A randomised phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993).

One hundred and sixteen women with measurable metastatic breast cancer participated in a randomised phase II study of single agent liposomal pegylated doxorubicin (Caelyx) given either as a 60 mg/m2 every 6 weeks (ARM A) or 50 mg/m2 every 4 weeks (ARM B) schedule. Patients were over 65 years of age or, if younger, had refused or been unsuitable for standard anthracyclines. The aims of the study were to evaluate toxicity and dose delivery with the two schedules and obtain further information on the response rate of liposomal pegylated doxorubicin as a single agent in anthracycline nai ve advanced breast cancer. Twenty-six patients had received prior adjuvant chemotherapy (including an anthracycline in 10). Sixteen had received non-anthracycline-based first-line chemotherapy for advanced disease. One hundred and eleven patients were evaluable for toxicity and 106 for response. The delivered dose intensity (DI) was 9.8 mg/m2 (95% CI, 7.2-10.4) with 37 (69%) achieving a DI of >90% on ARM A and 11.9 mg/m2 (95% CI, 7.5-12.8) with 37 (65%) achieving a DI of >90% on ARM B. The adverse event profiles of the two schedules were distinctly different. Mucositis was more common with the every 6 weeks regimen (35% CTC grade 3/4 in ARM A, 14% in ARM B) but palmar plantar erythrodysesthesia (PPE) was more frequent with the every 4 weeks regimen (2% CTC grade 3/4 in ARM A, 16% in ARM B). Confirmed objective partial responses by RECIST criteria were seen with both schedules; 15/51 (29%) on ARM A and 17/56 (31%) on ARM B. Liposomal pegylated doxorubicin showed significant activity in advanced breast cancer with a generally favourable side-effect profile. The high frequency of stomatitis seen with 6 weekly treatment makes this the less preferred of the two schedules tested.

The impact of chemotherapy dose density and dose intensity on breast cancer outcome: what have we learned?

Optimising chemotherapy dose density and dose intensity are strategies aimed at improving outcomes in adjuvant therapy for patients with breast cancer. There are, in theory, at least five models allowing the delivery of a higher overall drug dose intensity. These are reviewed in this article and vary according to three main variables: the dose per course, the interval between doses and the total cumulative dose. Cyclophosphamide, anthracyclines and taxanes are among the most active agents for the treatment of breast cancer and, as such, they have been or are currently the focus of prospective, randomised clinical trials testing some of these dose-intensity models in the adjuvant setting. The results of recent trials suggest that anthracyclines, but not cyclophosphamide, are associated with better outcomes if used at higher doses per course and at higher cumulative doses. However, care has to be taken with premenopausal women where an increased dose of anthracycline per course but a reduced cumulative dose appears to produce a worse outcome. Moreover, decreasing the interval between doses, for anthracyclines and cyclophosphamide, does not seem to provide, so far, additional benefits for women with locally advanced breast cancer. This approach is not feasible with docetaxel, since an increase in dose density induces unwanted side-effects. These results represent our current state of knowledge, but clinical trials are being performed to evaluate further the effect of dose intensity, dose density and cumulative dose of key therapeutic agents on patient outcomes.

Investigation of the shape of the R(0) absorption line in ν3, N2O recorded from an axisymmetric supersonic free jet expansion

The hydrodynamic structure of an axisymmetric supersonic expansion can be regarded as a series of concentric divergent cones, with decreasing particle densities as the cone angle increases. Different groups of molecules therefore contribute to high-resolution absorption line shapes when optically probing the expansion in a direction perpendicular to the jet axis. These groups are distinguished by the cone angle, inducing a specific Doppler shift, and by the particle density, contributing a specific weight to the absorption intensity. As a result different broader line profiles are observed compared to room temperature spectra. This effect is investigated here selecting as the working example the R(0), ν3 absorption line in N2O recorded using a Fourier transform interferometer. Independent impact pressure and quadrupole mass spectrometric measurements are performed leading to two complementary maps of the expansion, allowing the recorded absorption line shape to be quantitatively modeled. © 2006 Elsevier Ltd. All rights reserved.

Cytokine and antibody profiles in 1-year-old children vaccinated with either acellular or whole-cell pertussis vaccine during infancy.

Two different types of pertussis vaccines are currently available to protect children against whooping cough, the first-generation whole-cell (Pw) vaccines and the more recent acellular (Pa) vaccines. Both types provide good protection, yet induce different types of immune responses in 6-month-old infants, with a strong Th1 response induced by Pw vaccines compared to a mixed Th1/Th2 response and a delay in non-specific IFN-gamma secretions after the administration of Pa vaccines. We show here that at 13 months of age, most Pw- or Pa-vaccinated children display Bordetella pertussis-specific T-cell responses, in addition to significant antibody levels, although a higher Th2/Th1 cytokine ratio remained in Pa recipients compared to Pw recipients. In contrast, the proportion of children with tetanus toxin-specific T-cell responses was lower in Pa than in Pw vaccine recipients, although most children had protective anti-tetanus toxin IgG levels. In addition, the global Th2 bias observed in 6-month-old infants vaccinated with a Pa vaccine was normalized at 13 months.