37 research outputs found
Past continental shelf evolution increased Antarctic ice sheet sensitivity to climatic conditions
Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT
Background
The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve monthsâ trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority.
Objectives
To establish whether 6 monthsâ adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS).
Design
Phase III randomised, controlled, non-inferiority trial.
Setting
152 NHS Hospitals.
Participants
4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab.
Intervention
Randomisation (1:1) between six monthsâ or twelve monthsâ trastuzumab.
Main outcomes
Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model.
Results
Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-monthsâ trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96â1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-monthsâ trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-monthsâ trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p<0.0001). Health economic analysis showed significantly lower lifetime costs and similar lifetime QALYs, and thus a high probability that 6 months is cost-effective compared to 12 months. Patient reported experiences on the trial highlighted fatigue, and aches and pains most frequently.
Limitations
The type of chemotherapy and timing of trastuzumab changed through the recruitment phase of the study as standard practice altered.
Conclusions
PERSEPHONE demonstrated that in HER2-positive early breast cancer 6 monthsâ adjuvant trastuzumab was non-inferior to 12 months. There was significantly less cardiac toxicity and fewer severe adverse events with 6 monthsâ treatment.
Future work
On-going translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.
Trial registration
ISRCTN 52968807
Funding
National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98)
Urban water cycle and services ::an integrative perspective
The existing urban water cycles and services are crafted by the co-evolution over time and space of natural and anthropogenic systems. Those water-human systems interactions (e.g., water uses and related services) frame the different characteristics of supply and demand across the world. As a result of the preceding point, it is important to understand the relationship between competing uses, existing resources, and infrastructure requirements, as well as the subsequent variability in costs and prices, which becomes more complex in an urban context. The worldwide differences in water allocations and wastewater management tendencies, which depend to a large extent on climatic, topographical, and socioeconomic conditions, highlight the discrepancies in terms of inherent costs to achieve a sustainable water future and fulfil the sustainable development goals. To understand those differences, we present urban water worldwide trends, through key data sets, outlining water risk, sectoral characteristics (i.e., differences in water withdrawals), and water supply and sanitation access. In the end, an integrated view of managing the multiple water-related services seems desirable, highlighting a need for innovative governing, technical, and financing approaches
Methodology for inventorying greenhouse gas emissions from global cities
This paper describes the methodology and data used to determine greenhouse gas (GHG) emissions attributable to ten cities or city-regions: Los Angeles County, Denver City and County, Greater Toronto, New York City, Greater London, Geneva Canton, Greater Prague, Barcelona, Cape Town and Bangkok. Equations for determining emissions are developed for contributions from: electricity; heating and industrial fuels; ground transportation fuels; air and marine fuels; industrial processes; and waste. Gasoline consumption is estimated using three approaches: from local fuel sales; by scaling from regional fuel sales; and from counts of vehicle kilometres travelled. A simplified version of an intergovernmental panel on climate change (IPCC) method for estimating the GHG emissions from landfill waste is applied. Three measures of overall emissions are suggested: (i) actual emissions within the boundary of the city; (ii) single process emissions (from a life-cycle perspective) associated with the city's metabolism; and (iii) life-cycle emissions associated with the city's metabolism. The results and analysis of the study will be published in a second paper.Urban metabolism Life-cycle analysis Climate change
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Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT
Background
The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve monthsâ trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority.
Objectives
To establish whether 6 monthsâ adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS).
Design
Phase III randomised, controlled, non-inferiority trial.
Setting
152 NHS Hospitals.
Participants
4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab.
Intervention
Randomisation (1:1) between six monthsâ or twelve monthsâ trastuzumab.
Main outcomes
Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model.
Results
Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-monthsâ trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96â1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-monthsâ trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-monthsâ trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p<0.0001). Health economic analysis showed significantly lower lifetime costs and similar lifetime QALYs, and thus a high probability that 6 months is cost-effective compared to 12 months. Patient reported experiences on the trial highlighted fatigue, and aches and pains most frequently.
Limitations
The type of chemotherapy and timing of trastuzumab changed through the recruitment phase of the study as standard practice altered.
Conclusions
PERSEPHONE demonstrated that in HER2-positive early breast cancer 6 monthsâ adjuvant trastuzumab was non-inferior to 12 months. There was significantly less cardiac toxicity and fewer severe adverse events with 6 monthsâ treatment.
Future work
On-going translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.
Trial registration
ISRCTN 52968807
Funding
National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98)