Cost-effectiveness analysis of breast cancer adjuvant treatment: FEC 50 versus FEC 100 (FASG05 study).

BACKGROUND: The aim of the study was to assess the incremental cost-effectiveness ratio (ICER) of the FEC 100 compared with the FEC 50 in the FASG05 trial. MATERIALS AND METHODS: A cost-effectiveness analysis was performed using a multi-state Markov process model. Relevant clinical data introduced into the model were obtained from 10-year follow-up of the clinical trial FASG05. Survival curves for each health state were assessed by survival parametric model. The model allowed assessments from the start of adjuvant chemotherapy until death. The costs of adjuvant treatment and follow-up were estimated. The costs of recurrence were evaluated from the medical records of 146 patients. A prospective survey was performed on a cohort of 87 patients to quantify the resources external to the hospital (including cost of transportation). The inpatient costs were evaluated using the French diagnosis-related groups. The ambulatory costs were assessed using the French nomenclature. Costs were expressed in 2002 Euro (), according to the French societal perspective. The ICER assessed the cost of one additional life year saved. A discount rate of 5% per year was used for cost, and alternatively 0%, 3% and 5% for effectiveness. We validated the results with a probabilistic sensitivity analysis incorporating parametric and non-parametric bootstraps, and with the acceptability curves. RESULTS: The mean total discounting cost of adjuvant treatments was 11 465 for FEC 50 and 13 815 for FEC 100; the mean total discounting cost of recurrences was 14 636 and 13 503, respectively. According to the discount rate of effectiveness, the life expectancy was 16.5, 11.4 and 9.3 years for FEC 50 and 18.4, 12.5 and 10.2 years for FEC 100. The ICER (cost per life year saved) were 642, 1084 and 1460, respectively. The probability according to which FEC 50 is strictly dominated by FEC 100 was 0.15. CONCLUSION: The clinical benefit of FEC 100 generates a negligible cost increase when compared with FEC 50.     

Insulin binding by a cell line (HT 29) derived from human colonic cancer.

Insulin binding was demonstrated in cultured HT 29 cells originating from a human colon carcinoma. At 37 degrees and in complete medium, the binding of [125I]insulin (1-4x10-10M) reaches a maximum in 40 min and the cell associated radioactivity remains constant for at least 4 h. No degradation of the hormone is observed under these conditions. The binding is proportional to the number of cells and its pH optimum is 7.8. In the presence of excess insulin 50% of the [125I]insulin is dissociated from the complex after 10 min. At equilibrium, insulin binding is specific: proinsulin is 25 times less potent than native insulin in competing with [125I]insulin and related polypeptide hormones are inactive. Scatchard analysis indicates two classes of binding sites (1400 sites/cell of "high affinity" e.g. 4.7 x 108 M-1, and 20 000 sites of "low affinity" e.g. 4 x 107 M-1). The binding of insulin to this non-target cell shows the same kinetic characteristics and specificity as found for insulin in its target cells, except that HT 29 cells do not degrade the hormone. The problem of the correlation between insulin binding and a biological effect in these cells remains to be elucidated.     

Antiproliferative effects of the arotinoid Ro 40-8757 in human gastrointestinal and pancreatic cancer cell lines: combinations with 5-fluorouracil and interferon-alpha.

The arotinoid Ro 40-8757 was previously shown to inhibit the growth of a variety of human cancer cell lines derived from breast, lung and uterus. In view of the high incidence of human digestive cancers, and the slow progress in the development of new therapy, we examined in this paper several combinations between the new arotinoid Ro 40-8757, 5-fluorouracil (5FU) and interferon alpha-2a on the growth of nine human cancer cell lines derived from the gastrointestinal and pancreatic system. Half-maximal inhibition of cell proliferation by Ro 40-8757 was observed at concentrations ranging between 0.18 and 0.57 microM, and increased up to 4.7 microM in retinoid-resistant CAPAN 620 pancreatic cells. All-trans-retinoic acid was 70 times less potent. The sensitivity of HT29-5FU-resistant colonic cells was similar to that observed in the parental cells, suggesting an action independent of pyrimidine metabolism. Ro 40-8757 did not induce any differentiation on HT29 cells, as suggested by ultrastructural analysis. The arotinoid did not interact with receptor signal transduction pathways under the control of serum components, such as growth factors as half-maximal inhibiton of growth was similar in HT29-S-B6 cells cultured in the absence or presence of serum. Cell cycle analysis showed that Ro 40-8757 was not acting at a phase-specific transition in HT29 cells and, accordingly, did not induce overexpression of the protein kinase C (PKC)alpha isoform, or conversion of hyperphosphorylated p105 Rb into hypophosphorylated forms. However, the arotinoid induced significant accumulation of the dephosphorylated, active form of the tumour-suppressor protein. Combinations of Ro 40-8757 with 5FU and interferon alpha 2a resulted in an additive but not synergistic antiproliferative action in HT29 cells. Our data support the interest in Ro 40-8757 as a potent anti-cancer drug, especially in combination therapy with 5FU and interferon, in gastrointestinal and pancreatic cancers, where new active therapeutic modalities are urgently needed.     

Collaborative study for establishment of a global standard for the potency assay of human anti-D immunoglobulin

An international collaborative study aimed at establishing a global standard for the potency assay of anti-D immunoglobulin was started in 2002. 25 laboratories participated in this study run under the common aegis of the World Health Organization, the United States Food and Drug Administration (US-FDA) and the European Directorate for the Quality of Medicines (EDQM). The potencies of three candidate materials and the US-FDA standard (lot 3) included for comparison were evaluated using AutoAnalyzer, competitive enzyme-linked immunoassay (competitive EIA), flow cytometric methods or own "in-house" methods. Critical reagent, standardised procedures and standardised assay design were provided for either method, where appropriate. Central statistical evaluation of the potency data submitted by the participants was performed using a parallel line model. Agreement between laboratories and assay methods for all samples was observed. Intra-laboratory variability was lowest for laboratories performing flow cytometry and highest for laboratories that performed their in-house methods. Inter-laboratory variability was acceptable for all samples when assayed by AutoAnalyzer, competitive (EIA) and flow cytometric methods. It was concluded that sample A is most suitable to serve as a global standard and that sample C could serve as a reserve European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) batch provided that suitable stability is demonstrated. Sample A was adopted by the Ph. Eur. Commission at its 115th session (March 2003) as the first Ph. Eur. BRP (available from the EDQM: catalog number Y0000219) with the assigned potency of 285 IU/ampoule.     

Kallikrein gene downregulation in breast cancer

Recent evidence suggests that many members of the human kallikrein gene family are differentially regulated in breast cancer and other endocrine-related malignancies. In this study, we utilised the serial analysis of gene expression (SAGE) and expressed sequence tag (EST) databases of the Cancer Genome Anatomy Project (CGAP) to perform in silico analyses of the expression pattern of the 15 human kallikrein genes in normal and cancerous breast tissues and cell lines using different analytical tools such as Virtual Northern blotting, Digital Differential Display and X-profiler. Our results indicate that at least four kallikrein genes (KLK5, 6, 8, 10) are downregulated in breast cancer. Probing eight normal and 24 breast cancer SAGE libraries with gene-specific tags for each of the above kallikreins indicated moderate-to-high expression densities in normal breast (27-319 tags per million; tpm, in two to five out of eight libraries), compared to no or low expression (0 - 34 tpm in zero to two libraries out of 24) in breast cancer. These data were verified by screening the EST databases, where all mRNA clones isolated for these genes, except for one in each, were from normal breast libraries, with no clones detected from breast cancer tissues or cell lines (with the exception of KLK8). X-profiler comparison of two pools of normal and breast cancer libraries further verified the presence of significant downregulation of expression levels of 4 of the kallikreins genes (KLK5, 6, 10, 12). We experimentally verified the downregulation of these four kallikreins (KLK5, 6, 8, 10 and 12) by RT - PCR analysis.     

Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer

The purpose of the study was to evaluate the efficacy and safety of docetaxel plus epirubicin (ET) and of 5-fluorouracil plus epirubicin and cyclophosphamide (FEC) as first-line chemotherapy for metastatic breast cancer. A total of 142 patients (intent-to-treat (ITT)) with at least one measurable lesion were randomised to receive docetaxel 75 mg m(-2) plus epirubicin 75 mg m(-2) or 5-fluorouracil 500 mg m(-2) plus epirubicin 75 mg m(-2) and cyclophosphamide 500 mg m(-2) intravenously once every 3 weeks for up to eight cycles. Prophylactic granulocyte-colony-stimulating factor was only permitted after the first cycle, if required. Per-protocol analysis (n=132) gave an overall response rate for ET of 63.1% (95% confidence interval (CI), 50-78%) and for FEC 34.3% (95% CI, 23-47%) after a median seven and six cycles, respectively. Intent-to-treat population (n=142) gave an overall response rate for ET of 59% (95% CI, 47-70%) and for FEC 32% (95% CI, 21-43%) after a median seven and six cycles, respectively. The median response duration for ET was 8.6 months (95% CI, 7.2-9.6 months) and for FEC 7.8 months (95% CI, 6.5-10.4 months). The median time to progression (ITT) for ET was 7.8 months (95% CI, 5.8-9.6 months) and for FEC 5.9 months (95% CI, 4.6-7.8 months). After a median follow-up of 23.8 months, median survival (ITT) for ET and FEC were 34 and 28 months, respectively. Nonhaematologic grade 3-4 toxicities were infrequent in both arms. Haematologic toxicity was more common with ET and febrile neutropenia was reported in 13 patients (18.6%) in the ET group. Two deaths in the ET group were possibly related to study treatment. In conclusion, both ET and FEC were associated with acceptable toxicity. ET is a highly active first-line therapy for metastatic breast cancer.     

Cerebral processing in the minimally conscious state

We studied a patient in a minimally conscious state using PET and cognitive evoked potentials. Cerebral metabolism was below half of normal values. Auditory stimuli with emotional valence (infant cries and the patient's own name) induced a much more widespread activation than did meaningless noise; the activation pattern was comparable with that previously obtained in controls. Cognitive potentials showed preserved P300 responses to the patient's own name.