Design of Tumor Biomarker–Monitoring Trials: A Proposal by the European Group on Tumor Markers

Abstract

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker–guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy.

CNAPS in Therapy Monitoring

“…While the first approach is supported by logistic regression-, supporter vector machine-or neuronal network-models, the latter one often comprises even more complex approaches. In all cases a validation in an independent patient set is paramount to confirm the findings [1,2,19]. This is highly relevant for some groups of CNAPS biomarkers such as epigenetic markers and miRNAs.…”

“…For therapy monitoring studies, a meaningful number of patients with a certain cancer that undergo a homogeneous type of therapy with objectifiable, favorable and non-favorable outcomes have to be considered. Recently published guidelines support the professional validation of biomarkers for diagnostic and monitoring purposes [3,[18][19][20] as well as for the development and incorporation of biomarker studies in early clinical trials [1].…”

Current Evidence and Future Perspectives on the Effective Practice of Patient-Centered Laboratory Medicine

“…In response to this, the European Group on Tumor Markers has published a proposal on evaluation of new tumor markers (70 ). This describes a 4-phase approach, similar to the process used by the US Food and Drug Administration and others for the evaluation of new drugs (Table 3).…”

“…4. Benchmarking of existing and new tests in specified situations with commonly accepted measures of effectiveness using the models described above, including postimplementation audit (57,70 ). This must include the effects of preand postanalytical components of the testing process and must consider overall impact of the testing process on all relevant clinical outcomes.…”

Breaking a Vicious Cycle

“…Prognostic factors, such as regional lymph node status, provide an indication of the likely course of a patient's disease in the context of previously applied treatment (such as surgery), whereas predictive factors (also called treatment-response modif ers) provide an indication of whether a given treatment being considered will have a benef cial ef ect. Serial measurement of tumor biomarkers can monitor ongoing therapeutic benef t or emergence of a new event, such as cancer recurrence or progression (2). Pharmacogenetic biomarkers measure risk of toxicity or odds of benef t from anticancer drugs (3).…”