Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials

Background: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.
Methods: We undertook a meta-analysis of individual patient data for 10?801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.
Findings: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (=20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.
Interpretation: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.
Funding: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.

Exploring and comparing the experience and coping behaviour of men and women with colorectal cancer at diagnosis and during surgery

Aim. This paper is a report of a study exploring and comparing the experience of men and women with colorectal cancer at diagnosis and during surgery.

Background. Men have higher incidence and mortality rates for nearly all cancers and frequently use health behaviours that reflect their masculinity. There has been minimal investigation into the influence of gender on the experience of a ‘shared’ cancer.

Methods. From November 2006 to November 2008, a qualitative study was conducted involving 38 individuals (24 men, 14 women) with colorectal cancer. Data were generated using semi-structured interviews at four time points over an 18-month period. This paper reports the participants’ experience at diagnosis and during surgery (time point 1) with the purpose of examining the impact of gender on this experience.

Findings. In general, men appeared more accepting of their diagnosis. The majority of females seemed more emotional and more affected by the physical side effects. However, there was variation in both gender groups, with some men and women portraying both ‘masculine’ and ‘feminine’ traits. There was also individual variation in relation to context.

Conclusions. It appears that many men may have been experiencing side effects and/or psychological distress that they were reluctant to discuss, particularly as some men portrayed typical ‘masculine’ traits in public, but felt able to open up in private. Nurses should not make assumptions based on the traditional view of masculinity, and should determine how each man wants to deal with their diagnosis and not presume that all men need to ‘open up’ about their illness.

EURODIAB childhood type 1 diabetes incidence registers - results from the first 20 years. Oral presentation at the 47th EASD Annual Meeting, Lisbon, Portugal.

Background and aims: In 1989 a number of registers in Europe began recording new cases of type 1 diabetes diagnosed in children aged under 15 years using a common protocol. Trends in incidence rate during the 20 year period 1989-2008 are described.
Materials and methods: All registers operate in geographically defined regions and are based on a clinical diagnosis. When possible, completeness of registration in each register is assessed using capture-recapture methodology by identifying primary and secondary sources of ascertainment. The completeness estimate is obtained by identifying the numbers of cases identified by the primary source only, by the secondary source only and by both the primary and the secondary sources.
Results: Other registers have joined the Group since 1989, and 21 registers in 15 countries continue to submit registration data. In the first five years (1989-93) incidence rates varied from 3.2 per 100,000 in the Former Yugoslav Republic of Macedonia to 25.8 per 100,000 in the Stockholm area of Sweden. In the last five years (2004-2008) these same two registers again had the lowest and highest incidence, but rates had increased to 5.8 per 100,000 and 36.6 per 100,000, respectively. During the 20 year period all but two of the 21 registers showed statistically significant rates of increase (median rate of increase 4% per annum), and similar figures were obtained when this median rate of increase was estimated for the first half of the period (1989-98) and for the second half (1999-2008) . However, rates of increase differed significantly between the first half and the second half of the period for eight of the 17 registers with adequate coverage of both periods; four registers showing significantly higher rates of increase in the first half and four significantly higher rates in the second half.
Conclusion: The childhood type 1 diabetes incidence rate continues to rise across Europe by approximately 4% per annum, but the increase within a register is not necessarily uniform with periods of less rapid and more rapid increase in incidence occurring in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions are warranted.

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results: A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P <0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1lh for total clearance and 285l for volume of distribution, both allometrically modelled for a 70kg adult. Final estimates for absorption rate constant and bioavailability were 1.31h and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Human papillomavirus related head and neck cancer survival: A systematic review and meta-analysis

Human Papillomavirus (HPV) related oropharyngeal squamous cell carcinomas (OPSCCs) are reported to have improved prognosis and survival in comparison to other head and neck squamous cell cancers (HNSCCs). This systematic review and meta-analysis examines survival differences in HPV-positive HNSCC and OPSCC subtypes including tonsillar carcinoma in studies not previously investigated. Four electronic databases were searched from their inception till April 2011. A random effects meta-analysis was used to pool study estimates evaluating disease-specific (death from HNSCC), overall (all-cause mortality), progression-free and disease-free (recurrence free) survival outcomes in HPV-positive vs. HPV-negative HNSCCs. All statistical tests were two-sided. Forty-two studies were included. Patients with HPV-positive HNSCC had a 54% better overall survival compared to HPV-negative patients HR 0.46 (95% CI 0.37-0.57); the pooled HR for tonsillar cancer and OPSCC was 0.50 (95% CI 0.33-0.77) and HR 0.47 (95% CI 0.35-0.62) respectively. The pooled HR for disease specific survival was 0.28 (95% CI 0.19-0.40); similar effect sizes were found irrespective of the adjustment for confounders, HPV detection methods or study location. Both progression-free survival and disease-free survival were significantly improved in HPV-positive HNSCCs. HPV-positive HNSCCs and OPSCCs patients have a significantly lower disease specific mortality and are less likely to experience progression or recurrence of their cancer than HPV-negative patients; findings which have connotations for treatment selection in these patients.

Cytokine phenotype, genotype, and renal outcomes at cardiac surgery

Cardiac surgery modulates pro- and anti-inflammatory cytokine balance involving plasma tumour necrosis factor alpha (TNFa) and interleukin-10 (IL-10) together with urinary transforming growth factor beta-1 (TGFß1), interleukin-1 receptor antagonist (IL1ra) and tumour necrosis factor soluble receptor-2 (TNFsr2). Effects on post-operative renal function are unclear. We investigated if following cardiac surgery there is a relationship between cytokine (a) phenotype and renal outcome; (b) genotype and phenotype and (c) genotype and renal outcome. Since angiotensin-2 (AG2), modulates TGFß1 production, we determined whether angiotensin converting enzyme insertion/deletion (ACE I/D) genotype affects urinary TGFß1 phenotype as well as renal outcome.

The importance of solid-phase distribution on the oral bioaccessibility of Ni and Cr in soils overlying Palaeogene basalt lavas, Northern Ireland

Potentially toxic elements (PTEs) including nickel and chromium are often present in soils overlying basalt at concentrations above regulatory guidance values due to the presence of these elements in underlying geology. Oral bioaccessibility testing allows the risk posed by PTEs to human health to be assessed; however, bioaccessibility is controlled by factors including mineralogy, particle size, solid-phase speciation and encapsulation. X-ray diffraction was used to characterise the mineralogy of 12 soil samples overlying Palaeogene basalt lavas in Northern Ireland, and non-specific sequential extraction coupled with chemometric analysis was used to determine the distribution of elements amongst soil components in 3 of these samples. The data obtained were related to total concentration and oral bioaccessible concentration to determine whether a relationship exists between the overall concentrations of PTEs, their bioaccessibility and the soils mineralogy and geochemistry. Gastric phase bioaccessible fraction (BAF %) ranged from 0.4 to 5.4 % for chromium in soils overlying basalt and bioaccessible and total chromium concentrations are positively correlated. In contrast, the range of gastric phase BAF for nickel was greater (1.4–43.8 %), while no significant correlation was observed between bioaccessible and total nickel concentrations. However, nickel BAF was inversely correlated with total concentration. Solid-phase fractionation information showed that bioaccessible nickel was associated with calcium carbonate, aluminium oxide, iron oxide and clay-related components, while bioaccessible chromium was associated with clay-related components. This suggests that weathering significantly affects nickel bioaccessibility, but does not have the same effect on the bioaccessibility of chromium.