What is the latest management approach for Colorectal Cancer (CRC)?

Latest Management of Colorectal Cancer (CRC)

The latest management approach for colorectal cancer requires molecular profiling to guide personalized treatment decisions, with specific therapies based on tumor location, molecular subtypes, and disease stage. 1

Initial Assessment and Staging

• Complete staging workup should include:
  • Clinical examination
  • Blood counts and liver/renal function tests
  • Carcinoembryonic antigen (CEA) measurement
  • CT scan of abdomen and chest (or MRI)
  • Molecular profiling for:
    • RAS mutation status
    • BRAF V600E mutation
    • Microsatellite instability (MSI)/mismatch repair (MMR) status
    • Tumor mutational burden (TMB) when appropriate

Treatment Approach Based on Disease Stage

Metastatic Colorectal Cancer (mCRC)

First-line Treatment Options:

1. For MSI-H/dMMR tumors:

   • Pembrolizumab is recommended as first-line therapy 1

2. For MSS/pMMR RAS wild-type tumors:

   • Left-sided primary tumors: Chemotherapy plus anti-EGFR therapy (cetuximab or panitumumab) 1
   • Right-sided primary tumors: Chemotherapy plus anti-VEGF therapy (bevacizumab) 1

3. For RAS-mutant tumors:

   • Chemotherapy plus anti-VEGF therapy (bevacizumab) 1

4. Chemotherapy backbone options:

   • Doublet chemotherapy (FOLFOX or FOLFIRI) for most patients
   • Triplet chemotherapy (FOLFOXIRI) may be considered for selected patients with good performance status 1

Second-line and Beyond:

1. For BRAF V600E-mutant mCRC:

   • Encorafenib plus cetuximab is recommended after progression on first-line therapy 1, 2

2. For refractory mCRC:

   • Trifluridine-tipiracil with or without bevacizumab 1
   • Regorafenib for patients who have progressed on standard therapies 1, 3
   • These agents can be given in sequence; optimal order is not established 1

Oligometastatic Disease

1. Liver-limited metastases:

   • Potentially curative resection should be offered when feasible
   • Perioperative chemotherapy or surgery alone for resectable liver metastases 1
   • Stereotactic body radiation therapy (SBRT) may be recommended for patients with liver oligometastases who are not candidates for resection 1

2. Colorectal peritoneal metastases:

   • Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients
   • Hyperthermic intraperitoneal chemotherapy (HIPEC) is NOT recommended 1

Special Considerations

Elderly Patients

• Comprehensive geriatric assessment is recommended for patients >65 years of age requiring surgery 1
• Treatment decisions should consider physiological age rather than chronological age
• For frail elderly patients, sequential therapy starting with fluoropyrimidine monotherapy may be appropriate 1

Surveillance After Curative Treatment

• History and physical examination every 3 months for first 2 years, then every 6 months for next 5 years
• CEA testing at baseline and every 3 months for 2 years, then every 6 months for 2-5 years
• Colonoscopy within 1 year of resection (or 3-6 months postoperatively) 1

Common Pitfalls and Caveats

1. RAS/BRAF testing is mandatory before anti-EGFR therapy:

   • Cetuximab and panitumumab are ineffective and potentially harmful in RAS-mutant tumors 2
   • Always confirm wild-type status before initiating therapy

2. Primary tumor sidedness matters:

   • Right-sided tumors respond poorly to anti-EGFR therapy even if RAS wild-type
   • Left-sided tumors have better prognosis and response to targeted therapies

3. MSI/MMR testing is essential:

   • Immunotherapy is highly effective for MSI-H/dMMR tumors but ineffective for MSS/pMMR tumors without high TMB

4. Avoid selective internal radiation therapy:

   • Not routinely recommended for patients with liver metastases 1

5. Treatment sequencing is important:

   • Exposure to all active agents (fluoropyrimidines, oxaliplatin, irinotecan) across treatment lines improves overall survival
   • Consider treatment goals (symptom control vs. tumor shrinkage) when selecting intensity of therapy

The management of CRC has evolved significantly with molecular profiling now guiding treatment decisions. A multidisciplinary approach involving surgical oncologists, medical oncologists, radiation oncologists, and pathologists is essential for optimal outcomes.