Neoadjuvant therapy as a paradigm to develop systemic cancer therapy

Abstract

Neoadjuvant systemic therapy preceding definitive surgical resection permits the in vivo assessment of tumor response and induces pathologic downstaging in several malignancies. Since pathologic complete response (pCR) and biologic activity can be determined rapidly, the signal of efficacy of a systemic regimen is evident with a relatively small number of patients before long‐term follow‐up. Additionally, emerging data suggest that modulation of pharmacodynamic biomarkers after brief neoadjuvant therapy may correlate with long‐term clinical outcomes. Early evidence for in vivo resistance and elucidation of mechanisms of resistance may assist with selection of rational combinations of agents as subsequent therapy to improve outcomes. Evidence of biologic anti‐tumor activity in target‐enriched subsets can be determined with a small number of patients in proof of principal pilot trials. Biologic activity against molecular targets and downstream anti‐proliferative and pro‐apoptotic activity may help with the selection of the lowest effective dose, which may lead to efficacious and safe therapy. Therefore, this paradigm has the potential to enable the efficient use of resources and accelerate the pace of systemic therapy development. It may also be possible to determine molecular and biologic characteristics that predict for sensitivity. Drug Dev Res 69:388–397, 2008. © 2008 Wiley‐Liss, Inc.