What are the recommended first-line and second-line treatments for Stage IV metastatic colorectal cancer?

Treatment Recommendations for Stage IV Metastatic Colorectal Cancer

For stage IV metastatic colorectal cancer, the first-line treatment should be based on molecular profiling with doublet chemotherapy plus targeted therapy, while second-line treatment should switch the chemotherapy backbone and maintain appropriate targeted therapy based on molecular status. 1

First-Line Treatment Options

Molecular Testing Before Treatment

• Complete molecular profiling is essential:
  • RAS mutation status
  • BRAF mutation status
  • MSI-H/dMMR status
  • HER2 status (for left-sided tumors)

First-Line Treatment Algorithm

1. For RAS wild-type, left-sided tumors:

   • Preferred: Doublet chemotherapy (FOLFOX or FOLFIRI) + anti-EGFR antibody (cetuximab or panitumumab) 1, 2
   • FOLFOX/FOLFIRI + cetuximab or panitumumab has shown superior outcomes for left-sided tumors

2. For RAS wild-type, right-sided tumors:

   • Preferred: Doublet chemotherapy + bevacizumab 1, 2
   • Anti-EGFR antibodies are less effective for right-sided tumors

3. For RAS-mutated tumors:

   • Doublet chemotherapy + bevacizumab 1, 2

4. For BRAF V600E-mutated tumors:

   • Consider FOLFOXIRI + bevacizumab for fit patients 1
   • Alternative: Doublet chemotherapy + bevacizumab 1

5. For MSI-H/dMMR tumors:

   • Pembrolizumab is recommended as standard of care 1

Chemotherapy Regimens

• Doublet options:

  • FOLFOX: Oxaliplatin 85 mg/m² IV over 2h on day 1 + leucovorin 200 mg/m² IV over 2h followed by fluorouracil 400 mg/m² bolus and 600 mg/m² IV over 22h on days 1 and 2, every 2 weeks 1
  • FOLFIRI: Irinotecan 180 mg/m² + leucovorin 400 mg/m² + 5-FU 400 mg/m² bolus followed by 2400-3000 mg/m² over 46 hours, every 2 weeks
  • CAPOX (XELOX): Oxaliplatin 130 mg/m² IV day 1 + capecitabine 1000 mg/m² twice daily days 1-14, every 3 weeks 3

• Triplet option (for selected fit patients):

  • FOLFOXIRI + bevacizumab: Higher response rates but increased toxicity 1, 4
  • Not recommended for patients >75 years old, PS2, or significant comorbidities 1

• Less intensive options (for frail/elderly patients):

  • Fluoropyrimidine monotherapy + bevacizumab 1, 2
  • For left-sided RAS-wt tumors in frail patients: Consider anti-EGFR monotherapy 1

Maintenance Therapy

• After oxaliplatin-based therapy + bevacizumab:

  • Maintenance with fluoropyrimidine + bevacizumab after at least 4 months of induction 1
  • Consider oxaliplatin discontinuation after 3-4 months to prevent neurotoxicity 1

• After oxaliplatin-based therapy + anti-EGFR:

  • Maintenance with fluoropyrimidine + anti-EGFR mAbs 1

• After FOLFIRI-based therapy:

  • Continue full therapy until disease progression due to lack of cumulative toxicity 1

Second-Line Treatment

The second-line treatment should switch the chemotherapy backbone while maintaining appropriate targeted therapy based on molecular status. 1

1. After first-line oxaliplatin-based therapy:

   • Irinotecan-based therapy (FOLFIRI) or irinotecan monotherapy 1
   • Add bevacizumab regardless of prior bevacizumab use 1, 5
   • For RAS-wt left-sided tumors not previously treated with anti-EGFR: Consider FOLFIRI/irinotecan + cetuximab/panitumumab 1

2. After first-line irinotecan-based therapy:

   • Oxaliplatin-based therapy (FOLFOX or CAPOX) 1, 6
   • Add bevacizumab 1, 5

3. For BRAF V600E-mutated tumors:

   • Encorafenib + cetuximab (highest level of evidence) 1

4. For dMMR/MSI-H tumors:

   • Ipilimumab + nivolumab 1

Third-Line and Beyond

1. Consider reintroduction of initial induction therapy if patient did not progress during first-line induction 1

2. For pre-treated patients:

   • Regorafenib 1
   • Trifluridine-tipiracil 1

3. For RAS-wt and BRAF-wt patients not previously treated with EGFR antibodies:

   • Cetuximab or panitumumab as single agents 1
   • For irinotecan-refractory patients: Cetuximab + irinotecan preferred over cetuximab alone 1

4. For BRAF V600E-mutated tumors:

   • Encorafenib + cetuximab 1

5. For HER2-positive tumors:

   • Consider HER2 dual blockade, especially in RAS-wt tumors 1

Important Considerations and Pitfalls

• Avoid combining anti-VEGF and anti-EGFR agents - this combination increases toxicity without improving outcomes 1

• Do not use an alternative anti-EGFR antibody after failure on one anti-EGFR antibody 1

• When using bevacizumab:

  • Withhold for at least 28 days prior to elective surgery 5
  • Do not administer until at least 28 days following major surgery 5

• Monitor for toxicities:

  • Oxaliplatin: Neurotoxicity (consider discontinuation after 3-4 months) 1
  • Irinotecan: Diarrhea, neutropenia 1
  • Capecitabine: Hand-foot syndrome 3, 7
  • Bevacizumab: Increased risk of stroke and arterial events, especially in patients ≥65 years 1

• Radiological evaluation:

  • Every 8-12 weeks during active treatment (CT scan or MRI plus CEA levels) 1
  • More frequent monitoring may be needed for patients with potentially curable metastatic disease 1