In an adolescent with high‑risk stage II colon adenocarcinoma (microsatellite stable/proficient mismatch repair), should neoadjuvant chemotherapy be given?

Neoadjuvant Chemotherapy for High-Risk Stage II Colon Adenocarcinoma (MSS/pMMR)

Neoadjuvant chemotherapy should NOT be given to adolescents with high-risk stage II colon adenocarcinoma; instead, proceed directly to surgical resection followed by consideration of adjuvant chemotherapy based on high-risk features. 1

Standard Treatment Approach for Stage II Colon Cancer

The established treatment paradigm for colon cancer—including stage II disease—is surgical resection first, followed by selective adjuvant chemotherapy, not neoadjuvant therapy. 1 Unlike rectal cancer where neoadjuvant chemoradiotherapy is well-established, colon cancer has traditionally not utilized preoperative therapy. 1

Evidence Against Routine Adjuvant (and by Extension, Neoadjuvant) Therapy

Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. 2 A literature-based meta-analysis found no statistically significant survival benefit of adjuvant chemotherapy for stage II patients. 2 The best estimate of survival benefit, if it exists at all, is an absolute improvement in 5-year survival of only 2-4%. 2

The ASCO guidelines explicitly state: "The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended." 2

High-Risk Stage II Disease: When to Consider Adjuvant Therapy

While routine chemotherapy is not recommended, certain high-risk populations with stage II disease could be considered for adjuvant therapy (not neoadjuvant): 2

• T4 lesions (adherence to or invasion of local organs) 2, 3, 4
• Inadequately sampled lymph nodes (fewer than 12 nodes examined) 2
• Perforation or obstruction at presentation 2, 3, 4
• Poorly differentiated histology 2
• Lymphovascular or perineural invasion 3, 4
• Preoperative CEA >5 ng/mL 3
• Mucinous component >50% 4

Critical caveat: These features are prognostic markers (indicating worse outcomes), but there is no data to suggest they are predictive markers (indicating response to chemotherapy). 2 Patients with multiple adverse features have significantly worse outcomes (5-year disease-specific survival of 57% with ≥2 features vs. 95% with none), identifying a truly high-risk subgroup. 3

Microsatellite Status in This Patient

This adolescent has microsatellite stable (MSS)/proficient mismatch repair (pMMR) disease. This is relevant because:

• MSI-H tumors have improved stage-specific survival and may not benefit from standard fluorouracil-based adjuvant chemotherapy 2
• However, this patient's MSS status means they do not have the favorable prognosis associated with MSI-H disease 2
• MSS status does not change the fundamental recommendation against neoadjuvant therapy for colon cancer 2

Why Neoadjuvant Therapy Is Not Standard for Colon Cancer

Neoadjuvant chemotherapy has not been shown to significantly improve overall survival compared to surgery alone with postoperative adjuvant treatment in colon cancer. 1 The American College of Radiology explicitly states that neoadjuvant therapy for colon cancer remains investigational and is still in the exploratory stage of clinical trials. 1, 5

Potential disadvantages of neoadjuvant therapy include:

• Difficulty identifying areas for resection if complete response is achieved 1
• Delay in definitive surgical treatment for a curable malignancy
• Risk of disease progression during chemotherapy in non-responders

Recommended Management Algorithm

1. Proceed directly to surgical resection with en bloc removal of regional lymph nodes 2
2. Ensure adequate lymph node sampling (minimum 12 nodes) for accurate staging 6
3. After surgery, assess for high-risk features listed above 2, 3
4. If high-risk features are present, engage in shared decision-making about adjuvant chemotherapy:
   • Discuss the lack of direct evidence for benefit in stage II disease 2
   • Explain that indirect evidence from stage III trials suggests possible 2-4% absolute survival benefit 2
   • Consider patient age, comorbidities, and treatment preferences 2, 7
5. If adjuvant therapy is chosen, use FOLFOX or CAPEOX for 3-6 months 2
6. Consider clinical trial enrollment as the optimal approach for stage II disease 2

Special Consideration for Adolescent Patients

Adolescents with colon cancer represent an unusual population, as this malignancy typically affects older adults. Ensure thorough evaluation for hereditary cancer syndromes (though MSS/pMMR status makes Lynch syndrome less likely). The lack of comorbidities in adolescents may make them better candidates to tolerate adjuvant chemotherapy if high-risk features are present, but this does not change the recommendation against neoadjuvant therapy. 7