What is the treatment plan for individuals with colorectal neoplasms?

Treatment of Colorectal Neoplasms

For resectable colorectal cancer, surgical resection is the primary curative treatment, followed by adjuvant chemotherapy with CAPEOX (preferred) or mFOLFOX6 for 6 months in stage III disease; for metastatic disease, treatment depends on resectability status and molecular markers, with combination chemotherapy plus targeted therapy for potentially resectable cases and sequential therapy for clearly unresectable disease. 1

Resectable Disease

Surgical Management

• En bloc resection is the standard surgical approach for resectable colon cancer 1
• For stage III colon cancer (lymph node positive), complete resection of the primary tumor should be followed by adjuvant chemotherapy 2
• Solitary or confined liver or pulmonary metastases should be surgically resected when technically feasible 1

Adjuvant Chemotherapy for Stage III Disease

CAPEOX is the preferred adjuvant regimen based on the IDEA study results 1:

• Oxaliplatin 130 mg/m² IV over 2 hours, day 1
• Capecitabine 1,000 mg/m² orally twice daily, days 1-14
• Repeat every 3 weeks for 8 cycles 1

Alternative regimen: mFOLFOX6 1, 2:

• Oxaliplatin 85 mg/m² IV over 2 hours, day 1 2
• Leucovorin 400 mg/m² IV over 2 hours, day 1 2
• 5-FU 400 mg/m² IV bolus, day 1, followed by 1,200 mg/m²/day continuous infusion for 2 days 2
• Repeat every 2 weeks for 12 cycles 1, 2

Fluoropyrimidine monotherapy options (for patients unable to tolerate combination therapy) 1:

• Capecitabine 1,250 mg/m² orally twice daily, days 1-14, every 3 weeks for 8 cycles 1
• Simplified biweekly 5-FU/LV (sLV5FU2) for 12 cycles 1

Stage II Disease Considerations

• Adjuvant chemotherapy for stage II colon cancer remains controversial and should be reserved for high-risk patients 3, 4
• High-risk features include T4 tumors, poorly differentiated histology, lymphovascular invasion, bowel obstruction/perforation, and inadequate lymph node sampling 4
• The DYNAMIC study showed that ctDNA-detected minimal residual disease (MRD) may guide adjuvant therapy decisions, though survival differences between MRD-positive intervention and MRD-negative observation were not significant 1

Unresectable/Metastatic Disease

Initial Assessment and Stratification

Comprehensive staging must include 1:

• Clinical examination, blood counts, liver and renal function tests, CEA level 1
• CT scan of abdomen and chest (or MRI) 1
• Performance status assessment (ECOG or Karnofsky) 1, 5
• Molecular testing: RAS mutation status and MSI/dMMR status 1, 6
• FDG-PET for equivocal lesions before planned metastasectomy 1

Treatment Strategy Based on Resectability

Potentially Resectable Metastases (Conversion Therapy)

Use high-intensity combination chemotherapy with or without targeted therapy to achieve conversion to resectability 1, 6:

• FOLFOX or FOLFIRI as backbone regimens 1
• Add bevacizumab (anti-VEGF) for patients without contraindications 1, 6
• For RAS wild-type tumors, anti-EGFR antibodies (cetuximab or panitumumab) can be considered 7
• Do not combine two targeted drugs (bevacizumab + anti-EGFR) 1
• Reevaluate every 2 months for potential resection 1, 6
• If using bevacizumab, administer last dose at least 6 weeks before surgery; resume 6-8 weeks postoperatively if continuing 1, 6

MSI-H/dMMR Tumors

PD-1 immune checkpoint inhibitors (pembrolizumab or nivolumab) should be considered for first-line therapy in MSI-H/dMMR metastatic disease based on KEYNOTE-177 results 1, 6

Clearly Unresectable Disease

Sequential therapy starting with fluoropyrimidine monotherapy is non-inferior to upfront combination therapy for overall survival 1:

First-line options 1, 6:

• Fluoropyrimidine monotherapy (capecitabine or infusional 5-FU/LV) for patients prioritizing quality of life over rapid tumor shrinkage 1
• FOLFOX or FOLFIRI for patients requiring tumor control or symptom palliation 1, 6
• Combination chemotherapy ± bevacizumab for symptomatic patients with good performance status 6

Second-line therapy 1:

• Switch to alternative cytotoxic agent (oxaliplatin if irinotecan was used first-line, or vice versa) 1
• Reserved for patients maintaining good performance status 1

Special Situations

T4b Locally Advanced Colon Cancer

For asymptomatic, potentially resectable T4b disease 1:

• Conversion chemotherapy ± targeted therapy as first approach 1
• Concurrent chemoradiotherapy as alternative for sigmoid colon tumors 1
• Local radiotherapy can improve remission rates and increase conversion resection probability 1

For symptomatic T4b disease 1:

• Surgery for symptom relief followed by conversion therapy if potentially resectable 1
• Interventional embolization or endoscopic treatment plus systemic therapy as alternatives 1
• Endoscopic stent implantation for obstructing lesions 1

Liver-Only Metastases

• Locoregional chemotherapy (hepatic arterial infusion) may be considered for liver-confined disease 1
• Surgical resection remains preferred when technically feasible 1

Key Toxicity Management

Oxaliplatin-Related Neuropathy 2

• For persistent grade 2 neuropathy: reduce oxaliplatin to 75 mg/m² 2
• For persistent grade 3 neuropathy: consider discontinuing oxaliplatin 2
• For grade 4 neuropathy: permanently discontinue oxaliplatin 2
• Prolonging infusion time from 2 to 6 hours may mitigate acute toxicities 2

Myelosuppression 2

• For grade 4 neutropenia or febrile neutropenia: delay next dose until neutrophils ≥1.5 × 10⁹/L and platelets ≥75 × 10⁹/L, then reduce oxaliplatin to 75 mg/m² 2
• Same approach for grade 3-4 thrombocytopenia 2

Hypersensitivity Reactions 2

• Permanently discontinue oxaliplatin for any hypersensitivity reaction, including anaphylaxis 2
• Can occur within minutes of administration and during any cycle 2

Critical Pitfalls to Avoid

• Never use adjuvant chemotherapy duration less than 6 months for stage III disease unless toxicity mandates discontinuation 1
• Avoid combining bevacizumab with anti-EGFR antibodies - this combination is not recommended and may be harmful 1
• Do not use anti-EGFR antibodies in RAS-mutant tumors - they are ineffective and add unnecessary toxicity 6
• Do not overlook MSI/dMMR testing - these patients may benefit more from immunotherapy than chemotherapy 1, 6
• Avoid aggressive chemotherapy in patients with poor performance status (ECOG ≥3 or KPS <60%) - best supportive care is more appropriate 5
• Do not perform laparoscopic surgery for colon cancer outside of clinical trials 8