In resectable, non‑metastatic colon cancer (e.g., stage III), when should neoadjuvant chemotherapy be chosen instead of immediate surgery?

When to Choose Chemotherapy First vs Surgery First in Colon Cancer

For resectable, non-metastatic colon cancer (including stage III), surgery should be performed first, followed by adjuvant chemotherapy—neoadjuvant chemotherapy is not recommended and remains investigational. 1, 2

Standard Treatment Sequence for Resectable Colon Cancer

Proceed directly to surgical resection with en bloc removal of regional lymph nodes as the initial treatment for all resectable, non-metastatic colon cancer. 2 This represents the established standard of care across all major guidelines, regardless of stage or risk features. 1

Why Surgery First?

• Neoadjuvant chemotherapy delays definitive surgical resection, potentially compromising cure in what is otherwise a curable malignancy. 2
• Risk of disease progression during preoperative chemotherapy exists in patients who do not respond to treatment. 2
• No survival benefit has been demonstrated for neoadjuvant chemotherapy compared to surgery followed by adjuvant treatment in colon cancer. 2
• Unlike rectal cancer where neoadjuvant chemoradiation is well-established, colon cancer has traditionally not utilized preoperative therapy. 2

Post-Surgical Adjuvant Chemotherapy Algorithm

Stage I Disease

• No adjuvant therapy required. 1

Stage II Disease (Low-Risk)

• Observation is preferred for patients without high-risk features. 1
• Alternative options include enrollment in clinical trial or consideration of capecitabine or 5-FU/leucovorin monotherapy. 1
• FOLFOX is not appropriate for stage II disease without high-risk features due to long-term oxaliplatin toxicity concerns. 1

Stage II Disease (High-Risk)

High-risk features include: 1, 2

• T4 tumors (stage IIB/IIC)
• Poorly differentiated histology (grade 3 or 4, excluding MSI-high tumors)
• Lymphovascular invasion
• Perineural invasion
• Bowel obstruction at presentation
• Tumor perforation
• Inadequate lymph node sampling (<12 nodes examined)
• Close, indeterminate, or positive margins

Treatment approach:

• Consider adjuvant chemotherapy similar to stage III disease, but recognize the absolute survival benefit is only 2-4%. 2
• Fluoropyrimidine monotherapy for 6 months (capecitabine or 5-FU/leucovorin) is the standard approach for MSS/pMMR tumors. 3
• Do not routinely add oxaliplatin to stage II regimens, even with high-risk features, as it does not provide proven overall survival benefit and significantly increases toxicity. 3
• Clinical trial enrollment is strongly advised given the paucity of definitive benefit data. 2

Stage III Disease (Node-Positive)

All medically fit patients with stage III disease must receive 6 months of adjuvant chemotherapy after complete resection. 1, 3 This provides approximately 15% absolute survival benefit and 30% relative risk reduction in mortality. 3

Recommended regimens (in order of preference): 1

• mFOLFOX6 (modified FOLFOX 6) - Category 1, standard of care
• FLOX (bolus 5-FU/LV/oxaliplatin) - Category 1
• CapeOx (capecitabine/oxaliplatin) - Category 1
• Single-agent capecitabine or 5-FU/LV for patients in whom oxaliplatin is inappropriate

Critical Surgical Requirements

• Ensure adequate lymph node sampling (≥12 nodes) to allow accurate pathological staging and avoid under-staging. 2, 3
• Colectomy with en bloc removal of regional lymph nodes is the surgical procedure of choice. 1

Special Circumstances Where Chemotherapy May Precede Surgery

Locally Unresectable or Medically Inoperable Disease

If the cancer is locally unresectable or the patient is medically inoperable, chemotherapy is recommended with the goal of converting the lesion to a resectable state. 1

Obstructing Colon Cancer

For resectable colon cancer causing overt obstruction, options include: 1

• Resection with diversion
• Stent insertion followed by colectomy
• Diversion followed by colectomy

Local obstruction relief should be performed first, followed by systemic therapy, with primary lesion resection at appropriate timing. 1

Synchronous Metastatic Disease (Stage IV)

For patients with resectable synchronous liver or lung metastases, neoadjuvant chemotherapy may be considered after symptom relief, followed by colon resection and simultaneous or staged resection of metastatic lesions. 1

• Preferred neoadjuvant regimen is oxaliplatin-based (FOLFOX/CAPEOX), with duration limited to 2-3 months to minimize drug-induced liver damage. 1
• The order of surgical resection depends on comprehensive assessment of which lesion (primary vs metastatic) is the dominant factor affecting survival and quality of life. 1

Common Pitfalls to Avoid

• Do not delay surgery in resectable, non-metastatic colon cancer to administer neoadjuvant chemotherapy outside of a clinical trial. 2
• Do not offer adjuvant chemotherapy to unselected stage II patients without risk stratification and discussion of minimal absolute benefit (2-4%). 2, 3
• Do not add oxaliplatin routinely to stage II regimens even with high-risk features. 3
• Do not forget to check MSI/MMR status before treating stage II disease, as MSI-high tumors may not benefit from standard fluorouracil-based chemotherapy. 2, 3
• Do not use bevacizumab, cetuximab, panitumumab, or irinotecan in adjuvant therapy for non-metastatic disease outside clinical trials. 1