Background

Approximately 10% to 15% of colorectal cancer patients exhibit mismatch repair deficient (dMMR) findings, where the protein function responsible for correcting genetic mutations is impaired. These cancer cells accumulate a large number of mutations across the genome, characterized by the massive expression of neoantigens that clearly distinguish them from normal cells. Paradoxically, 5-fluorouracil (5-FU)-based cytotoxic chemotherapy, which has been the standard therapy for locally advanced stages, has failed to provide significant therapeutic benefits for dMMR tumors.

Existing clinical guidelines have recommended adjuvant chemotherapy following surgery for patients with stage III disease, particularly those with large tumors or concomitant lymph node metastasis. As the extent of tumor invasion increases, the scope of bowel resection expands, resulting in permanent sequelae such as a permanent stoma or urinary and defecation dysfunction. A persistent challenge remained: if residual micrometastases after surgery led to recurrence, the response rate to targeted anticancer agents also declined, drastically reducing the expectation of a cure. This is why a new treatment paradigm to preemptively shrink tumors and eradicate micrometastatic cancer by activating the systemic immune system before surgery was desperately needed.

Key Findings

This clinical study, published in the international journal The Lancet, followed the long-term therapeutic outcomes of neoadjuvant therapy using dual immunotherapy in patients with locally advanced dMMR colon cancer. Patients received a combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab before surgery.

Follow-up results showed that the 3-year disease-free survival (DFS) and 5-year overall survival (OS) rates for the group receiving preoperative immune combination therapy both reached 100%. All treated patients survived without cancer recurrence or related death during the follow-up period. Compared to previous clinical results in which the 3-year DFS for standard adjuvant chemotherapy remained around 70% to 80%, therapeutic outcomes have improved dramatically.

These results indicate that immune checkpoint inhibitors not only induced a strong systemic immune response that eliminated the primary tumor prior to resection but also eradicated potential micrometastases. Despite the relatively short treatment period of approximately 4 weeks, it induced multiple pathological complete responses while controlling the risk of surgical delay or fatal immune toxicity within a stable range.

Implications and Outlook

Experts predict that this long-term follow-up data will serve as a decisive turning point to fundamentally change treatment guidelines for locally advanced dMMR colon cancer. This is because scientific evidence has been established to justify omitting the arduous chemotherapy that followed surgery. The likelihood of establishing a treatment strategy as a clinical guideline that maximizes the chance of a cure while minimizing physical pain and side effects for patients has increased.

The clinical achievement of a 100% long-term survival rate is expected to accelerate the expansion of a non-surgical "watch and wait" strategy that omits tumor resection surgery. This has laid the groundwork for extending the organ-preserving approach, previously attempted only in rectal cancer, to colon cancer.

The challenges also coexist. The financial burden of medical costs associated with the combination use of high-cost immune checkpoint inhibitors, as well as barriers to their inclusion in national insurance coverage, must be addressed. A management system to closely monitor autoimmune-related adverse reactions that may occur in a small number of patients must also be supported. Establishing accurate imaging and endoscopic diagnostic criteria to determine complete remission after immunotherapy is cited as the central task for the next clinical study.