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.

An MSK trial of neoadjuvant dostarlumab for MSI-high locally advanced rectal cancer showed a 100% complete clinical response rate. This groundbreaking result allows for non-operative management, sparing patients from chemotherapy, radiation, and life-altering surgery, potentially representing a cure with immunotherapy alone.

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.

In a study of neoadjuvant Dostarlamab for MSI-high tumors, 100% of rectal cancer patients achieved a clinical complete response, compared to 82% of colon cancer patients. Experts find this high degree of discordance surprising and currently lack a clear biological explanation, as such differences are not typically observed in the metastatic setting.

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.

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.

The COMET study found combining chemotherapy with atezolizumab did not improve overall survival versus atezolizumab alone. However, it nearly eliminated early progressive disease (2.8% vs. 32.4%), suggesting a critical role for patients with high tumor burden who cannot risk initial progression on monotherapy.

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.