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.

A leading hypothesis for why adding immunotherapy to chemoradiation failed is that radiation, particularly for central tumors, destroys the very lymphocytes immunotherapy aims to activate. This biological mechanism suggests the radiation essentially canceled out the drug's intended effect.

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.

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.

For MSI-high patients responding to immunotherapy, a lingering mass on a CT scan may not be active cancer. A negative ctDNA test can help confirm that the visible lesion is likely just scar tissue, potentially averting unnecessary surgery.

A potential complication of successful neoadjuvant immunotherapy in rectal cancer is the development of stenosing scar tissue. This can block the lumen, making endoscopic surveillance impossible and necessitating surgery for a patient who may have otherwise achieved a complete clinical response.

Dr. Radvanyi advocates for a paradigm shift: treating almost all cancers with neoadjuvant immunotherapy immediately after diagnosis. This "kickstarts" an immune response before standard treatments like surgery and chemotherapy, which are known to be immunosuppressive, can weaken the patient's natural defenses against the tumor.