Cost-effectiveness of febrile neutropenia prevention with primary versus secondary G-CSF prophylaxis for adjuvant chemotherapy in breast cancer: a systematic review

The adoption of primary (PP) versus secondary prophylaxis (SP) of febrile neutropenia (FN), with granulocyte colony-stimulating factors (G-CSF), for adjuvant chemotherapy (AC) regimens in breast cancer (BC) could be affected by its “value for money”. This systematic review examined (i) cost-effectiveness of PP versus SP, (ii) FN threshold at which PP is cost-effective including the guidelines 20 % threshold and (iii) potential impact of G-CSF efficacy assumptions on outcomes. The systematic review identified all cost-effectiveness/cost-utility analyses (CEA/CUA) involving PP versus SP G-CSF for AC in BC that met predefined inclusion/exclusion criteria. Five relevant CEA/CUA were identified. These CEA/CUA examined different AC regimens (TAC = 2; FEC-D = 1; TC = 2) and G-CSF formulations (filgrastim “F” = 4; pegfilgrastim “P” = 4) with varying baseline FN—risk (range 22–32 %), mortality (range 1.4–6.0 %) and utility (range 0.33–0.47). The potential G-CSF benefit, including FN risk reduction with P versus F, varied among models. Overall, relative to SP, PP was not associated with good value for money, as per commonly utilized CE thresholds, at the baseline FN rates examined, including the consensus 20 % FN threshold, in most of these studies. The value for money associated with PP versus SP was primarily dependent on G-CSF benefit assumptions including reduced FN mortality and improved BC survival. PP G-CSF for FN prevention in BC patients undergoing AC may not be a cost-effective strategy at the guidelines 20 % FN threshold

Comparison between the disease-specific Airways Questionnaire 20 and the generic 15D instruments in COPD

<p>Abstract</p> <p>Background</p> <p>Given that the assessment of health-related quality of life (HRQoL) is an essential outcome measure to optimize chronic obstructive pulmonary disease (COPD) patient management, there is a need for a short and fast, reliable and valid instrument for routine use in clinical practice. The objective of this study was to analyse the relationship between the disease-specific Airways questionnaire (AQ20) and the generic 15D health-related quality of life (HRQoL) instrument simultaneously in a large cohort of patients with COPD. We also compare the HRQoL of COPD patients with that of the general population.</p> <p>Methods</p> <p>The AQ20 and 15D were administered to 739 COPD patients representing an unselected hospital-based COPD population. The completion rates and validity of, and correlations among the questions and dimension scores were examined. A factor analysis with varimax rotation was performed in order to find subsets of highly correlating items of the questionnaires.</p> <p>Results</p> <p>The summary scores of AQ20 and 15D were highly correlated (r = - 0.71, p < 0.01). In AQ20 over 50% of patients reported frequent cough, breathlessness during domestic work, and chest problem limiting their full enjoyment of life. 15D results showed a noteworthy decrease of HRQoL in breathing, mobility, sleeping, usual activities, discomfort and symptoms, vitality, and sexual activity (scores ≤ 0.75). Compared to the age- and gender-standardized Finnish general population, the COPD patients were statistically significantly worse off on 13 of 15 dimensions.</p> <p>Conclusions</p> <p>The AQ20 and 15D summary scores are comparable in terms of measuring HRQoL in COPD patients. The data support the validity of 15D to measure the quality of life in COPD. COPD compromises the HRQoL broadly, as reflected by the generic instrument. Both questionnaires are simple and short, and could easily be used in clinical practice with high completion rates.</p

Prophylaxis of chemotherapy-induced febrile neutropenia with granulocyte colony-stimulating factors: where are we now?

Updated international guidelines published in 2006 have broadened the scope for the use of granulocyte colony-stimulating factor (G-CSF) in supporting delivery of myelosuppressive chemotherapy. G-CSF prophylaxis is now recommended when the overall risk of febrile neutropenia (FN) due to regimen and individual patient factors is ≥20%, for supporting dose-dense and dose-intense chemotherapy and to help maintain dose density where dose reductions have been shown to compromise outcomes. Indeed, there is now a large body of evidence for the efficacy of G-CSFs in supporting dose-dense chemotherapy. Predictive tools that can help target those patients who are most at risk of FN are now becoming available. Recent analyses have shown that, by reducing the risk of FN and chemotherapy dose delays and reductions, G-CSF prophylaxis can potentially enhance survival benefits in patients receiving chemotherapy in curative settings. Accumulating data from ‘real-world’ clinical practice settings indicate that patients often receive abbreviated courses of daily G-CSF and consequently obtain a reduced level of FN protection. A single dose of PEGylated G-CSF (pegfilgrastim) may provide a more effective, as well as a more convenient, alternative to daily G-CSF. Prospective studies are needed to validate the importance of delivering the full dose intensity of standard chemotherapy regimens, with G-CSF support where appropriate, across a range of settings. These studies should also incorporate prospective evaluation of risk stratification for neutropenia and its complications

Phase-specific and lifetime costs of cancer care in Ontario, Canada

BACKGROUND: Cancer is a major public health issue and represents a significant economic burden to health care systems worldwide. The objective of this analysis was to estimate phase-specific, 5-year and lifetime net costs for the 21 most prevalent cancer sites, and remaining tumour sites combined, in Ontario, Canada. METHODS: We selected all adult patients diagnosed with a primary cancer between 1997 and 2007, with valid ICD-O site and histology codes, and who survived 30 days or more after diagnosis, from the Ontario Cancer Registry (N = 394,092). Patients were linked to treatment data from Cancer Care Ontario and administrative health care databases at the Institute for Clinical and Evaluative Sciences. Net costs (i.e., cost difference between patients and matched non-cancer control subjects) were estimated by phase of care and sex, and used to estimate 5-year and lifetime costs. RESULTS: Mean net costs of care (2009 CAD) were highest in the initial (6 months post-diagnosis) and terminal (12 months pre-death) phases, and lowest in the (3 months) pre-diagnosis and continuing phases of care. Phase-specific net costs were generally lowest for melanoma and highest for brain cancer. Mean 5-year net costs varied from less than $25,000 for melanoma, thyroid and testicular cancers to more than$60,000 for multiple myeloma and leukemia. Lifetime costs ranged from less than $55,000 for lung and liver cancers to over$110,000 for leukemia, multiple myeloma, lymphoma and breast cancer. CONCLUSIONS: Costs of cancer care are substantial and vary by cancer site, phase of care and time horizon analyzed. These cost estimates are valuable to decision makers to understand the economic burden of cancer care and may be useful inputs to researchers undertaking cancer-related economic evaluations

Dual TNFα-induced effects on NRF2 mediated antioxidant defence in astrocyte-rich cultures: role of protein kinase activation

Tumor necrosis factor-α (TNFα) is a pleiotropic molecule that can have both protective and detrimental effects in neurodegeneration. Here we have investigated the temporal effects of TNFα on the inducible Nrf2 system in astrocyte-rich cultures by determination of glutathione (GSH) levels, γglutamylcysteine ligase (γGCL) activity, the protein levels of Nrf2, Keap1, the catalytic and modulatory subunit of γGCL (γGCL-C and γGCL-M respectively). Astrocyte-rich cultures were exposed for 24 or 72 h to different concentrations of TNFα. Acute exposure (24 h) of astrocyte-rich cultures to 10 ng/mL of TNFα increased GSH, γGCL activity, the protein levels of γGCL-M, γGCL-C and Nrf2 in parallel with decreased levels of Keap1. Antioxidant responsive element (ARE)-mediated transcription was blocked by inhibitors of ERK1/2, JNK and Akt whereas inactivation of p38 and GSK3β further enhanced transcription. In contrast treatment with TNFα for 72 h decreased components of the Nrf2 system in parallel with an increase of Keap1. Stimulation of the Nrf2 system by tBHQ was intact after 24 h but blocked after 72 h treatment with TNFα. This down-regulation after 72 h correlated with activation of p38 MAPK and GSK3β, since inhibition of these signalling pathways reversed this effect. The upregulation of the Nrf2 system by TNFα (24 h treatment) protected the cells from oxidative stress through elevated γGCL activity whereas the down-regulation (72 h treatment) caused pronounced oxidative toxicity. One of the important implications of the results is that in a situation where Nrf2 is decreased, such as in Alzheimer’s disease, the effect of TNFα is detrimental.Fil: Correa, Fernando Gabriel. University Goteborg; Suecia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mallard, Carina. University Goteborg; SueciaFil: Nilsson, Michael. University Goteborg; SueciaFil: Sandberg, Mats. University Goteborg; Sueci

Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp

History of clinical transplantation

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations is surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipient had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts