Key Facts

Colorectal cancer (CRC) is one of the most common and deadly cancers in the UK, but outcomes are significantly better with early detection. The NHS bowel cancer screening programme and FIT-based triage have improved stage at diagnosis.

Epidemiology

CRC is the 3rd most common cancer in the UK (~42,900 cases/year) and the 2nd most common cause of cancer death (~16,800/year). Lifetime risk is approximately 1 in 15. Incidence increases sharply after age 50. Male:female ratio ~1.2:1. Incidence is rising in younger adults (<50 years) in the UK and globally.

Aetiology

Sporadic (~75%):

• Age >50, adenomatous polyps, obesity, physical inactivity, processed/red meat, smoking, alcohol, diabetes

Hereditary (~5-10%):

• Lynch syndrome (HNPCC): ~3-5% of CRC; autosomal dominant; mutations in MMR genes (MLH1, MSH2, MSH6, PMS2); lifetime CRC risk ~50-80%
• Familial adenomatous polyposis (FAP): APC gene; >100 adenomas; near 100% CRC risk by age 40 without surgery
• MUTYH-associated polyposis (MAP): autosomal recessive
• Peutz-Jeghers, juvenile polyposis: hamartomatous polyposis syndromes

Inflammatory (~1%):

• Ulcerative colitis/Crohn's colitis (>8-10 years of extensive disease)

Pathophysiology

The adenoma-carcinoma sequence (Vogelstein model) describes stepwise accumulation of mutations: APC loss (gatekeeper) → KRAS activation → SMAD4 loss → TP53 loss. This takes approximately 10 years, providing a window for screening and polyp removal. An alternative serrated pathway (CpG island methylator phenotype — CIMP) accounts for ~15-20% of CRC, arising from sessile serrated lesions (right colon, MSI-high, BRAF mutation).

Right-Sided (Caecum/Ascending Colon)

• Iron deficiency anaemia (often the only finding)
• Vague abdominal pain (RIF)
• Palpable RIF mass
• Weight loss
• Occult bleeding (rarely overt PR bleeding)

Left-Sided (Descending/Sigmoid Colon)

• Change in bowel habit (usually increased frequency/looser stools)
• Rectal bleeding (often mixed with stool)
• Colicky abdominal pain
• Tenesmus
• May present acutely with large bowel obstruction

Rectal Cancer

• Rectal bleeding (bright red, on/mixed with stool)
• Mucus PR
• Tenesmus and urgency
• Sensation of incomplete evacuation

Red Flags (NICE NG12 — 2WW Referral)

• Age ≥40 with unexplained weight loss + abdominal pain
• Age ≥50 with unexplained rectal bleeding
• Age ≥60 with change in bowel habit or iron deficiency anaemia
• Rectal/abdominal mass
• FIT ≥10 μg Hb/g in symptomatic patients

Bedside

• DRE: palpable rectal mass (~40% of rectal cancers within reach)
• FIT (faecal immunochemical test): ≥10 μg Hb/g in symptomatic patients triggers referral; ≥120 μg Hb/g in screening

Bloods

• FBC: iron deficiency anaemia
• LFTs: liver metastases
• CEA (carcinoembryonic antigen): baseline for post-operative monitoring (not diagnostic)
• U&Es: baseline

Imaging

• CT thorax/abdomen/pelvis: staging (TNM)
• MRI pelvis: essential for rectal cancer — local staging (T and N), mesorectal fascia involvement, EMVI status
• PET-CT: if oligometastatic disease being considered for resection
• CT colonography: alternative to colonoscopy if incomplete or contraindicated

Special Tests

• Colonoscopy + biopsy: gold standard diagnostic investigation
• Molecular profiling: RAS/BRAF mutation, MSI/dMMR status — guide targeted therapy and immunotherapy
• Lynch syndrome screening: IHC for MMR proteins on all CRC specimens (universal screening recommended); germline testing if deficient
• CT liver: detailed assessment if hepatic metastases for potential resection

Non-pharmacological

• Colorectal cancer MDT: all cases — surgeon, oncologist, radiologist, pathologist, CNS
• Enhanced recovery after surgery (ERAS): pre-habilitation, early mobilisation, early nutrition
• Stoma counselling: if stoma likely

Pharmacological

• Adjuvant chemotherapy (Stage III — node-positive):
  • FOLFOX (5-FU, leucovorin, oxaliplatin) × 3-6 months — reduces recurrence by ~20% (MOSAIC trial)
  • Capecitabine monotherapy if oxaliplatin not tolerated (X-ACT trial)
  • Stage II: selective adjuvant chemo if high-risk features (T4, <12 nodes examined, poorly differentiated, LVI, perforation)
• Neoadjuvant for rectal cancer:
  • Long-course chemoradiotherapy (capecitabine + 45 Gy) for threatened mesorectal fascia
  • Short-course radiotherapy (25 Gy in 5 fractions) followed by surgery
  • Total neoadjuvant therapy (TNT): emerging — chemotherapy + radiotherapy before surgery (RAPIDO trial)
• Metastatic CRC:
  • FOLFOX/FOLFIRI ± bevacizumab (anti-VEGF) or cetuximab/panitumumab (anti-EGFR — RAS wild-type only)
  • Immunotherapy: pembrolizumab for MSI-high/dMMR CRC (KEYNOTE-177 trial)

Surgical/Interventional

• Right hemicolectomy: caecal/ascending colon tumours
• Left hemicolectomy: descending colon
• Sigmoid colectomy: sigmoid tumours
• Anterior resection: upper/mid rectal cancer (sphincter-preserving)
• Abdominoperineal resection (APR): low rectal cancer with permanent colostomy
• TME (total mesorectal excision): standard for rectal cancer — reduces local recurrence
• Laparoscopic/robotic surgery: standard of care where available
• Liver resection: for resectable hepatic metastases (20-40% 5-year survival)
• Emergency surgery: obstruction (stenting as bridge to surgery or Hartmann's procedure), perforation

Referral Criteria

• 2WW referral per NICE NG12 criteria (see red flags above)
• All confirmed CRC to colorectal cancer MDT
• Genetics referral if Lynch syndrome, FAP, or CRC <50 years
• Hepatobiliary MDT for liver metastases

Overall 5-year survival is approximately 55%. Stage-dependent: Stage I ~90%, Stage II ~80%, Stage III ~65%, Stage IV ~10-15%. Screen-detected CRC has significantly better stage distribution and outcomes. Adjuvant FOLFOX improves 5-year DFS from ~60% to ~73% in stage III. MSI-high/dMMR CRC has better prognosis in early stages but poorer response to 5-FU alone; responds well to immunotherapy in advanced disease. Local recurrence after TME for rectal cancer is <5%. Rising incidence in under-50s is a concern.

Dukes/TNM Staging Correlation

Key Trials