Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.

METHODS: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.

FINDINGS: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.

INTERPRETATION: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.

FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

O Papel dos Estilos Educativos Parentais na Sintomatologia Ansiosa de Adolescentes do 3º Ciclo do Ensino Básico

A literatura realça a importância do impacto do comportamento parental no desenvolvimento de ansiedade em crianças e adolescentes. Dado a pertinência do tema, o foco do presente estudo visa analisar o papel que a perceção dos adolescentes sobre os estilos educativos parentais tem sobre a manifestação de sintomatologia ansiosa. A amostra desta investigação envolveu 136 adolescentes do 3º ciclo do ensino básico, 48 rapazes e 88 raparigas com idades compreendidas entre os 12 e os 15 anos, com uma média de idades de 13,2 anos, recolhida no Colégio São Martinho em Coimbra. O protocolo de investigação incluiu os seguintes instrumentos de colheita de dados: Questionário Sociodemográfico, State-Trait Anxiety Inventory for Children (STAIC) e EMBU-A. Os resultados do estudo sugerem que os adolescentes mais velhos manifestam maior sintomatologia ansiosa, estatisticamente significativa ao nível da ansiedade-estado. No que respeita ao desempenho académico, são os adolescentes com elevado insucesso escolar que exteriorizam mais ansiedade-traço. Porém, não foram encontradas diferenças significativas na manifestação da ansiedade dos adolescentes em função das variáveis género, posição na fratria e habilitações literárias dos pais. Por seu lado, em relação aos estilos educativos parentais, os jovens que têm maior insucesso escolar percecionam níveis elevados de sobreproteção da mãe, e de rejeição do pai e da mãe. Os adolescentes que têm um pai com mais baixo nível de escolaridade percecionam maior rejeição materna, e são os filhos de mães com menos habilitações literárias que sentem maior sobreproteção da mãe e rejeição do pai. Verificou-se, em particular, uma associação significativa entre a rejeição paterna e níveis mais elevados de sintomatologia ansiosa. O modelo preditivo avançado no estudo confirma que a rejeição paterna, em conjunto com a idade do adolescente, são bons preditores da sintomatologia ansiosa. Especificamente, a rejeição paterna é evidenciada como o melhor preditor da sintomatologia ansiosa, sendo o principal responsável pela manifestação de ansiedade nos adolescentes. Os resultados sugerem que a rejeição do pai desencadeia níveis elevados de sintomatologia ansiosa. Assim, este estudo permite concluir que a rejeição paterna é o estilo educativo parental que exerce maior influência na manifestação de ansiedade nos adolescentes. / The literature highlights the importance of the impact of parental behavior on the development of anxiety in children and adolescents. Given the relevance of the topic, the focus of this study is to analyze the role that the adolescents’ perception about parental rearing styles have on the manifestation of anxiety symptoms. The sample of this research involved 136 adolescents from the 3rd cycle of basic education, 48 boys and 88 girls aged between 12 and 15 years, with a mean age of 13,2 years, gathered in Colégio São Martinho in Coimbra. The investigation protocol included the following data collection instruments: Sociodemographic Questionnaire, State-Trait Anxiety Inventory for Children (STAIC) and the EMBU-A. The results of the study suggest that older adolescents show greater anxiety symptoms, statistically significant at the level of state anxiety. With regard to academic performance, are adolescents with high failure rates that externalize more trait anxiety. However, there were significant differences in the manifestation of anxiety in adolescents function of the variables gender, sibling position and educational background of the parents. For its part, in relation to parental rearing styles, young people who have higher academic failure perceive high levels of overprotection of the mother, and rejection of father and mother. Adolescents who have a father with the lowest educational level perceive greater maternal rejection, and are the children of mothers with less qualification who feel greater overprotection of the mother and father's rejection. There was, in particular, a significant association between paternal rejection and higher levels of anxiety symptoms. The predictive model advanced in the study confirms that parental rejection, together with the adolescents’ age, are good predictors of anxiety symptoms. Specifically, parental rejection is evidenced as the best predictor of anxiety symptoms, being primarily responsible for the manifestation of anxiety in adolescents. The results suggest that the father rejection triggers high levels of anxiety symptoms. Thus, this study shows that rejection is the paternal parental rearing style that has more influence on the manifestation of anxiety in adolescents.

Omega-3 Fatty Acids are Related to Abnormal Emotion Processing in Adolescent Boys with Attention Deficit Hyperactivity Disorder

Background In addition to the core symptoms, attention deficit hyperactivity disorder (ADHD) is associated with poor emotion regulation. There is some evidence that children and young adults with ADHD have lower omega-3 levels and that supplementation with omega-3 can improve both ADHD and affective symptoms. We therefore investigated differences between ADHD and non-ADHD children in omega-3/6 fatty acid plasma levels and the relationship between those indices and emotion-elicited event-related potentials (ERPs). Methods Children/adolescents with (n=31) and without ADHD (n=32) were compared in their plasma omega-3/6 indices and corresponding ERPs during an emotion processing task. Results Children with ADHD had lower mean omega-3/6 and ERP abnormalities in emotion processing, independent of emotional valence relative to control children. ERP abnormalities were significantly associated with lower omega-3 levels in the ADHD group. Conclusions The findings reveal for the first time that lower omega-3 fatty acids are associated with impaired emotion processing in ADHD children.

Omega-3 Fatty Acids are Inversely Related to Callous and Unemotional Traits in Adolescent Boys with Attention Deficit Hyperactivity Disorder

A number of research studies have reported abnormal plasma fatty acid profiles in children with ADHD along with some benefit of n−3 to symptoms of ADHD. However, it is currently unclear whether (lower) long chain-polyunsaturated fatty acids (LC-PUFAs) are related to ADHD pathology or to associated behaviours. The aim of this study was to test whether (1) ADHD children have abnormal plasma LC-PUFA levels and (2) ADHD symptoms and associated behaviours are correlated with LC-PUFA levels. Seventy-two, male children with (n=29) and without a clinical diagnosis of ADHD (n=43) were compared in their plasma levels of LC-PUFA. Plasma DHA was higher in the control group prior to statistical correction. Callous–unemotional (CU) traits were found to be significantly negatively related to both eicosapentaenoic acid (EPA), and total omega-3 in the ADHD group. The findings unveil for the first time that CU and anti-social traits in ADHD are associated with lower omega-3 levels.