Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor

BACKGROUND: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. METHODS: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID). RESULTS: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles. CONCLUSIONS: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs

Diagnostic and therapeutic approaches for nonmetastatic breast cancer in Canada, and their associated costs

In an era of fiscal restraint, it is important to evaluate the resources required to diagnose and treat serious illnesses. As breast cancer is the major malignancy affecting Canadian women, Statistics Canada has analysed the resources required to manage this disease in Canada, and the associated costs. Here we report the cost of initial diagnosis and treatment of nonmetastatic breast cancer, including adjuvant therapies. Treatment algorithms for Stages I, II, and III of the disease were derived by age group (< 50 or ≥ 50 years old), principally from Canadian cancer registry data, supplemented, where necessary, by the results of surveys of Canadian oncologists. Data were obtained on breast cancer incidence by age, diagnostic work-up, stage at diagnosis, initial treatment, follow-up practice, duration of hospitalization and direct care costs. The direct health care costs associated with ‘standard’ diagnostic and therapeutic approaches were calculated for a cohort of 17 700 Canadian women diagnosed in 1995. Early stage (Stages I and II) breast cancer represented 87% of all incident cases, with 77% of cases occurring in women ≥ 50 years. Variations were noted in the rate of partial vs total mastectomy, according to stage and age group. Direct costs for diagnosis and initial treatment ranged from $8014 for Stage II women ≥ 50 years old, to$10 897 for Stage III women < 50 years old. Except for Stage III women < 50 years old, the largest expenditure was for hospitalization for surgery, followed by radiotherapy costs. Chemotherapy was the largest cost component for Stage III women < 50 years old. This report describes the cost of diagnosis and initial treatment of nonmetastatic breast cancer in Canada, assuming current practice patterns. A second report will describe the lifetime costs of treating all stages of breast cancer. These data will then be incorporated into Statistics Canada's Population Health Model (POHEM) to perform cost-effectiveness studies of new therapeutic interventions for breast cancer, such as the cost-effectiveness of day surgery, or of radiotherapy to all breast cancer patients undergoing breast surgery. © 1999 Cancer Research Campaig

A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m−2 by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1–9) per patient. The median cumulative dose was 449 mg m−2. Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1–50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4–52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h−1 m−2 and an area under the curve of 6.00 μg ml−1 h−1 was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance. © 1999 Cancer Research Campaig

Patient's needs and preferences in routine follow-up after treatment for breast cancer

The purpose of the study was to analyse the needs of women who participated in a routine follow-up programme after treatment for primary breast cancer. A cross-sectional survey was conducted using a postal questionnaire among women without any sign of relapse during the routine follow-up period. The questionnaire was sent 2-4 years after primary surgical treatment. Most important to patients was information on long-term effects of treatment and prognosis, discussion of prevention of breast cancer and hereditary factors and changes in the untreated breast. Patients preferred additional investigations (such as X-ray and blood tests) to be part of routine follow-up visits. Less satisfaction with interpersonal aspects and higher scores on the Hospital Anxiety and Depression Scale (HADS) scale were related to stronger preferences for additional investigation. Receiving adjuvant hormonal or radiotherapy was related to a preference for a more intensive follow-up schedule. There were no significant differences between patients treated with mastectomy compared to treated with breast-conserving therapy. During routine follow-up after a diagnosis of breast cancer, not all patients needed all types of information. When introducing alternative follow-up schedules, individual patients' information needs and preferences should be identified early and incorporated into the follow-up routine care, to target resources and maximise the likelihood that positive patient outcomes will result

Effects on quality of life of weekly docetaxel-based chemotherapy in patients with locally advanced or metastatic breast cancer: results of a single-centre randomized phase 3 trial

<p>Abstract</p> <p>Background</p> <p>To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer.</p> <p>Methods</p> <p>Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed.</p> <p>Results</p> <p>From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm.</p> <p>Conclusions</p> <p>In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00540800">NCT00540800</a>.</p

Predictors of Long-Term Care Utilization by Dutch Hospital Patients aged 65+

Background Long-term care is often associated with high health care expenditures. In the Netherlands, an ageing population will likely increase the demand for long-term care within the near future. The development of risk profiles will not only be useful for projecting future demand, but also for providing clues that may prevent or delay long-term care utilization. Here, we report our identification of predictors of long-term care utilization in a cohort of hospital patients aged 65+ following their discharge from hospital discharge and who, prior to hospital admission, were living at home. Methods The data were obtained from three national databases in the Netherlands: the national hospital discharge register, the long-term care expenses register and the population register. Multinomial logistic regression was applied to determine which variables were the best predictors of long-term care utilization. The model included demographic characteristics and several medical diagnoses. The outcome variables were discharge to home with no formal care (reference category), discharge to home with home care, admission to a nursing home and admission to a home for the elderly. Results The study cohort consisted of 262,439 hospitalized patients. A higher age, longer stay in the hospital and absence of

Tuning hardness in calcite by incorporation of amino acids

Structural biominerals are inorganic/organic composites that exhibit remarkable mechanical properties. However, the structure–property relationships of even the simplest building unit—mineral single crystals containing embedded macromolecules—remain poorly understood. Here, by means of a model biomineral made from calcite single crystals containing glycine (0–7 mol%) or aspartic acid (0–4 mol%), we elucidate the origin of the superior hardness of biogenic calcite. We analysed lattice distortions in these model crystals by using X-ray diffraction and molecular dynamics simulations, and by means of solid-state nuclear magnetic resonance show that the amino acids are incorporated as individual molecules. We also demonstrate that nanoindentation hardness increased with amino acid content, reaching values equivalent to their biogenic counterparts. A dislocation pinning model reveals that the enhanced hardness is determined by the force required to cut covalent bonds in the molecules

Panax ginseng Modulates Cytokines in Bone Marrow Toxicity and Myelopoiesis: Ginsenoside Rg1 Partially Supports Myelopoiesis

In this study, we have demonstrated that Korean Panax ginseng (KG) significantly enhances myelopoiesis in vitro and reconstitutes bone marrow after 5-flurouracil-induced (5FU) myelosuppression in mice. KG promoted total white blood cell, lymphocyte, neutrophil and platelet counts and improved body weight, spleen weight, and thymus weight. The number of CFU-GM in bone marrow cells of mice and serum levels of IL-3 and GM-CSF were significantly improved after KG treatment. KG induced significant c-Kit, SCF and IL-1 mRNA expression in spleen. Moreover, treatment with KG led to marked improvements in 5FU-induced histopathological changes in bone marrow and spleen, and partial suppression of thymus damage. The levels of IL-3 and GM-CSF in cultured bone marrow cells after 24 h stimulation with KG were considerably increased. The mechanism underlying promotion of myelopoiesis by KG was assessed by monitoring gene expression at two time-points of 4 and 8 h. Treatment with Rg1 (0.5, 1 and 1.5 µmol) specifically enhanced c-Kit, IL-6 and TNF-α mRNA expression in cultured bone marrow cells. Our results collectively suggest that the anti-myelotoxicity activity and promotion of myelopoiesis by KG are mediated through cytokines. Moreover, the ginsenoside, Rg1, supports the role of KG in myelopoiesis to some extent