Colorectal Cancer Treatment Algorithm

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NCCN & ESMO Aligned Treatment Pathways

Initial Assessment & Staging

Required Staging

  • • CT chest, abdomen, pelvis with contrast
  • • Pelvic MRI for rectal cancer
  • • CEA baseline level
  • • Performance status (ECOG)
  • • Multidisciplinary team review

Molecular Testing (All Stages)

  • • MSI/MMR status - Universal testing
  • • RAS testing (KRAS/NRAS) - Mandatory
  • • BRAF V600E - Prognostic significance
  • • HER2 amplification - Consider if RAS wild-type
  • • Tumor sidedness - Left vs right colon

Treatment Decision Algorithm

Stage I-III (Curative Intent)

Stage I (T1-2, N0)
Treatment: Surgery alone
• No adjuvant chemotherapy required
• Follow-up surveillance only
• Consider high-risk features
Stage II (T3-4, N0)
High Risk Features:
  • • T4 disease
  • • Grade 3/4 tumor
  • • LVI present
  • • <12 lymph nodes examined
  • • Bowel obstruction/perforation
MSI-H: No adjuvant chemotherapy
MSS + High Risk: Consider FOLFOX/CAPOX
Stage III (Any T, N+)
Standard Adjuvant:
  • • FOLFOX (6 months)
  • • CAPOX (6 months)
  • • Consider 3 months if low risk
MSI-H Stage III: Standard chemotherapy still recommended

Stage IV (Metastatic Disease)

First-Line Treatment Selection
RAS Wild-Type (30-40%)
Left-sided primary:
FOLFOX/FOLFIRI + Cetuximab
or Panitumumab
Right-sided primary:
FOLFOX/FOLFIRI + Bevacizumab
EGFR inhibitors less effective
Consider BRAF status: BRAF mutant has poor prognosis
RAS Mutant (60-70%)
Standard backbone:
FOLFOX or FOLFIRI + Bevacizumab
HER2 amplified (3-5%):
Trastuzumab + Pertuzumab
Consider clinical trial
MSI-H (4%): Consider pembrolizumab monotherapy
Second & Third-Line Options
Second-Line
  • • Alternative backbone (FOLFOX↔FOLFIRI)
  • • Switch biologics if RAS WT
  • • Aflibercept + FOLFIRI
  • • Regorafenib (third-line)
Third-Line+
  • • Regorafenib
  • • Trifluridine/tipiracil (TAS-102)
  • • Encorafenib + cetuximab (BRAF V600E)
  • • Clinical trials
Special Populations
  • • MSI-H: Pembrolizumab
  • • HER2+: Trastuzumab-based
  • • NTRK fusion: Larotrectinib
  • • BRAF V600E: Encorafenib combo

Key Clinical Decision Points

Resectability Assessment

  • • Upfront resectable: Surgery first
  • • Borderline resectable: Neoadjuvant chemotherapy
  • • Unresectable: Palliative systemic therapy
  • • Consider conversion to resectability

Biomarker Testing Timeline

  • • MSI/MMR: At diagnosis (all stages)
  • • RAS/BRAF: Before first-line (Stage IV)
  • • HER2: If RAS wild-type and considering options
  • • Liquid biopsy: If tissue insufficient

Evidence Base & Guidelines

• NCCN Guidelines Version 3.2025 - Colon Cancer

• ESMO Clinical Practice Guidelines 2023 - Colorectal Cancer

• NICE NG151 - Colorectal cancer (2020, updated 2023)

• MOSAIC, IDEA, KEYNOTE-177, BEACON CRC trials