What is the recommended treatment for an adolescent with high‑risk stage II colon adenocarcinoma?

Treatment for Stage II High-Risk Adolescent Colon Adenocarcinoma

Offer fluoropyrimidine monotherapy (capecitabine or infusional 5-FU/leucovorin) for 6 months after confirming high-risk features and microsatellite stable (MSS) or proficient mismatch repair (pMMR) status. 1, 2

Initial Assessment and Risk Stratification

Before making any treatment decision, you must confirm adequate surgical staging and identify high-risk features:

• Verify that at least 12 lymph nodes were examined in the surgical specimen to ensure proper staging and avoid understaging 1, 2
• Test for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status immediately, as this fundamentally changes treatment recommendations 1, 2

High-Risk Features That Justify Chemotherapy

The following features define high-risk stage II disease and warrant consideration of adjuvant therapy 3, 1, 2:

• T4 tumors (stage IIB/IIC) – most important high-risk feature 1, 2
• Fewer than 12 lymph nodes examined 3, 1, 2
• Poorly differentiated or undifferentiated histology 3, 1, 2
• Lymphovascular invasion 3, 1, 4, 5
• Perineural invasion 3, 1, 2
• Bowel obstruction or tumor perforation at presentation 3, 1, 5
• Grade BD3 tumor budding (≥10 buds) 3, 1

The presence of multiple high-risk features strengthens the case for chemotherapy, with 5-year disease-free survival dropping from 87.3% with one risk factor to 74.8% with two or more 1

Treatment Algorithm

Step 1: MSI/MMR Status Determines Treatment Path

If dMMR/MSI-H:

• Do NOT routinely offer fluoropyrimidine-based chemotherapy, even with high-risk features, as these tumors have better prognosis and derive minimal benefit from fluoropyrimidines 1, 2
• Oxaliplatin-containing regimens may be considered only through shared decision-making if multiple high-risk factors are present 1
• Note: High-risk features remain prognostic even in dMMR/MSI-H tumors, but the treatment benefit is uncertain 6

If MSS/pMMR (most common):

• Proceed to Step 2 for chemotherapy consideration 1, 2

Step 2: Recommended Chemotherapy Regimen for MSS/pMMR High-Risk Stage II

Standard approach: Fluoropyrimidine monotherapy for 6 months 1, 2

Regimen options:

• Capecitabine 1,250 mg/m² orally twice daily on days 1-14 every 3 weeks for 8 cycles 1
• Infusional 5-FU/leucovorin (sLV5FU2) every 2 weeks for 12 cycles 1, 2

Capecitabine advantages: At least as effective as bolus 5-FU/LV, causes less myelosuppression (though more hand-foot syndrome), avoids central venous catheter complications, and is well-tolerated even in elderly patients 1, 2

Step 3: What NOT to Do – Critical Pitfalls

Do NOT add oxaliplatin routinely to stage II regimens, even with high-risk features 1, 2, 7:

• The FDA label shows no statistically significant disease-free survival improvement in stage II patients treated with oxaliplatin (5-year DFS 83.7% with oxaliplatin vs 79.9% without, HR 0.84, p=0.258) 7
• No overall survival benefit was demonstrated (HR 1.00,95% CI 0.70-1.41) 7
• Oxaliplatin significantly increases toxicity, particularly peripheral neuropathy 1, 2, 7
• Multiple research studies confirm multiagent chemotherapy provides no benefit and may cause harm in stage II disease 8

Special Considerations for Adolescent Patients

Age alone should NOT alter treatment recommendations 3, 1, 2:

• Younger low-risk patients should NOT receive chemotherapy based solely on age 3, 1
• There is no compelling evidence that younger patients with low-risk stage II disease benefit from adjuvant chemotherapy 3
• The decision must be based on high-risk features, not age 1, 2

Timing and Practical Implementation

• Start adjuvant chemotherapy within 6-8 weeks of surgery, ideally as soon as the patient has recovered from surgical complications 1, 2
• The absolute survival benefit of chemotherapy in stage II disease is modest (typically <5%, often 2-4%) 1
• Treatment-related mortality is <1%, but morbidity includes fatigue, gastrointestinal symptoms, and potential severe complications 1

Shared Decision-Making Framework

Discuss the following with the patient and family:

• The modest absolute benefit (3-5% improvement in survival) versus chemotherapy-related toxicity 3, 1
• The 5-year cancer-specific survival with surgery alone is approximately 84.7% for stage IIA disease 1
• High-risk features increase recurrence risk, justifying chemotherapy consideration 1, 5
• Patient preference is critical given the limited survival gain and real toxicity risks 1

Common Errors to Avoid

• Do not offer chemotherapy to unselected stage II patients without risk stratification – harms outweigh benefits 3, 1, 2
• Do not forget to check MSI/MMR status before treating stage II disease 1, 2
• Do not add oxaliplatin routinely – this is definitively not beneficial in stage II 1, 2, 7
• Do not use inadequate nodal sampling as the sole indication without confirming the quality of the surgical specimen 1