Trials like the dostarlimab study in rectal cancer and NICHE in colon cancer show neoadjuvant immunotherapy can induce profound responses in MSI-high tumors. This is creating a new paradigm where major surgery might be avoided entirely for some patients, marking a significant shift in treatment strategy.

A significant challenge in assessing complete response after neoadjuvant immunotherapy for rectal cancer is the presence of mucin pools. These imaging abnormalities can persist for up to two years, mimicking residual tumor and complicating decisions about non-operative management.

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.

Following positive Phase III data for adjuvant atezolizumab plus chemotherapy in Stage III MSI-high colon cancer, clinicians are extrapolating this approach to high-risk Stage II patients. For some, they favor using immunotherapy alone, omitting chemotherapy due to its perceived limited additional benefit in the Stage II setting.

While immunotherapy is largely ineffective in metastatic microsatellite stable (MSS) colorectal cancer, emerging data suggests it may have surprising efficacy in the early-stage (neoadjuvant) setting. This differential response is likely due to a more favorable tumor microenvironment in earlier disease, suggesting a new therapeutic window.

Unlike rectal cancer where MRI is effective, there is no reliable imaging to monitor for complete response in colon cancer. The alternative, frequent colonoscopies, is impractical and unsafe. This lack of viable surveillance tools makes non-operative management too risky, even with promising response rates to immunotherapy.

Retrospective data suggests patients with MSI-high rectal cancer might not just respond poorly to standard neoadjuvant chemoradiation (TNT), but their disease could actually progress. This makes immunotherapy a potentially safer and more effective first-line neoadjuvant choice, not just an alternative.

Despite the ATOMIC trial (adjuvant FOLFOX + atezolizumab) being practice-changing and included in NCCN guidelines for stage 3 MSI-high colon cancer, experts from major academic centers would not use it. They cite the high toxicity of chemotherapy and superior data from neoadjuvant immunotherapy trials like NICHE2, which achieve excellent outcomes without any chemotherapy.