Strategies to Improve Recruitment to a De-escalation Trial:a Mixed-methods Study of the OPTIMA Prelim Trial in Early Breast Cancer

Aims: De-escalation trials are challenging and sometimes may fail due to poor recruitment. The OPTIMA Prelim randomised controlled trial (ISRCTN42400492) randomised patients with early stage breast cancer to chemotherapy versus ‘test-directed’ chemotherapy, with a possible outcome of no chemotherapy, which could confer less treatment relative to routine practice. Despite encountering challenges, OPTIMA Prelim reached its recruitment target ahead of schedule. This study reports the root causes of recruitment challenges and the strategies used to successfully overcome them. Materials and methods: A mixed-methods recruitment intervention (QuinteT Recruitment Intervention) was used to investigate the recruitment difficulties and feedback findings to inform interventions and optimise ongoing recruitment. Quantitative site-level recruitment data, audio-recorded recruitment appointments (n = 46), qualitative interviews (n = 22) with trialists/recruiting staff (oncologists/nurses) and patient-facing documentation were analysed using descriptive, thematic and conversation analyses. Findings were triangulated to inform a ‘plan of action’ to optimise recruitment. Results: Despite best intentions, oncologists' routine practices complicated recruitment. Discomfort about deviating from the usual practice of recommending chemotherapy according to tumour clinicopathological features meant that not all eligible patients were approached. Audio-recorded recruitment appointments revealed how routine practices undermined recruitment. A tendency to justify chemotherapy provision before presenting the randomised controlled trial and subtly indicating that chemotherapy would be more/less beneficial undermined equipoise and made it difficult for patients to engage with OPTIMA Prelim. To tackle these challenges, individual and group recruiter feedback focussed on communication issues and vignettes of eligible patients were discussed to address discomforts around approaching patients. ‘Tips’ documents concerning structuring discussions and conveying equipoise were disseminated across sites, together with revisions to the Patient Information Sheet. Conclusions: This is the first study illuminating the tension between oncologists' routine practices and recruitment to de-escalation trials. Although time and resources are required, these challenges can be addressed through specific feedback and training as the trial is underway

OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer

Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk in hormone-sensitive HER2-negative node-negative early breast cancer, allowing patients with low risk to safely avoid chemotherapy. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) aims to validate MPA’s as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population

Scaling a waterfall: a meta-ethnography of adolescent progression through the stages of HIV care in sub-Saharan Africa.

INTRODUCTION: Observational studies have shown considerable attrition among adolescents living with HIV across the "cascade" of HIV care in sub-Saharan Africa, leading to higher mortality rates compared to HIV-infected adults or children. We synthesized evidence from qualitative studies on factors that promote or undermine engagement with HIV services among adolescents living with HIV in sub-Saharan Africa. METHODS: We systematically searched five databases for studies published between 2005 and 2016 that met pre-defined inclusion criteria. We used a meta-ethnographic approach to identify first, second and third order constructs from eligible studies, and applied a socio-ecological framework to situate our results across different levels of influence, and in relation to each stage of the HIV cascade. RESULTS AND DISCUSSION: We identified 3089 citations, of which 24 articles were eligible for inclusion. Of these, 17 were from Southern Africa while 11 were from Eastern Africa. 6 explored issues related to HIV testing, 11 explored treatment adherence, and 7 covered multiple stages of the cascade. Twelve third-order constructs emerged to explain adolescents' engagement in HIV care. Stigma was the most salient factor impeding adolescents' interactions with HIV care over the past decade. Self-efficacy to adapt to life with HIV and support from family or social networks were critical enablers supporting uptake and retention in HIV care and treatment programmes. Provision of adolescent-friendly services and health systems issues, such as the availability of efficient, confidential and comfortable services, were also reported to drive sustained care engagement. Individual-level factors, including past illness experiences, identifying mechanisms to manage pill-taking in social situations, financial (in)stability and the presence/absence of future aspirations also shaped adolescents HIV care engagement. CONCLUSIONS: Adolescents' initial and ongoing use of HIV care was frequently undermined by individual-level issues; although family, community and health systems factors played important roles. Interventions should prioritise addressing psychosocial issues among adolescents to promote individual-level engagement with HIV care, and ultimately reduce mortality. Further research should explore issues relating to care linkage and ART initiation in different settings, particularly as "test and treat" policies are scaled up

Variable water input controls evolution of the Lesser Antilles volcanic arc

Oceanic lithosphere carries volatiles, notably water, into the mantle through subduction at convergent plate boundaries. This subducted water exercises control on the production of magma, earthquakes, formation of continental crust and mineral resources. Identifying different potential fluid sources (sediments, crust and mantle lithosphere) and tracing fluids from their release to the surface has proved challenging1. Atlantic subduction zones are a valuable endmember when studying this deep water cycle because hydration in Atlantic lithosphere, produced by slow spreading, is expected to be highly non-uniform2. Here, as part of a multi-disciplinary project in the Lesser Antilles volcanic arc3, we studied boron trace element and isotopic fingerprints of melt inclusions. These reveal that serpentine—that is, hydrated mantle rather than crust or sediments—is a dominant supplier of subducted water to the central arc. This serpentine is most likely to reside in a set of major fracture zones subducted beneath the central arc over approximately the past ten million years. The current dehydration of these fracture zones coincides with the current locations of the highest rates of earthquakes and prominent low shear velocities, whereas the preceding history of dehydration is consistent with the locations of higher volcanic productivity and thicker arc crust. These combined geochemical and geophysical data indicate that the structure and hydration of the subducted plate are directly connected to the evolution of the arc and its associated seismic and volcanic hazards

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

INTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Triplet therapy with palbociclib, taselisib and fulvestrant in PIK3CA mutant breast cancer and doublet palbociclib and taselisib in pathway mutant solid cancers

Cyclin-dependent kinase-4/6 (CDK4/6) and phosphatidylinositol 3-kinase (PI3K) inhibitors synergise in PIK3CA mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA mutant, ER-positive HER2-negative was 37.5% (95% CI 18.8-59.4). Durable disease control was observed in PIK3CA mutant ER-negative breast cancer and other solid tumors, with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS) (HR 4.2, 95% CI 1.3-13.1, p=0.02). Early ctDNA dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR 5.2, 95% CI 1.4-19.4, p=0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy

The QuinteT Recruitment Intervention supported five randomized trials to recruit to target: a mixed-methods evaluation

ObjectiveTo evaluate the impact of the Quintet Recruitment Intervention (QRI) on recruitment in challenging randomized controlled trials (RCTs) that have applied the intervention. The QRI aims to understand recruitment difficulties, and then implements ‘QRI-actions’ to address these as recruitment proceeds.Study Design and SettingA mixed-methods study, comprising: a) before-and-after comparisons of recruitment rates and numbers of patients approached, and b) qualitative case studies, including documentary analysis and interviews with RCT investigators.ResultsFive UK-based publicly-funded RCTs were included in the evaluation. All recruited to target. RCT2 and RCT5 both received up-front pre-recruitment training before the intervention was applied. RCT2 did not encounter recruitment issues and recruited above target from its outset. Recruitment difficulties, particularly communication issues, were identified and addressed through QRI-actions in RCTs 1, 3, 4 and 5. Randomization rates significantly improved post-QRI-action in RCTs 1,3, and 4. QRI-actions addressed issues with approaching eligible patients in RCTs 3 and 5, which both saw significant increases in patients approached. Trial investigators reported that the QRI had unearthed issues they had been unaware of, and reportedly changed their practices post QRI-action.ConclusionThere is promising evidence to suggest the QRI can support recruitment to difficult RCTs. This needs to be substantiated with future controlled evaluations