Matheson, Alastair

Abstract Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancérologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research.

It is widely accepted that traditional models of clinical investigation are becoming unsustainable in oncology and that trials must become more efficient in matching effective treatments to the patients most likely to benefit. In 2008, gastrointestinal oncologists from many countries began a collaboration to improve the design and conduct of clinical trials in their field, through the auspices of a French/U.S. charitable foundation, ARCAD. Whether this model of academic collaboration will be judged a success will depend on the quality of its scientific output during the next few years and whether this output, alongside that of other scientists, groups, and institutions, ultimately leads to more efficient trials and improved treatment options for patients.