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.

Even with negative biopsies, post-immunotherapy scans and scopes can show residual masses or mucin pools that are mistaken for active cancer. This makes determining a true complete clinical response difficult and can lead to unnecessary surgeries where no cancer is found, as these changes can take years to resolve.

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.

Data from the Checkmate 743 trial shows that patients who stopped dual immunotherapy (Nivo/Ipi) due to toxicity can still achieve long-term benefits. A third of these patients had an ongoing response at three years, despite stopping treatment after only four months on average, providing confidence in the regimen.

After immunotherapy, many colorectal cancer patients have residual nodules on scans that appear to be partial responses. However, ctDNA testing can confirm these are often just scar tissue, not active disease. This provides the confidence to stop therapy at the two-year mark and avoid unnecessary surgeries for what are effectively complete responses.

In the Podium-303 trial, adding retifanlimab to chemotherapy improved the overall response rate by 11%. However, its most significant impact was doubling the median duration of response from 7.2 to 14 months, providing a much more durable benefit for patients after chemotherapy is stopped.

Data from trials like CheckMate 816 shows that achieving a Pathologic Complete Response (PCR) after neoadjuvant chemo-immunotherapy is a powerful early surrogate endpoint. Patients with PCR demonstrate markedly improved overall and event-free survival.

For patients who previously received immunotherapy (IO), a recurrence more than 12 months after completing treatment makes re-challenging with an IO agent a reasonable option. The likelihood of benefit is lower if the recurrence is within 6-12 months and minimal if under 6 months.