclusion

The combination of biweekly vinorelbine and UFT in patients with metastatic breast cancer pretreated with anthracyclines and taxanes is a well tolerated and effective regimen. AEMPS Trial Registration No.: 00-0534.     

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

Background:

We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients.

Methods:

Consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan–Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy.

Results:

Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49–2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy.

Conclusion:

Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.     

Pharmacokinetics of 4′-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m₂ THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t_1/2), 3.15 min; terminal elimination half-life (t _1/2), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml^–1mg^–1m^–2, resulting in a mean plasma clearance of 86.91 h^–1m^–2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadrimycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r=0.800,P<0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.     

Presence of HER4 associates with increased sensitivity to Herceptin™ in patients with metastatic breast cancer

Introduction  

HER2 overexpression, or rather HER2 gene amplification, is indicative for Herceptin therapy in both metastatic and pre-metastatic breast cancer patients. Patient's individual sensitivity to Herceptin treatment, however, varies enormously and spans from effectual responsiveness over acquired insensitivity to complete resistance from the outset. Thus no predictive information can be deduced from HER2 determination so that molecular biomarkers indicative for Herceptin sensitivity or resistance need to be identified. Both ErbB receptor-dependent signalling molecules as well as HER2-related ErbB receptor tyrosine kinases, known to mutually interact and to cross-regulate each other are prime candidates to be involved in cellular susceptibility to Herceptin.     

Erythropoietin-stimulating agents and clinical outcomes in metastatic breast cancer patients with chemotherapy-induced anemia: a closed debate?

Erythropoietin-stimulating agents (ESAs) are used in breast cancer patients with chemotherapy-induced anemia to alleviate anemia and in turn, reduce fatigue. These drugs may also decrease overall survival and increase the incidence of serious adverse effects such as thrombovascular events (TVEs). This review evaluates the evidence to date on administering ESAs to breast cancer patients with chemotherapy-induced anemia. Our findings suggest a clear need for well-designed clinical trials that follow current Food and Drug Administration (FDA) ESA label changes to guide clinical practice in an effort to reduce harm to these patients.     

Dose-escalation phase I study in metastatic breast cancer patients with combination of paclitaxel and tegafur·uracil

The study present the results of the dose-setting study of concomitant weekly administration of paclitaxel and tegafur·uracil (UFT) for metastatic breast cancer. Eligible patients who entered the study underwent two or more courses of weekly paclitaxel + UFT therapy as the protocol therapy. The initial dose (level 1) was paclitaxel, 80 mg/m(2) and UFT, 400 mg/day. At level 2, paclitaxel remained the same, but UFT was increased to 600 mg/day. At level 3, only paclitaxel was increased to 90 mg/m(2). Twelve patients were enrolled in this study between September 2000 and September 2002. Three patients were assigned to level 1. Grade 3 liver dysfunction (increased aspartate aminotransferase and alanine aminotransferase) was noted in one patient and grade 4 neutropenia was noted in one patient, showing that dose-limiting toxicity was detected in 2/3 patients. In accordance with the protocol, UFT was fixed at 400 mg/day and paclitaxel was decreased to 60 mg/m(2) at level -1, and then increased to 70 mg/m(2) at level 0. The overall effective rate after completion of two courses was 33% (3/9) including one case of complete response and two cases of partial responses. The remaining patients presented with stable diseases and no patient had progressive disease. In this study, weekly paclitaxel with concomitant UFT was administered. The recommended doses of paclitaxel and UFT were determined to be 70 mg/m(2) and 400 mg/day, respectively. As the toxicity profile shows, the highest toxicity level of this regimen was neutropenia and liver dysfunction, and dose-limiting toxicity was neutropenia.     

Loco-regional treatment in metastatic breast cancer patients: Is there a survival benefit?

A number of studies have recently demonstrated a survival benefit in stage IV breast cancer patients following surgical resection of the primary tumor. Here, we investigate the relationship between loco-regional treatment and survival in patients with metastatic breast cancer and evaluate the impact of different loco-regional treatments. We conducted a systematic review of the literature using PubMed to analyze studies with the following criteria: Type of loco-regional treatment (surgery alone or combined with radiation, radiotherapy), overall survival, progression-free survival, selection factors for local treatment, and complication rates. Thirteen studies evaluated the effect of loco-regional treatment on overall survival with overall median survival increasing from a range of 12.6–28.3 months among patients without surgery to a range of 25–42 months among patients with surgery. In addition, six studies reported a 3-year survival benefit of 28–95% and 17–79% in women with and without loco-regional therapy respectively. Two studies did not find any improvement in overall survival. One study found an improvement in 5-year breast cancer-specific survival of 27% with negative surgical margins versus 12% with no surgery. Three studies reported an advantage in progression-free survival in the treatment group compared with the non-treatment group. Loco-regional treatment for breast cancer patients with distant metastases at diagnosis is an important issue because of possible improvement of survival or disease-free survival. The possibility of surgery and/or radiotherapy following induction chemotherapy should be weighed and left to individual practice. Participation in randomized controlled trials should be encouraged.     

Assessment of tumor response to chemotherapy in patients with breast cancer using ~（18）F-FLT： a meta-analysis

Purpose： To determine the diagnostic performance of 3＇-deoxy-3＇-18F-fluorothymidine positron emission tomography/computed tomography（FLT PET/CT） and FLT PET for evaluating response to chemotherapy in patients with breast cancer.
Methods： Databases such as Pub Med（MEDLINE included） and excerpta medica database（EMBASE）, were searched for relevant original articles. The included studies were assessed for methodological quality with quality assessment of diagnosis accuracy studies（QUADAS） score tool. Histopathological analysis and/or clinical and/or radiological follow-up for at least 6 months were used as the reference standard. The data were extracted by two reviewers independently to analyze the sensitivity, specificity, summary receiver operating characteristic（SROC） curve, area under the curve（AUC）, and heterogeneity.
Results： The present study analyzed a total of 4 selected articles. The pool sensitivity was 0.773 [95% confidence interval（CI）： 0.594-0.900]. The pooled specificity was 0.685（95% CI： 0.479-0.849） on basis of FEM. The pooled LR^＋, LR^-, and DOR were 2.874（1.492-5.538）, 0.293（0.146-0.589）, and 14.891（3.238-68.475）, respectively. The AUC was 0.8636（±0.0655）, and the Q＊ index was 0.7942（±0.0636）.
Conclusions： Our results indicate that 18^F-FLT PET/CT or PET is useful to predict chemotherapy response in breast cancer with reasonable sensitivity, specificity and DOR. However, future larger scale clinical trials will be needed to assess the regimen of 18^F-FLT PET/CT or PET in monitoring the response to chemotherapy in breast cancer patients.     

HER2. a 'predictive factor' ready to use in the daily management of breast cancer patients?

The past few years have witnessed an exponential increase in studies trying to identify molecular markers in patients with breast tumours that might predict for the success or failure of hormonal therapy or chemotherapy. HER2, a tyrosine kinase membrane receptor of the epidermal growth factor receptor family, has been the most widely studied marker in this respect. This paper attempts to critically review to what extent HER2 may improve 'treatment individualisation' for the breast cancer patient.     

Correlation of Fcγ receptors on peripheral blood mononuclear cells and survival in patients with metastatic breast cancer

Summary Patients with carcinomas have elevated levels of Fc receptors for IgG (FcR) on their peripheral blood mononuclear cells (PBMC). The purpose of the present study was to determine whether there is a correlation between FcR levels on PBMC and survival in patients with metastatic breast cancer. Binding assays were performed on PBMC using¹²⁵I-labeled fibrinogen complexed with rabbit IgG (or as a control F(ab)₂) anti-human fibrinogen. Twenty-two metastatic breast cancer patients had significantly (p<0.001) elevated FcR levels as compared to either 22 breast cancer patients receiving adjuvant chemotherapy following mastectomy without clinical evidence of tumor, or to 34 non-malignant controls. Significantly more metastatic patients with elevated FcR levels died at 6 months (p<0.001) as compared to those with low levels. A direct correlation between FcR levels and hazard probability was found (correlation coefficient = 0.3321, p<0.005). These results raise the possibility that FcR levels on PMBC from metastatic breast cancer patients may be clinically useful as a prognostic marker of disease activity.     

Pegylated liposomal doxorubicin in combination with gemcitabine: a phase II study in anthracycline-naïve and anthracycline pretreated metastatic breast cancer patients

Background: The aim of the study was to assess the toxicity profile, activity in terms of response rate, time to progression, overall survival, and quality of life of pegylated liposomal doxorubicin (PLD) and gemcitabine combination in chemo-naïve and pretreated metastatic breast cancer (MBC) women. Methods: Patients were eligible if they had disease progression to prior chemotherapy (anthracycline-including or not) for early breast cancer or MBC. Patients received PLD 25 mg/m² intravenously on day 1 plus gemcitabine 800 mg/m² intravenously on days 1 and 8 of each 21-day cycle. Results: Of 50 patients enrolled, 37 had received prior adjuvant chemotherapy (24 with an anthracycline) and 23 prior chemotherapy for metastatic disease (6 with an anthracycline). Two complete responses and 20 partial responses were achieved in 46 assessable patients (overall response rate: 47.8%). Responses were observed in 14 (46.6%) of 30 patients with previous anthracycline exposure. Median response duration was 7 months, median duration of clinical benefit 8 months, time to progression 7 months. At a median follow-up of 10 months, 79.4% patients were alive at 1 year. No neutropenic complication was observed. Non-hematological toxicities were mild. One patient previously treated with an anthracycline developed a transient decrease (26%) in the left ventricular ejection fraction, with cardiac function recovering within 6 months. Conclusion: Because of the non-overlapping toxicity profiles of both PLD and gemcitabine, this combination can be regarded as a reliable therapeutic option for patients who have failed previous treatments, including anthracycline, for MBC.     

Treatment of advanced breast cancer with a metronomic schedule of oral vinorelbine: what is the opinion of Italian oncologists?

Background: The aim of this study was to record the opinions of Italian oncologists about the use of oral vinorelbine administered metronomically in patients with advanced breast cancer.

Methods: A series of meetings were held throughout Italy, and participants were asked how much they agreed with each of the several statements.

Results: The majority of oncologists agreed that the concept of the minimum biologically effective dose should be used for drugs administered metronomically. Over 50% agreed that metronomic vinorelbine is an option in first-line chemotherapy for patients with advanced breast cancer, including those with a terminal illness and the elderly, as well as in young and fit patients. Just over one-third of experts agreed that a combination of two chemotherapy agents instead of one is not desirable in metastatic breast cancer because of increased toxicity. Most experts agreed that the main aim of a first-line therapy is to control the disease over time and to preserve quality of life.

Conclusion: Metronomically administered oral vinorelbine, either as monotherapy or in combination with other drugs, is effective in the long-term treatment of patients with advanced breast cancer. The clinical profiles of patients should be carefully considered to determine the appropriate treatment strategy.     

Carboplatin activity in untreated metastatic breast cancer patients — results of a phase II study

Summary Due to the favourable results previously obtained with cisplatin in breast cancer (54%_response rate), we studied a second-generation platinum analogue, carboplatin, in patients with previously untreated breast cancer. A total of 20 patients were entered in the study and all were evaluable. The median age was 57 years and all patients were in menopause. Karnofsky scores of 80–100 and 40–70 were registered in 14 and 6 cases, respectively. The predominant metastatic site was soft tissue in 12 subjects, visceral organs in 5 and bone in 3; 14 patients had >2 metastatic sites. Carboplatin was given i. v. at a dose of 400 mg/m² on day 1, with a 3-week rest period. In 13 patients who did not respond or whose disease recurred after carboplatin treatment, the CMFVP, CAP or FAC regimen was given as second line treatment. Carboplatin activity was observed in 4 patients [2 complete remissions (CRs) and 2 partial responses (PRs)], for a response rate of 20% (4/20); the 2 PRs were observed in soft tissue and bone and the 2 CRs, in lung, liver and bone. Remission lasted 2–10 months ( , 4 months). CMFVP given as second-line chemotherapy to 13 patients produced 7 PRs (7/13, 54%). Toxicity was moderate, producing no drugrelated deaths. Anemia (grade I–II) was recorded in seven patients; grade I–II leukopenia, in six; and grade III–IV leukopenia in two (median leukocyte nadir, 1,600/mm³). Thrombocytopenia was observed in three cases (grades I, II and III; median platelet nadir, 47,800/mm³). Unpleasant nausca/vomiting was pronouced (12 cases of grade III–IV) in 19 subjects. There were no cases of neuro- or nephrotoxicity. Due to permanent myelosuppression, no more than five cycles could be given. Our study showed that, unlike cisplatin, carboplatin given at a dose of 400 mg/m² has low antitumorigenic activity in breast cancer patients and produces pronounced myelotoxicity. Additional first-line chemotherapy studies using carboplatin are needed to define the antitumorigenic activity of this platinum analogueAbbreviations CMFVP cyclophosphamide, methotrexate, fluorouracil, vincrisine, prednisolone - CAP cyclophosphamide, Adriamycin, platinum - FAC fluorouracil, Adriamycin, cyclophosphamide     

Fulvestrant 500 mg in postmenopausal patients with metastatic breast cancer: the initial clinical experience

Background

Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies.

Methods

A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated.

Results

Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms.

Conclusions

Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.