Methodological Challenges in Online Trials

Health care and health care services are increasingly being delivered over the Internet. There is a strong argument that interventions delivered online should also be evaluated online to maximize the trial’s external validity. Conducting a trial online can help reduce research costs and improve some aspects of internal validity. To date, there are relatively few trials of health interventions that have been conducted entirely online. In this paper we describe the major methodological issues that arise in trials (recruitment, randomization, fidelity of the intervention, retention, and data quality), consider how the online context affects these issues, and use our experience of one online trial evaluating an intervention to help hazardous drinkers drink less (DownYourDrink) to illustrate potential solutions. Further work is needed to develop online trial methodology.     

Neutrophil–lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival

Elevated neutrophil–lymphocyte ratio (NLR) may predict worse outcomes in cancer, including glioblastoma (GBM). This study assessed whether change in NLR during focal radiotherapy and concomitant temozolomide (RT-TMZ) provides further prognostic information. This was a retrospective review of patients treated with RT-TMZ for histologically confirmed GBM from January 2004 to September 2010. Variables assessed included age, ECOG performance status (PS), dexamethasone use and extent of surgery. Hematological results were collected at baseline, during and 4 weeks post RT-TMZ. Kaplan–Meier method was used to calculate overall survival (OS). Multivariable analysis (MVA) assessed for joint effect of covariates on OS and Pearson Correlation Coefficients assessed for association between dexamethasone dose and NLR change. With a median age of 55 (range 18–70), 369 patients were included. Median follow up was 15.1 month (range 1.6–134.6). The OS was 66.1% (95% CI 61.2–70.6) and 31.4 (95% CI 26.8–36.1) at 1 and 2 years, respectively. On univariate analysis, both decrease in NLR post RT-TMZ (HR 0.641, p?<?0.0001) and baseline NLR?<?7.5 (HR 0.628, p?<?0.0001) were associated with longer OS. On MVA decrease in NLR (HR 0.727, 95% CI 0.578–0.915), age (HR 1.025, 95% CI 1.012–1.038), baseline neutrophil (<8) (HR 0.689, 95% CI 0.532–0.891), total TMZ cycles (HR 0.89, 95% CI 0.867–0.913) and PS (HR 0.476, 95% CI 0.332–0.683) were independent predictors of OS. These findings suggest that a decrease in NLR during RT-TMZ, accounting for known prognostic factors, is an independent prognostic factor for survival in GBM.     

Immune checkpoint inhibitors: Navigating a new paradigm of treatment toxicities

Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune‐based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune‐based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management.     

A randomized phase II trial of veliparib,radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study

BackgroundTemozolomide offers minimal benefit in patients with glioblastoma with unmethylated O⁶-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.MethodsVERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.ResultsA total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.ConclusionThe veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.     

Development and implementation of a national quality improvement skills curriculum for urology residents in the United Kingdom: A prospective multi-method,multi-center study

Background

Surgical quality improvement (QI) is a global priority. We report the design and proof-of concept testing of a QI skills curriculum for urology residents.

Test–retest reliability of an online measure of past week alcohol consumption (the TOT-AL), and comparison with face-to-face interview

Objective

This paper reports on the development of a new online measure of beverage-specific past week alcohol consumption (the TOT-AL), its test–retest reliability, and comparability with the face-to-face approach of ascertaining alcohol intake.

Methods

University students participating in the reliability study completed the TOT-AL twice on the same day with at least 3 h apart. Students in the comparability study attended a face-to-face interview and completed the TOT-AL on the same day, in a randomised order, at least 3 h apart.

Results

There was a strong correlation between the repeated measurements of the TOT-AL (r = 0.99; 95% CI: 0.98, 0.99) and between the units calculated by the TOT-AL and the face-to face interview (r = 0.97; 95% CI: 0.95, 0.99). A high level of agreement between measurements was also observed in a Bland–Altman analysis.

Conclusions

The TOT-AL is a reliable, time efficient means of ascertaining alcohol intake, equivalent to that obtained face-to-face. These findings support the use of this approach to online alcohol assessment in populations with access to the Internet.     

The DYD-RCT protocol: an on-line randomised controlled trial of an interactive computer-based intervention compared with a standard information website to reduce alcohol consumption among hazardous drinkers

Background  

Excessive alcohol consumption is a significant public health problem throughout the world. Although there are a range of effective interventions to help heavy drinkers reduce their alcohol consumption, these have little proven population-level impact. Researchers internationally are looking at the potential of Internet interventions in this area.