Editor's Note:The decision on whether high-risk MSI-H (microsatellite instability-high) stage II colorectal cancer patients should receive adjuvant therapy remains controversial. Dr. Ashwin Somasundaram, a medical professor at the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, shares his insights on this complex issue.

Limited Benefit of the FL Regimen

Extensive follow-up and treatment strategies have provided guidance for adjuvant therapy in high-risk MSI-H stage II colorectal cancer patients. Chemotherapy offers limited absolute benefit for stage II colorectal cancer patients and is therefore not routinely recommended. However, the presence of high-risk features increases the chance of recurrence and potentially enhances the benefit of adjuvant therapy. The most significant risk factors include T4 tumors and stage IIB and IIC cancers (T4N0), which have a higher recurrence risk than stage IIIA cancers. Most guidelines recommend chemotherapy for these cases.

However, the prognosis for the T4N0 and MSI-H subgroups is much better than for the microsatellite stable (MSS) subgroup, and the optimal treatment for these patients remains unclear. To answer this question, it is essential to thoroughly review previous treatment recommendations, which form the foundation of current guidelines.

The multicenter MOSAIC study included 899 patients with stage II colorectal cancer (regardless of microsatellite status), randomly assigned to receive adjuvant therapy with either fluorouracil/leucovorin (FL) alone or combined with oxaliplatin (FOLFOX). Among these, 569 were high-risk patients, and the hazard ratio (HR) for overall survival (OS) between the FOLFOX and FL groups was 0.91 (95% CI [0.61, 1.36]). The ACCENT database analysis also showed limited benefit from adding oxaliplatin to FL in high-risk stage II colorectal cancer patients, even in those with multiple high-risk features, including T4 primary tumors.

Most of these adjuvant therapy studies assessed mismatch repair-proficient or MSS cancers. Although patients with deficient mismatch repair (dMMR) or MSI-H stage II and III colorectal cancer have improved prognoses, the benefit of chemotherapy remains unclear. Small studies comparing FL as adjuvant therapy versus surgery alone in MSI-H stage II colorectal cancer patients have shown no survival benefit and even potential harm (OS; HR: 2.95, 95% CI [1.02, 8.54]). Thus, FL alone should not be considered for stage II colorectal cancer treatment.

The Advantage of Oxaliplatin

Given the limited benefit of FL, oxaliplatin is typically added when adjuvant therapy is chosen for MSI-H/dMMR stage II colorectal cancer. This recommendation is mainly based on retrospective analyses of small patient groups in clinical trials.

In a French retrospective study of 149 high-risk dMMR stage II colorectal cancer patients, 24 received FOLFOX adjuvant chemotherapy, 116 underwent surgery alone, and only 9 received FL. Compared with surgery alone, FOLFOX-treated patients showed a trend toward improved disease-free survival (DFS; HR: 0.13, 95% CI [0.02, 1.05]; P = 0.06), a benefit not observed with FL. However, the small sample size limits the strength of this analysis. Other studies, such as the NSABP C-07 trial, have reported benefits from adding oxaliplatin to FL, regardless of MMR status.

In the subgroup analysis of the MOSAIC trial, both DFS and OS appeared to favor FOLFOX (DFS; HR: 0.48, 95% CI [0.21, 1.12]; P = 0.08; OS; HR: 0.41, 95% CI [0.16, 1.07]; P = 0.69). Given these data limitations, the ASCO expert panel recommends shared decision-making with patients and suggests using oxaliplatin-based regimens for adjuvant therapy in high-risk dMMR stage II colorectal cancer.

We are currently awaiting results from the completed ATOMIC trial (NCT02912559), which is evaluating atezolizumab combined with chemotherapy in resected dMMR stage III colorectal cancer. If atezolizumab proves beneficial, its application in stage II cancer may also be considered.

ctDNA MRD as a Decision-Making Tool

One of the most promising tools for managing resectable high-risk stage II colorectal cancer is ctDNA-guided MRD (minimal residual disease) assessment. The DYNAMIC study reported that ctDNA-guided adjuvant chemotherapy had no impact on two-year disease-free survival in stage II colorectal cancer patients. However, although ctDNA clearance was observed in both MSI-H and MSS patients, the limited subgroup analysis prevented accurate assessment of MSI-H patients.

In contrast, the CIRCULATE-Japan study found that among 100 patients with BRAF wild-type and MSI-H tumors, those who were ctDNA-negative at four weeks experienced improved DFS (HR: 4.14, 95% CI [1.3, 12.9]; P = 0.015) compared to BRAF wild-type and MSS patients. Notably, ctDNA positivity, regardless of BRAF or MSI status, was linked to poorer DFS (HR: 11.68, 95% CI [8.61, 15.85]; P < 0.001), surpassing other clinicopathological factors like BRAF and MSI status.

These findings suggest that ctDNA MRD should also be integrated into shared decision-making and thoroughly evaluated and reported.

Looking Ahead

The evidence highlights the necessity of large, randomized controlled trials specifically designed to address these complex issues. Ongoing studies will be crucial in determining the best strategies for treating high-risk MSI-H stage II colorectal cancer and refining adjuvant therapy decisions.