Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Staff Perceptions and Capability in using the Mental Capacity Act to Assess Decision Making in those with Acquired Brain Injury and Executive Dysfunction

AbstractThe purpose of this article is to establish the perceptions and capability of social care professionals (SCPs) in using the Mental Capacity Act (MCA) 2005 to assess decision-making capacity in those who have executive dysfunction and issues pertaining to the frontal lobe paradox, in comparison to health care professionals (HCPs). HCPs and SCPs from inpatient and community neurorehabilitation teams, social care teams and a best interest assessor team were contacted via convenience sampling and participated in semi-structured interviews. Data from these consultations were analysed using a form of thematic analysis known as template analysis. Four over-arching template themes were identified: ‘assessment structure’, ‘implications of brain injury’, ‘professionals’ capability/expertise’ and ‘consent, self-report and mental capacity’. The findings suggest that SCPs would benefit from bespoke practice guidance designed to help with the application of the MCA with the acquired brain injury/long-term neurological conditions population—particularly where there is a concern about a person’s ability to understand, apply or use information outside of an assessment or supportive conversation.</jats:p

Contributions and Shares in Business Companies

Background: Early childhood caries affects nearly half the population of Australian children aged 5 years and has the potential to negatively impact their growth and development. To address this issue, an Early Childhood Oral Health (ECOH) program, facilitated by Child and Family Health Nurses (CFHNs), commenced in 2007 in New South Wales, Australia. This study builds on the previous evaluation of the program. It aims to explore the perceptions of CFHNs regarding the implementation of the ECOH program in South Western Sydney and the challenges and barriers related to its sustainability. Methods: A descriptive qualitative design was used in this study. Two focus groups were conducted with 22 CFHNs who were sampled from two Community Health Centres in South Western Sydney, Australia. Data were transcribed verbatim and thematic analysis was undertaken. Results: Most CFHNs acknowledged the importance of early childhood oral health promotion and were providing education, oral assessments and referrals during child health checks. Many stressed the need for collaboration with other health professionals to help broaden the scope of the program. Some barriers to implementing the program included confusion regarding the correct referral process, limited feedback from dental services and the lack of oral health awareness among parents. Conclusion: The study findings suggest that the ECOH program is being sustained and effectively implemented into practice by CFHNs. Improvement in the referral and feedback process as well as enhancing parental knowledge of the importance of infant and child oral health could further strengthen the effectiveness of the program. Expanding oral health education opportunities into general practice is advocated, while regular on-line training for CFHNs is preferred. Future research should include strategies to reduce non-attendances, and an assessment of the impact on the prevalence of childhood caries of the ECOH program

Adeno-Associated Viral Gene Delivery of Wild-Type Human Tau Induces Progressive Hyperphosphorylation and Neuronal Cell Death in the Hippocampi of Middle-Aged Rats

Tau aggregation and the subsequent formation of neurofibrillary tangles are hallmarks of Alzheimer&rsquo;s disease (AD) and other dementias. While accumulation of tau aggregates is believed to contribute to cell death and neurodegeneration, tau aggregation and hyperphosphorylation are also correlated with cognitive impairment in AD. To understand the role of tau in neurodegeneration, we used adeno-associated virus serotype 9 (AAV9) to express human wild-type 4-repeat, 0-N-terminus tau isoform (AAV-htau) in the Cornu ammonis area 1 (CA1) region of the dorsal hippocampus of adult 6-month-old Fischer 344 rats. AAV expressing green fluorescent protein (AAV-GFP) or uninjected rats were used as controls. To characterize early phenotypes, we investigated pathological changes at 3, 8, and 12 weeks post-injection of AAV-htau. Our results show that at 3 weeks post-injection, there was already robust expression of human tau in the CA1 region of animals injected with AAV-htau compared to those injected with AAV-GFP or the uninjected controls. At 12 weeks post-injection, area CA1 showed a statistically significant reduction in cell number and a thinner neuronal layer all throughout the anterior dorsal hippocampus, as well as redistribution to the somatodendritic areas of CA1. We also found hyperphosphorylation of tau at all three timepoints. In spite of this pathology, we did not find any hippocampal-dependent cognitive impairment in rats overexpressing human tau. These results provide evidence of AAV-htau as a progressive model of tauopathy pathology to study changes in phosphorylation status and neuronal cell death that might precede cognitive impairment

Abstract P1-18-37: Treatment patterns and outcomes associated with sequential and non-sequential use of CDK4 and 6i for HR+, HER2- MBC in the real world

Abstract Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4 &amp; 6i) provide significant benefit for patients (pts) with HR+, HER2- MBC, however, clinical questions remain regarding the optimal sequence (seq) of treatments (tx). Prior analyses of real world (rw) abemaciclib indicate up to 50% of pts have had prior palbociclib or ribociclib for MBC and published studies regarding seq and non-seq tx outcomes have had limited sample sizes. To our knowledge, the current study represents the largest rw analysis of CDK4 &amp; 6i tx seq to date. Methods: US electronic medical records were retrospectively analyzed from the ConcertAI Oncology Dataset. Pts received abemaciclib and ≥ 1 other systemic tx line for HR+, HER2- MBC; the study period was 11/1995 (date of first MBC dx in dataset) to 10/2020 (end of follow-up). Tx sequences were identified and grouped to enable outcomes analyses. Data for 4 select groups (grp) are presented: grp 1 (1L CDK4 &amp; 6i to 2L CDK4 &amp; 6i), grp 2 (1L CDK4 &amp; 6i to 2L non-CDK4 &amp; 6i), grp 3 (2L CDK4 &amp; 6i to 3L CDK4 &amp; 6i), grp 4 (2L CDK4 &amp; 6i to 3L non- CDK4 &amp; 6i). Progression-free survival (PFS) from regimen start date to disease progression or death was analyzed by line using Kaplan-Meier method; pts were censored on the start date of the subsequent tx or end of follow-up if a progression event was not reported. Pts were characterized as having primary or secondary endocrine resistance per ESMO guidelines, if applicable. Pt characteristics at initiation of 1st CDK4 &amp; 6i and median PFS are summarized descriptively. Results: Of 690pts, the majority were white (n=555, 80%), had a median age of 61yrs (range 26-86) and were treated in community oncology practices (80%) in southern US (47%). Most pt characteristics between grp 1 vs grp 2 were not statistically different except for pts participating in clinical trials [grp 1 (n=3; 2%) vs grp 2 (n=12; 13%)]. Pts in grp 4 were younger than grp 3, with a median age of 60 and 67yrs, respectively (p&amp;lt;0.05). In the overall cohort, the most prevalent tx seq grp was 1L CDK4 &amp; 6i followed by 2L CDK4 &amp; 6i (n=165). There was significant treatment regimen heterogeneity across all grps, with the most frequent being 1L palbociclib/AI followed by 2L abemaciclib/fulvestrant received by 26 (16%) pts. Abemaciclib was prevalent in 1L (n=92; 13%), 2L (n= 204; 30%), 3L (n=122; 18%), ≥4L (n=344; 50%). Pts receiving seq CDK4 &amp; 6i experienced a substantial PFS benefit in the subsequent line (grp 1: 17mo; grp 3: 11mo), while pts in non-seq grps experienced a numerically lower PFS from the non-CDK4 &amp; 6i tx in the subsequent line (grp 2: 8mo; grp 4: 8mo). Median PFS for each grp is described in Table 1. Results of cox proportional hazards models will be presented. Conclusions: Seq CDK4 &amp; 6i appears to deliver substantial 2L PFS in pts who had a meaningful PFS on 1L CDK4 &amp; 6i. These results appear consistent for pts receiving 3L CDK4 &amp; 6i who had a meaningful PFS to 2L CDK4 &amp; 6i. While most pts received 1L CDK4 &amp; 6i to 2L CDK4 &amp; 6i, there was marked tx heterogeneity across all seqs in this predominantly community oncology sample, reinforcing the continued lack of consensus on this topic. While these results are hypothesis generating, these data serve as further rationale for additional prospective and retrospective studies evaluating the potential utilization and outcomes of CDK4 &amp; 6i, after progression on a previous CDK4 &amp; 6i. Table 1.Grp 11L CDK4 &amp; 6i to 2L CDK4 &amp; 6i n=165Grp 21L CDK4 &amp; 6ito 2L non-CDK4 &amp; 6i n=94Grp 32L CDK4 &amp; 6i to 3L CDK4 &amp; 6i n=115Grp 42L CDK4 &amp; 6i to 3L non-CDK4 &amp; 6i n=121Line 1No. of Events/Pts78/16572/94Median (m)18.459.8095% CI[15.0, 23.2][6.4, 14.2]Line 2No. of Events/Pts55/16540/9455/11587/121Median (m)17.308.3917.308.2995% CI[9.8, 33.4][5.9, 10.5][12.1, 21.0][6.2, 9.9]Line 3No. of Events/Pts46/11557/121Median (m)11.227.8695% CI[6.8, 14.0][5.5, 11.3] Citation Format: Kevin M Kalinsky, Megan Kruse, Emily Nash Smyth, Claudia M Guimaraes, Santosh Gautam, Alnecia R Nisbett, Maxine D Fisher, Zhanglin Lin Cui, Lee Bowman. Treatment patterns and outcomes associated with sequential and non-sequential use of CDK4 and 6i for HR+, HER2- MBC in the real world [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-37.</jats:p