Evaluation of biases present in the cohort multiple randomised controlled trial design: a simulation study

Background The cohort multiple randomised controlled trial (cmRCT) design provides an opportunity to incorporate the benefits of randomisation within clinical practice; thus reducing costs, integrating electronic healthcare records, and improving external validity. This study aims to address a key concern of the cmRCT design: refusal to treatment is only present in the intervention arm, and this may lead to bias and reduce statistical power. Methods We used simulation studies to assess the effect of this refusal, both random and related to event risk, on bias of the effect estimator and statistical power. A series of simulations were undertaken that represent a cmRCT trial with time-to-event endpoint. Intention-to-treat (ITT), per protocol (PP), and instrumental variable (IV) analysis methods, two stage predictor substitution and two stage residual inclusion, were compared for various refusal scenarios. Results We found the IV methods provide a less biased estimator for the causal effect when refusal is present in the intervention arm, with the two stage residual inclusion method performing best with regards to minimum bias and sufficient power. We demonstrate that sample sizes should be adapted based on expected and actual refusal rates in order to be sufficiently powered for IV analysis. Conclusion We recommend running both an IV and ITT analyses in an individually randomised cmRCT as it is expected that the effect size of interest, or the effect we would observe in clinical practice, would lie somewhere between that estimated with ITT and IV analyses. The optimum (in terms of bias and power) instrumental variable method was the two stage residual inclusion method. We recommend using adaptive power calculations, updating them as refusal rates are collected in the trial recruitment phase in order to be sufficiently powered for IV analysis

Improving Quality of Life in Rectal Cancer Patients : Development and Evaluation of a MRI-guided Radiation Boost Strategy

The 'cohort multiple Randomized Controlled Trial' design is an efficient and representative alternative to collect patient-reported outcomes and to evaluate experimental treatments in a routine care setting. It was implemented succesfully in a routine care rectal cancer setting and has resulted in satisfactory response rates to questionnaire and rates of patients randomized in trials. Since boost radiation can be used to increase the rate of pathological responses in rectal cancer patients undergoing chemoradiation, a new MRI-guided treatment was developed and is currently being evaluated using the cmRCT design in order to increase the percentage of patients that can proceed to organ-preserving treatment stratagies instead of radical surgery. Thereby, boost radiation aims to improve patients' qualty of life

Improving Quality of Life in Rectal Cancer Patients : Development and Evaluation of a MRI-guided Radiation Boost Strategy

The 'cohort multiple Randomized Controlled Trial' design is an efficient and representative alternative to collect patient-reported outcomes and to evaluate experimental treatments in a routine care setting. It was implemented succesfully in a routine care rectal cancer setting and has resulted in satisfactory response rates to questionnaire and rates of patients randomized in trials. Since boost radiation can be used to increase the rate of pathological responses in rectal cancer patients undergoing chemoradiation, a new MRI-guided treatment was developed and is currently being evaluated using the cmRCT design in order to increase the percentage of patients that can proceed to organ-preserving treatment stratagies instead of radical surgery. Thereby, boost radiation aims to improve patients' qualty of life

EXPRESSION OF THE VASOPRESSIN AND GASTRIN-RELEASING PEPTIDE GENES IN SMALL-CELL LUNG-CARCINOMA CELL-LINES

Various polypeptide hormones including vasopressin (VP) and gastrin-releasing peptide (GRP) are produced by small cell lung carcinomas (SCLC). VP as well as GRP have mitogenic effects on several cell types and are proposed to be autocrine growth factors. In this study the presence of VP mRNA, oxytocin (OT) mRNA and GRP mRNA was investigated in cell lines derived from SCLCs. Out of 26 cell lines 3 contained low amounts of VP mRNA (GLC-8, SCLC-21H and NCI-H345) and 7 contained abundant GRP mRNA (GLC-16, GLC-1-M13, SCLC-22H, NCI-H249, NCI-H345, NCI-H449 and NCI-H450). The GRP mRNA-containing cell lines belong to the classic SCLC type, whereas VP mRNA was found in two classic and one variant cell line. None of the SCLC cell lines contained detectable levels of OT mRNA. Of the three VP-expressing SCLC cell lines, GLC-8 had the highest level of VP mRNA. Both the length of the transcript and the hybridization with different probes containing exons A and C of the VP gene suggest that the detected transcript is a normal VP messenger. SCLC GLC-8 contained low levels of VP immunoreactivity and VP receptors. In GLC-8 an autocrine role of VP may be suspected