Methods for Stratification and Validation Cohorts: A Scoping Review

Personalized medicine requires large cohorts for patient stratification and validation of patient clustering. However, standards and harmonized practices on the methods and tools to be used for the design and management of cohorts in personalized medicine remain to be defined. This study aims to describe the current state-of-the-art in this area. A scoping review was conducted searching in PubMed, EMBASE, Web of Science, Psycinfo and Cochrane Library for reviews about tools and methods related to cohorts used in personalized medicine. The search focused on cancer, stroke and Alzheimer's disease and was limited to reports in English, French, German, Italian and Spanish published from 2005 to April 2020. The screening process was reported through a PRISMA flowchart. Fifty reviews were included, mostly including information about how data were generated (25/50) and about tools used for data management and analysis (24/50). No direct information was found about the quality of data and the requirements to monitor associated clinical data. A scarcity of information and standards was found in specific areas such as sample size calculation. With this information, comprehensive guidelines could be developed in the future to improve the reproducibility and robustness in the design and management of cohorts in personalized medicine studies

Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: The need for further revision of dose and schedule

Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy. We analyzed 180 individuals that were candidates for a treatment with 5-FU class drugs for the most common DPD mutation, IVS14+1G>A, and detected four heterozygous patients. We recorded the toxicities for all 180 individuals after the first two chemotherapy cycles and found that three of the four patients, although they were treated with a dose reduction in 50 % on the basis of the genetic analysis, all showed severe toxicities that resulted in hospitalization of patient and premature discontinuation of treatment. One patient with mutated DPD was not treated with chemotherapy upon the clinician's decision because of his DPD mutated genotype and the presence of microsatellite instability. Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14+1G>A mutations

Postoperative carcinoembryonic antigen (CEA) association with survival and oxaliplatin benefit in stage II colon cancer (CC): Post hoc analysis of the MOSAIC trial

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Study designs for clinical trials applied to personalised medicine: a scoping review

International audienceObjective Personalised medicine (PM) allows treating patients based on their individual demographic, genomic or biological characteristics for tailoring the ‘right treatment for the right person at the right time’. Robust methodology is required for PM clinical trials, to correctly identify groups of participants and treatments. As an initial step for the development of new recommendations on trial designs for PM, we aimed to present an overview of the study designs that have been used in this field. Design Scoping review. Methods We searched (April 2020) PubMed, Embase and the Cochrane Library for all reports in English, French, German, Italian and Spanish, describing study designs for clinical trials applied to PM. Study selection and data extraction were performed in duplicate resolving disagreements by consensus or by involving a third expert reviewer. We extracted information on the characteristics of trial designs and examples of current applications of these approaches. The extracted information was used to generate a new classification of trial designs for PM. Results We identified 21 trial designs, 10 subtypes and 30 variations of trial designs applied to PM, which we classified into four core categories (namely, Master protocol, Randomise-all, Biomarker strategy and Enrichment). We found 131 clinical trials using these designs, of which the great majority were master protocols (86/131, 65.6%). Most of the trials were phase II studies (75/131, 57.2%) in the field of oncology (113/131, 86.3%). We identified 34 main features of trial designs regarding different aspects (eg, framework, control group, randomisation). The four core categories and 34 features were merged into a double-entry table to create a new classification of trial designs for PM. Conclusions A variety of trial designs exists and is applied to PM. A new classification of trial designs is proposed to help readers to navigate the complex field of PM clinical trials

Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer

Background: Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. Methods: A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. Results: A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23-0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74-1.64)). Consistent results were reported in overall survival (OS; P=0.075). Conclusions: As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted