Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer.

OPINION STATEMENT: Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well-designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice.