Management of Rising ctDNA After Resection of Stage II Colon Cancer
In a 35-year-old patient with stage II colon cancer and rising postoperative ctDNA, initiate adjuvant chemotherapy with fluoropyrimidine monotherapy (capecitabine or infusional 5-FU/leucovorin) for 6 months, as ctDNA positivity provides direct evidence of minimal residual disease and identifies patients at very high risk of recurrence.
Understanding the Prognostic Significance of ctDNA Positivity
Postoperative ctDNA detection indicates minimal residual disease and dramatically increases recurrence risk, with hazard ratios ranging from 10.98 to 32.02 depending on timing of detection 1, 2, 3.
In stage II colon cancer patients not receiving adjuvant chemotherapy, 79% of ctDNA-positive patients experienced recurrence compared to only 9.8% of ctDNA-negative patients (HR 18; 95% CI 7.9-40) 1.
ctDNA positivity is the most significant independent predictor of recurrence, outperforming all traditional clinicopathological risk factors in multivariate analyses 2.
Serial ctDNA monitoring detects recurrence an average of 5 months earlier than radiological imaging, with 92% overall accuracy 2.
Treatment Algorithm for ctDNA-Positive Stage II Disease
Step 1: Confirm Adequate Staging and Molecular Testing
Verify that ≥12 lymph nodes were examined in the surgical specimen to ensure accurate stage II classification 4.
Obtain MMR/MSI status immediately if not already done, as this fundamentally alters treatment recommendations 4, 5.
Step 2: Initiate Adjuvant Chemotherapy Based on MMR Status
For MMR-proficient (pMMR) or MSS tumors:
Start fluoropyrimidine monotherapy within 6-8 weeks of surgery: capecitabine 1,250 mg/m² orally twice daily on days 1-14 every 3 weeks for 8 cycles, OR infusional 5-FU/leucovorin (sLV5FU2 regimen) every 2 weeks for 12 cycles 6, 4.
Do NOT routinely add oxaliplatin even with ctDNA positivity, as there is no proven overall survival benefit in stage II disease and it significantly increases peripheral neuropathy risk 4.
For MMR-deficient (dMMR) or MSI-high tumors:
Consider observation versus chemotherapy through shared decision-making, as dMMR tumors have excellent prognosis and uncertain benefit from fluoropyrimidine therapy 5.
If chemotherapy is chosen due to ctDNA positivity, use fluoropyrimidine monotherapy without oxaliplatin 5.
Step 3: Serial ctDNA Monitoring During and After Treatment
Repeat ctDNA testing after completion of adjuvant chemotherapy to assess treatment response and residual disease 2.
ctDNA clearance during chemotherapy is associated with recurrence-free status, while persistent positivity after chemotherapy predicts extremely high recurrence risk (HR 12.76) 2.
Continue ctDNA surveillance every 3-6 months during follow-up as it detects recurrence earlier than CEA or imaging 2, 7.
Critical Nuances and Divergent Evidence
The DYNAMIC Study Context
The most recent Chinese Society of Clinical Oncology (CSCO) 2025 guidelines reference the DYNAMIC study, noting that while ctDNA-guided strategies may change adjuvant chemotherapy decisions, there were no significant survival differences between intervention in MRD-positive patients and observation in MRD-negative patients 6.
However, this finding reflects the study design limitation where ctDNA-negative patients were observed (appropriate) while ctDNA-positive patients received treatment, preventing direct comparison of treated versus untreated ctDNA-positive patients 6.
The overwhelming evidence from multiple independent studies demonstrates that untreated ctDNA-positive patients have 10-18 times higher recurrence risk, making treatment the prudent approach 1, 2, 3.
ESMO Guidelines on ctDNA
The 2020 ESMO guidelines state that ctDNA results from ongoing trials must be awaited before acceptance in routine practice 6.
However, these guidelines predate the substantial body of evidence published from 2021-2025 demonstrating ctDNA's robust prognostic value 8, 2, 3.
In the context of a patient with documented rising ctDNA, the evidence of minimal residual disease is direct and actionable, even as standardization efforts continue 1, 8.
Common Pitfalls to Avoid
Do not withhold chemotherapy based solely on stage II classification when ctDNA provides molecular evidence of residual disease 1, 2.
Do not add oxaliplatin reflexively to ctDNA-positive stage II patients, as toxicity outweighs unproven benefit 4.
Do not rely on CEA or imaging alone for surveillance in ctDNA-positive patients, as ctDNA detects recurrence months earlier 2.
Do not treat dMMR/MSI-high tumors with fluoropyrimidine monotherapy without thorough discussion, as benefit is uncertain even with ctDNA positivity 5.
Do not delay treatment initiation beyond 8 weeks postoperatively once the patient has recovered from surgery 4.
Special Considerations for This Young Patient
At age 35, this patient has decades of life expectancy, making prevention of recurrence particularly important for long-term quality of life and survival 4.
Young age alone does not justify oxaliplatin addition, but the patient can better tolerate fluoropyrimidine therapy than elderly patients 4.
Consider Lynch syndrome testing given the young age, as this would influence surveillance strategies for other cancers 5.