Key Facts

Colorectal cancer is common and highly preventable through screening. The adenoma-carcinoma sequence provides a window for early detection and polypectomy. Treatment is multimodal, with surgery for early disease and systemic therapy for advanced disease.

Epidemiology

• UK incidence: approximately 42,900 new cases per year (4th most common cancer)
• Mortality: approximately 16,500 deaths per year (2nd most common cause of cancer death)
• Peak incidence: 70-79 years
• Male:female ratio approximately 1.2:1
• 5-year survival: approximately 60% overall; >90% for Stage I
• Incidence declining in screening-age population due to polypectomy at screening

Aetiology

• Sporadic (75-80%): accumulation of somatic mutations; risk factors include age, red/processed meat, obesity, alcohol, smoking, physical inactivity
• Hereditary:
  • Lynch syndrome (HNPCC): 3-5% of CRC; autosomal dominant; MMR mutations (MLH1, MSH2, MSH6, PMS2); 80% lifetime CRC risk
  • FAP (familial adenomatous polyposis): <1%; APC gene mutation; >100 polyps by age 20; near 100% CRC risk without prophylactic colectomy
  • MUTYH-associated polyposis: autosomal recessive; attenuated polyposis
• Inflammatory bowel disease: UC (8-10× risk after 20 years of pancolitis); Crohn's colitis

Pathophysiology

• Adenoma-carcinoma sequence (Vogelstein model): sequential mutations (APC → KRAS → TP53) over 10-15 years
• Microsatellite instability (MSI) pathway: defective MMR → accumulation of mutations at microsatellite repeats; sporadic (MLH1 promoter methylation) or hereditary (Lynch syndrome)
• Serrated pathway: BRAF mutation → sessile serrated lesions → CRC (right-sided)
• Spread: direct invasion → lymphatic → haematogenous (liver most common, then lung) → peritoneal

Right-Sided Colon Cancer

• Iron deficiency anaemia (insidious blood loss)
• Vague abdominal pain
• Palpable right iliac fossa mass
• Weight loss
• Often presents late (large bowel calibre allows growth without obstruction)

Left-Sided Colon Cancer

• Change in bowel habit (increasing constipation or alternating)
• Rectal bleeding (mixed with stool)
• Colicky abdominal pain
• Tenesmus
• May present as large bowel obstruction

Rectal Cancer

• Fresh rectal bleeding
• Mucus per rectum
• Tenesmus
• Sense of incomplete evacuation
• Palpable on digital rectal examination

Red Flags

• Unexplained iron deficiency anaemia (any age)
• Rectal bleeding with change in bowel habit
• Abdominal mass
• Large bowel obstruction
• New-onset symptoms >50 years with weight loss

Bedside

• Digital rectal examination (essential; palpable low rectal tumours)
• Abdominal examination (mass, hepatomegaly)
• FIT (faecal immunochemical test): quantitative; >10 mcg Hb/g faeces is positive

Bloods

• FBC (iron deficiency anaemia)
• U&Es, LFTs (liver metastases)
• CEA: baseline (not diagnostic; prognostic and monitoring)
• Iron studies (ferritin, transferrin saturation)

Imaging

• Colonoscopy: gold standard for diagnosis; allows biopsy and polypectomy
• CT colonography (virtual colonoscopy): alternative if colonoscopy incomplete or patient unfit
• CT chest/abdomen/pelvis: staging
• MRI pelvis: local staging for rectal cancer (T and N staging, CRM involvement)
• PET-CT: if potentially resectable metastatic disease

Special Tests

• Histopathology: adenocarcinoma subtype, grade, lymphovascular invasion
• MMR immunohistochemistry / MSI testing: all CRC (Lynch screening and treatment implications)
• RAS (KRAS/NRAS) and BRAF mutation testing: for metastatic disease (guides targeted therapy)
• Staging laparoscopy: if peritoneal disease suspected

Non-pharmacological

• MDT discussion
• Enhanced recovery after surgery (ERAS) protocol
• Stoma care specialist nurse if stoma formed
• Psychological support

Pharmacological

• Adjuvant chemotherapy (Stage III, selected Stage II with high-risk features):
  • FOLFOX (5-FU + leucovorin + oxaliplatin) × 6 months (MOSAIC trial) or 3 months (IDEA trial for low-risk Stage III)
  • Capecitabine monotherapy (alternative for Stage III; X-ACT trial)
• Neoadjuvant (rectal cancer):
  • Long-course chemoradiotherapy (capecitabine + 45-50.4 Gy RT over 5 weeks) then surgery at 6-8 weeks
  • Short-course RT (25 Gy in 5 fractions) then surgery at 1 week or delayed
  • Total neoadjuvant therapy (TNT): chemotherapy + RT before surgery (RAPIDO, PRODIGE 23 trials)
• Metastatic CRC:
  • RAS wild-type, left-sided: FOLFOX/FOLFIRI + cetuximab (anti-EGFR)
  • RAS wild-type, right-sided: FOLFOX/FOLFIRI + bevacizumab (anti-VEGF)
  • RAS mutant: FOLFOX/FOLFIRI + bevacizumab
  • MSI-H/dMMR: pembrolizumab first-line (KEYNOTE-177)
  • BRAF V600E: encorafenib + cetuximab (BEACON trial)

Surgical/Interventional

• Right hemicolectomy: caecal and ascending colon tumours
• Left hemicolectomy: descending colon tumours
• Sigmoid colectomy: sigmoid tumours
• Anterior resection: upper/mid rectal tumours
• Abdominoperineal resection (APR): low rectal tumours (permanent colostomy)
• TME (total mesorectal excision): standard for rectal cancer surgery
• Liver resection: potentially curative for isolated liver metastases (20-40% 5-year survival)
• Lung metastasectomy: selected cases
• Emergency surgery: obstruction (stenting as bridge to surgery or Hartmann's procedure), perforation

Referral Criteria

• NICE NG12 2-week wait criteria
• Positive FIT: urgent colonoscopy
• All confirmed CRC: MDT discussion
• Family history meeting criteria: genetics referral and surveillance colonoscopy

• Overall 5-year survival: 60%
• Stage I (Dukes A): >90%
• Stage II (Dukes B): 80%
• Stage III (Dukes C): 65% (with adjuvant chemotherapy)
• Stage IV (Dukes D): 10-15% (higher with resectable metastatic disease: 30-40%)
• MSI-H tumours: better prognosis at Stage II; respond well to immunotherapy at Stage IV
• CEA surveillance: rising CEA after treatment indicates recurrence
• Follow-up: CT surveillance, CEA monitoring, colonoscopy at 1 and 3 years post-surgery

Dukes vs TNM Staging

NHS Bowel Cancer Screening Programme