Evidence Gaps, De-escalation Opportunities, and Test Selection

Dr. Weinberg addresses where evidence is strongest versus where the field risks getting ahead of itself.

Although the prognostic value is clearly established with growing data, predictive value for guiding therapeutic decisions remains less mature.

He notes that negative interventional escalation trials (ALTAIR with trifluridine/tipiracil, and early Australian escalation studies) suggest that simply giving "more of the same" therapy doesn't rescue ctDNA-positive patients.

He believes the field is moving toward breaking down traditional stage-based risk stratification (where stage III automatically receives adjuvant chemotherapy and stage II usually doesn't) in favor of positive/negative ctDNA status combined with other risk features, potentially complemented by AI-based histologic analysis.

De-escalation represents the most powerful near-term application.

He's already de-escalating most patients with stage II colorectal cancer, requiring strong justification for adjuvant chemotherapy even in T4N0 cases.

Regarding potential harms, Dr. Weinberg acknowledges concern about under-treating ctDNA-negative stage III patients by withholding standard adjuvant therapy without adequate prospective randomized data, though stage II risk is already low enough to support de-escalation comfort.

He also discusses non-operative rectal cancer management, suggesting ctDNA-negative status could increase comfort pursuing organ-preservation approaches, whereas positive results wouldn't necessarily mandate permanent ostomy but would warrant further study.