While neoadjuvant immunotherapy shows astounding success in MSI-high rectal cancer, the primary difficulty for clinicians lies in accurately assessing complete response via endoscopy and MRI, and managing unique complications like mucin pools or stenosis, rather than simply administering the treatment.

Unlike rectal cancer where MRI aids response assessment, MSI-high colon cancer lacks a reliable imaging modality to confirm a pathologic complete response after neoadjuvant immunotherapy. This makes a "watch and wait" approach far more challenging and not currently recommended outside of a clinical trial.

For patients over 75 with metastatic gastric cancer, a common practice is to reduce the oxaliplatin dose from 85 to 65 mg/m² and universally omit the 5-FU bolus from the FOLFOX regimen. This pragmatic approach aims to maintain efficacy while minimizing toxicity in a more vulnerable population.

While the ATOMIC trial established FOLFOX plus atezolizumab as a new standard for adjuvant therapy in MSI-high colon cancer, its design lacked an immunotherapy-only arm. This leaves a critical, unanswered question about the actual contribution and necessity of the chemotherapy component.

The practice-changing DYNAMIC trial showed that a ctDNA-guided strategy for stage II colorectal cancer reduces adjuvant chemotherapy use by 50%. Despite this significant de-escalation of treatment, patient outcomes and survival rates were identical to the standard-of-care approach.

Despite the success of ctDNA-guided de-escalation in Stage II disease, the DYNAMIC-3 trial in Stage III patients showed that ctDNA-negative patients had worse outcomes with de-escalated therapy. This serves as a critical warning against this de-escalation strategy in higher-risk patients for now.

The next frontier in CSCC isn't just about new drugs, but about optimizing existing ones. A key research area is determining the minimum number of immunotherapy doses required for an optimal response—potentially just one or two—to limit toxicity, reduce treatment burden, and personalize care for high-risk patients.

In a phase 2 trial, the combination of zanidatumab and FOLFOX achieved a remarkable 95% response rate after two key modifications were made: adding prophylactic loperamide and dropping the 5-FU bolus. This suggests the bolus adds toxicity without clear benefit in this specific, potent combination.

A meta-analysis of over 3,000 patients shows that neoadjuvant chemotherapy for MSS colon cancer provides a 5% improvement in survival. This benefit is clinically meaningful and equivalent in magnitude to the landmark addition of oxaliplatin to 5-FU in the original MOSAIC trial.