The frequency of assessment of progression in randomized oncology clinical trials

Abstract

Background: Progression in tumor assessments is often detected at a follow-up appointment rather than when actual change in progression has occurred, which can bias PFS outcomes.Aim: We sought to evaluate the frequency of tumor assessment scans in clinical trials of anti-cancer interventions and to compare this to recommended (National Comprehensive Cancer Network) and real-world frequencies of tumor assessments.Methods: In a cross-sectional analysis, we searched for articles published in the three top oncology journals between July 2017 and June 2020. We included articles that were RCTs of patients that had unresectable or metastatic solid tumors and used an intervention that was designed to be anti-tumor. We abstracted median PFS survival for each group, the PFS hazard ratio, frequency of tumor assessment scans, tumor type, intervention type, and information regarding the study.Results: We found that, in the 182 comparisons (163 articles), less frequent tumor assessment (occurring more than 9 weeks between assessments) was associated with higher median PFS values for both the intervention group (p < .0001) and the control group (p < .0001). PFS hazard ratios for studies scanning for tumors every 10 or more weeks were no different than for studies scanning for tumors more frequently (p = .88). Data on the frequency of tumor assessments in the real world is sparse. Conclusion:We found that less frequent tumor assessment frequency was associated with longer median PFS in both intervention and control groups of clinical oncology trials but was not associated with differences in PFS hazard ratios. Future research is needed to compare real world to trial assessment.clinical trial, progression, tumor assessment 1 | BACKGROUND Progression-free survival (PFS) is one of the most common primary endpoints in oncology clinical trials, 1 and is a composite of death or tumor growth after treatment. Because the measurement of PFS primarily relies on tumor assessment, it can be biased by variables such as the timing and methodology of tumor assessment. As such, the increasing use of PFS in place of other well-established outcomes, such as overall survival, in oncology trials should rely on measurements with minimal bias and consistent protocols.

A seamless phase II/III design with dose optimization for oncology drug development

“…We propose ORR as the surrogate endpoint for the interim analysis (dose optimization and preliminary efficacy evaluations) because it matures quicker (eg, two or three tumor assessments with median scan frequency of every 8 weeks 53 ) than time‐to‐event endpoints such as PFS and OS, and had been accepted in many cases for accelerated approvals depending on the context of use 29 . Slight modifications of the SDDO framework would allow the use of PFS for such decision‐making (especially, when PFS is a better predictor of OS than ORR).…”

Data Challenges for Externally Controlled Trials: Viewpoint

“…In this example, simple reporting standardization of study follow-up, including in general practice, was found to be influential in outcome assessments, with a lack of systematic follow-up resulting in an underestimation of mortality [ 44 ]. Similarly, the frequency of assessment scans has been shown to be associated with higher median PFS for both treated and untreated populations [ 45 ]. As such, where assessments of PFS are made using real-world data with low or high frequency of assessments relative to the comparator data, the potential for bias may be high.…”

Management of Cutaneous Immune-Related Adverse Events in Patients With Cancer Treated With Immune Checkpoint Inhibitors

“…Inclusion criteria for the systematic review were (1) articles published between January 1, 2010, and June 1, 2020, (2) articles written in the English language; and (3) original articles, brief reports, case reports, and research letters that reported primarily on cirAE management. Exclusion criteria included (1) articles published before 2010, (2) articles written in a language other than English, and (3) review articles, books, and editorials.…”

“…We searched 4 major databases, including PubMed, Embase European, Web of Science, and Google Scholar, with selected key words 1 according to PRISMA guidelines (eFigure and eMethods in the Supplement). The search was performed on June 26, 2020.…”

“…According to a recent study, 43.6% of patients with cancer in the US are eligible for ICI therapy, and up to 12.5% of patients respond to this therapy. 1 Immunotherapy drugs include monoclonal antibodies directed against cytotoxic T-lymphocyte associated protein 4 (CTLA-4; eg, ipilimumab), programmed cell death 1 (PD-1; eg, nivolumab, pembrolizumab, and cemiplimab), and programmed cell death ligand 1 (PD-L1; eg, avelumab, atezolizumab, and durvalumab). As these ICIs become more prevalent in oncology, reports of cutaneous immune-related adverse events (cirAEs) have also increased (eTable 1 in the Supplement).…”