1. Epidemiology & Risk Factors
- Most common sites: sigmoid colon, rectum, ascending colon
- Risk factors:
- Age >50, family history, Lynch syndrome, FAP
- Inflammatory bowel disease (ulcerative colitis, Crohn’s)
- Lifestyle: red/processed meat, obesity, alcohol, smoking
- Low fiber diet
2. Pathophysiology
- Adenoma-carcinoma sequence: APC mutation → KRAS mutation → TP53 mutation
- Microsatellite instability (MSI): due to MMR deficiency
- Chromosomal instability (CIN): common in sporadic CRC
3. Molecular Classification
| Marker | Frequency | Clinical Implication |
|---|---|---|
| KRAS/NRAS mutation | ~40% | Predicts lack of response to anti-EGFR therapy |
| BRAF V600E mutation | 5–10% | Poor prognosis; may guide therapy (BRAF inhibitors ± anti-EGFR) |
| MMR/MSI status | ~15% early-stage | dMMR/MSI-H → immunotherapy sensitive |
| HER2 amplification | <5% | Potential for anti-HER2 therapy in metastatic disease |
4. Clinical Presentation
- Left-sided (rectum/sigmoid): hematochezia, altered bowel habits, obstruction
- Right-sided (ascending colon): anemia, fatigue, occult bleeding
- Advanced/metastatic: liver metastases, lung metastases, peritoneal spread
5. Diagnosis & Staging
- Colonoscopy with biopsy → gold standard
- CT chest/abdomen/pelvis → assess metastases
- MRI pelvis → for rectal cancer staging
- CEA tumor marker → surveillance and monitoring
- Molecular testing: KRAS/NRAS, BRAF, MMR/MSI
Staging: TNM system (I–IV)
6. Treatment Overview
| Stage | Treatment | Notes |
|---|---|---|
| I | Surgery alone | Good prognosis |
| II | Surgery ± adjuvant chemo (FOLFOX or 5-FU/LV) | High-risk features; dMMR stage II may not benefit from 5-FU monotherapy |
| III | Surgery + adjuvant chemo (FOLFOX preferred) | 6 months standard; CAPOX alternative |
| IV (resectable metastases) | Surgery ± perioperative chemo | Metastasectomy if liver/lung isolated lesions |
| IV (unresectable) | Systemic chemo ± biologics | FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab (anti-VEGF) or cetuximab/panitumumab (if RAS WT, left-sided) |
Targeted & Immunotherapy:
- RAS WT: anti-EGFR therapy
- BRAF V600E: BRAF inhibitor combos
- dMMR/MSI-H: pembrolizumab or nivolumab ± ipilimumab
7. Surveillance After Resection
- History & physical + CEA: every 3–6 months × 2 years, then every 6 months × 3 years
- CT chest/abdomen/pelvis: every 6–12 months × 3 years
- Colonoscopy: 1 year post-op, then 3 years, then 5 years
8. Common Adverse Effects of Therapy
| Drug/Class | Key Toxicities | Monitoring |
|---|---|---|
| 5-FU / Capecitabine | Diarrhea, mucositis, myelosuppression | CBC, electrolytes |
| Oxaliplatin | Peripheral neuropathy, cold sensitivity | Neuro exam |
| Irinotecan | Early (cholinergic) & late diarrhea | Hydration, loperamide, atropine |
| Bevacizumab | HTN, proteinuria, GI perforation, bleeding | BP, urinalysis |
| Cetuximab / Panitumumab | Acneiform rash, hypomagnesemia | Skin care, Mg monitoring |
| Immunotherapy | Colitis, hepatitis, endocrinopathies | LFTs, TFTs, symptoms |
9. Key Clinical Pearls
- Left-sided, RAS WT: better response to anti-EGFR therapy
- Right-sided, RAS WT: better response to chemo + bevacizumab
- dMMR/MSI-H: poor response to 5-FU monotherapy, responsive to checkpoint inhibitors
- Single liver or lung metastasis: consider curative-intent resection