Survival for oesophageal, stomach and small intestine cancers in Europe 1999-2007: Results from EUROCARE-5

Background: European regional variation in cancer survival was reported in the EUROCARE-4 study for patients diagnosed in 1995-1999. Relative survival (RS) estimates are here updated for patients diagnosed with cancer of the oesophagus, stomach and small intestine from 2000 to 2007. Trends in RS from 1999-2001 to 2005-2007 are presented to monitor and discuss improvements in patient survival in Europe. Materials and methods: EUROCARE-5 data from 29 countries (87 cancer registries) were used to investigate 1- and 5-year RS. Using registry-specific life-tables stratified by age, gender and calendar year, age-standardised 'complete analysis' RS estimates by country and region were calculated for Northern, Southern, Eastern and Central Europe, and for Ireland and United Kingdom (UK). Survival trends of patients in periods 1999-2001, 2002-2004 and 2005-2007 were investigated using the 'period' RS approach. We computed the 5-year RS conditional on surviving the first year (5-year conditional survival), as the ratio of age-standardised 5-year RS to 1-year RS. Results Oesophageal cancer 1- and 5-year RS (40% and 12%, respectively) remained poor in Europe. Patient survival was worst in Eastern (8%), Northern (11%) and Southern Europe (10%). Europe-wide, there was a 3% improvement in oesophageal cancer 5-year survival by 2005-2007, with Ireland and the UK (3%), and Central Europe (4%) showing large improvements. Europe-wide, stomach cancer 5-year RS was 25%. Ireland and UK (17%) and Eastern Europe (19%) had the poorest 5-year patient survival. Southern Europe had the best 5-year survival (30%), though only showing an improvement of 2% by 2005-2007. Small intestine cancer 5-year RS for Europe was 48%, with Central Europe having the best (54%), and Ireland and UK the poorest (37%). Five-year patient survival improvement for Europe was 8% by 2005-2007, with Central, Southern and Eastern Europe showing the greatest increases (≥9%). Conclusions Survival for these cancer sites, particularly oesophageal cancer, remains poor in Europe with wide variation. Further investigation into the wide variation, including analysis by histology and anatomical sub-site, will yield insights to better monitor and explain the improvements in survival observed over time.

Any versus long-term prescribing of high risk medications in older people using 2012 Beers Criteria: results from three cross-sectional samples of primary care records for 2003/4, 2007/8 and 2011/12

Background: High risk medications are commonly prescribed to older US patients. Currently, less is known about high risk medication prescribing in other Western Countries, including the UK. We measured trends and correlates of high risk medication prescribing in a subset of the older UK population (community/institutionalized) to inform harm minimization efforts. Methods: Three cross-sectional samples from primary care electronic clinical records (UK Clinical Practice Research Datalink, CPRD) in fiscal years 2003/04, 2007/08 and 2011/12 were taken. This yielded a sample of 13,900 people aged 65 years or over from 504 UK general practices. High risk medications were defined by 2012 Beers Criteria adapted for the UK. Using descriptive statistical methods and regression modelling, prevalence of ‘any’ (drugs prescribed at least once per year) and ‘long-term’ (drugs prescribed all quarters of year) high risk medication prescribing and correlates were determined. Results: While polypharmacy rates have risen sharply, high risk medication prevalence has remained stable across a decade. A third of older (65+) people are exposed to high risk medications, but only half of the total prevalence was long-term (any = 38.4 % [95 % CI: 36.3, 40.5]; long-term = 17.4 % [15.9, 19.9] in 2011/12). Long-term but not any high risk medication exposure was associated with older ages (85 years or over). Women and people with higher polypharmacy burden were at greater risk of exposure; lower socio-economic status was not associated. Ten drugs/drug classes accounted for most of high risk medication prescribing in 2011/12. Conclusions: High risk medication prescribing has not increased over time against a background of increasing polypharmacy in the UK. Half of patients receiving high risk medications do so for less than a year. Reducing or optimising the use of a limited number of drugs could dramatically reduce high risk medications in older people. Further research is needed to investigate why the oldest old and women are at greater risk. Interventions to reduce high risk medications may need to target shorter and long-term use separately.

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial

BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.

METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.

FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.

INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Sustained intraocular VEGF neutralization results in retinal neurodegeneration in the Ins2Akita diabetic mouse

Current therapies that target vascular endothelial growth factor (VEGF) have become a mainstream therapy for the management of diabetic macular oedema. The treatment involves monthly repeated intravitreal injections of VEGF inhibitors. VEGF is an important growth factor for many retinal cells, including different types of neurons. In this study, we investigated the adverse effect of multiple intravitreal anti-VEGF injections (200 ng/μl/eye anti-mouse VEGF164, once every 2 weeks totalling 5-6 injections) to retinal neurons in Ins2(Akita) diabetic mice. Funduscopic examination revealed the development of cotton wool spot-like lesions in anti-VEGF treated Ins2(Akita) mice after 5 injections. Histological investigation showed focal swellings of retinal nerve fibres with neurofilament disruption. Furthermore, anti-VEGF-treated Ins2(Akita) mice exhibited impaired electroretinographic responses, characterized by reduced scotopic a- and b-wave and oscillatory potentials. Immunofluorescent staining revealed impairment of photoreceptors, disruptions of synaptic structures and loss of amacrine and retinal ganglion cells in anti-VEGF treated Ins2(Akita) mice. Anti-VEGF-treated WT mice also presented mild amacrine and ganglion cell death, but no overt abnormalities in photoreceptors and synaptic structures. At the vascular level, exacerbated albumin leakage was observed in anti-VEGF injected diabetic mice. Our results suggest that sustained intraocular VEGF neutralization induces retinal neurodegeneration and vascular damage in the diabetic eye.

Survival of patients with skin melanoma in Europe increases further: Results of the EUROCARE-5 study

Background In Europe skin melanoma (SM) survival has increased over time. The aims were to evaluate recent trends and differences between countries and regions of Europe.

Methods Relative survival (RS) estimates and geographical comparisons were based on 241,485 patients aged 15 years and over with a diagnosis of invasive SM in Europe (2000-2007). Survival time trends during 1999-2007 were estimated using the period approach, for 213,101 patients. Age, gender, sub-sites and morphology subgroups were considered. 

Results In European patients, estimated 5-year RS was 83% (95% confidence interval, CI 83-84%). The highest values were found for patients resident in Northern (88%; 87-88%) and Central (88%; 87-88%) Europe, followed by Ireland and United Kingdom (UK) (86%; 85-86%) and Southern Europe (83%; 82-83%). The lowest survival was in Eastern Europe (74%; 74-75%). Within regions the intercountry absolute difference in percentage points of RS varied from 4% (North) to 34% (East). RS decreased markedly with patients' age and was higher in women than men. Differences according to SM morphology and skin sub-sites also emerged. Survival has slightly increased from 1999 to 2007, with a small improvement in Northern and the most pronounced improvement in Eastern Europe. 

Discussion SM survival is high and still increasing in European patients. The gap between Northern and Southern and especially Eastern European countries, although still present, diminished over time. Differences in stage distribution at diagnosis may explain most of the geographical differences. However, part of the improvement in survival may be attributed to overdiagnosis from early diagnosis practices.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Mode of prostate cancer detection is associated with the psychological wellbeing of survivors: results from the PiCTure study

Purpose: Many men with prostate cancer are asymptomatic, diagnosed following prostate specific antigen (PSA) testing. We investigate whether mode of detection, i.e. ‘PSA detected’ or ‘clinically detected’, was associated with psychological wellbeing among prostate cancer survivors. Methods: A cross-sectional postal questionnaire was administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors up to 18 years post-diagnosis, identified through population-based cancer registries in Ireland. Psychological wellbeing was assessed using the Depression Anxiety Stress Scale-21. Logistic regression was used to investigate associations between mode of detection and depression, anxiety and stress, adjusting for socio-demographic and clinical confounders. Results: The response rate was 54 % (3348/6262). Fifty-nine percent of survivors were diagnosed with asymptomatic PSA-tested disease. Prevalence of depression (13.8 vs 20.7 %; p < 0.001), anxiety (13.6 vs 20.9 %; p < 0.001) and stress (8.7 vs 13.8 %; p < 0.001) were significantly lower among survivors diagnosed with PSA-detected, than clinically detected disease. After adjusting for clinical and socio-demographic factors, survivors with clinically detected disease had significantly higher risk of depression (odds ratio (OR) = 1.46 95 % CI 1.18, 1.80; p = 0.001), anxiety (OR = 1.36 95 % CI 1.09, 1.68; p = 0.006) and stress (OR = 1.43 95 % CI 1.11, 1.85; p = 0.006) than survivors with PSA-detected disease. Conclusions: These findings contribute to the ongoing debate on benefits and risks of PSA testing and may be considered by policy makers formulating population-based prostate cancer screening policies. The relatively high prevalence of negative psychological states among survivors means that a ‘risk-adapted approach’ should be implemented to screen survivors most at risk of psychological morbidity for psychological health, and mode of detection could be considered as a risk stratum.

Effect of major lifestyle risk factors, independent and jointly, on life expectancy with and without cardiovascular disease: results from the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES)

Seldom have studies taken account of changes in lifestyle habits in the elderly, or investigated their impact on disease-free life expectancy (LE) and LE with cardiovascular disease (CVD). Using data on subjects aged 50+ years from three European cohorts (RCPH, ESTHER and Tromsø), we used multi-state Markov models to calculate the independent and joint effects of smoking, physical activity, obesity and alcohol consumption on LE with and without CVD. Men and women aged 50 years who have a favourable lifestyle (overweight but not obese, light/moderate drinker, non-smoker and participates in vigorous physical activity) lived between 7.4 (in Tromsø men) and 15.7 (in ESTHER women) years longer than those with an unfavourable lifestyle (overweight but not obese, light/moderate drinker, smoker and does not participate in physical activity). The greater part of the extra life years was in terms of "disease-free" years, though a healthy lifestyle was also associated with extra years lived after a CVD event. There are sizeable benefits to LE without CVD and also for survival after CVD onset when people favour a lifestyle characterized by salutary behaviours. Remaining a non-smoker yielded the greatest extra years in overall LE, when compared to the effects of routinely taking physical activity, being overweight but not obese, and drinking in moderation. The majority of the overall LE benefit is in disease free years. Therefore, it is important for policy makers and the public to know that prevention through maintaining a favourable lifestyle is "never too late".

Alcohol use and positive screening results for depression and anxiety are highly prevalent among chinese children with strabismus

Purpose: To study associations between strabismus and alcohol use, anxiety, and depression among 10- to 17-year-old children in Guangdong, southern China. Design: Cross-sectional, population-based study. Methods: Among 7537 children aged 6-17 years from 9 randomly selected primary and middle schools, ocular alignment was assessed with the Hirschberg light reflex, cover-uncover testing, and alternate cover testing at distance (6 m) and near (40 cm). Additionally, 4000 children (53.1%) aged 10+ years received self-administered questionnaires containing screening questions on alcohol use, anxiety, and depression. Results: Examinations were completed on 7464 of 7537 subjects (99.0%), including 3928 boys (52.6%), with a mean age of 11.1 ± 1.8 years. The prevalence of any strabismus, including exotropia (2.7%), esotropia (0.2%), and intermittent exotropia (3.9%), was 6.8%. Strabismus was more prevalent in urban students (7.3%) and female subjects (7.4%) compared to rural students (6.0%) and male subjects (6.2%) (all P <.05). In multivariate regression models, any strabismus was associated with older age and rural vs urban residence. Among 3903 children (97.6%) answering questionnaires, history of alcohol use (62.3% vs 36.3%) and positive screening responses for depression (26.0% vs 11.6%) and anxiety (10.3% vs 4.9%) were significantly (P <.01 for all) more common among children with strabismus. Conclusion: These Chinese children with strabismus had a significantly higher prevalence of alcohol use and possible markers of emotional problems than children without strabismus. Further research should focus on the appropriateness of classifying surgical treatment for strabismus as "cosmetic" (ineligible for reimbursement) under China's rural health insurance.