Key Facts

Pancreatic cancer is one of the most lethal malignancies, with an overall 5-year survival of <10%. Late presentation, early metastasis, and resistance to chemotherapy contribute to the dismal prognosis.

Epidemiology

~10,500 new cases per year in the UK (10th most common cancer but 5th cause of cancer death). Incidence is rising. Median age at diagnosis 72 years. Slight male predominance. Lifetime risk ~1 in 70.

Aetiology

• Smoking: strongest modifiable risk factor (2x risk, 25% attributable fraction)
• Chronic pancreatitis: 15x risk (especially hereditary pancreatitis — 50x)
• New-onset diabetes: 1-2% of new diabetes >50 years will have pancreatic cancer within 3 years
• Obesity: 20% increased risk
• Family history: 5-10% have familial predisposition (BRCA2, PALB2, ATM, STK11/Peutz-Jeghers, Lynch syndrome, FAMMM)
• Chronic alcohol excess: via chronic pancreatitis rather than direct effect

Pathophysiology

PDAC arises from pancreatic intraepithelial neoplasia (PanIN) through stepwise genetic mutations: KRAS (>90%, earliest), CDKN2A/p16, TP53, SMAD4 (DPC4). The tumour creates a dense desmoplastic stroma (hypoxic, immunosuppressive microenvironment) that limits drug delivery and immune cell infiltration. Perineural invasion is characteristic and contributes to severe pain. Early lymphatic and haematogenous metastasis (liver, peritoneum, lungs) is common.

Head of Pancreas (60-70%)

• Painless progressive obstructive jaundice (dark urine, pale stools, pruritus)
• Courvoisier's sign: palpable, non-tender gallbladder + painless jaundice
• Weight loss
• Steatorrhoea (biliary obstruction → reduced bile salts → fat malabsorption)
• New-onset diabetes

Body/Tail (30-40%)

• Epigastric pain radiating to back (often dull, constant, worse lying flat)
• Weight loss (often profound — >10% body weight)
• New-onset diabetes
• Present later → even poorer prognosis

Metastatic Disease

• Hepatomegaly, ascites (peritoneal carcinomatosis)
• Sister Mary Joseph nodule, Virchow's node
• Trousseau syndrome (migratory thrombophlebitis — paraneoplastic DVT)

Red Flags

• Painless jaundice in any age group
• New diabetes >50 years with weight loss
• Unexplained weight loss with back/epigastric pain
• Migratory thrombophlebitis (Trousseau syndrome)
• NICE NG12: urgent 2WW referral for ≥40 with jaundice, or CT within 2 weeks for upper abdominal mass

Bedside

• History: weight loss, jaundice, new diabetes, smoking/alcohol, family history
• Examination: jaundice, palpable gallbladder, hepatomegaly, ascites, Virchow's node

Bloods

• LFTs: obstructive pattern (raised ALP, GGT, conjugated bilirubin)
• CA19-9: raised in ~80% of PDAC; >37 U/mL; useful for monitoring treatment response; can be falsely raised in obstructive jaundice, cholangitis; falsely normal in Lewis antigen-negative patients (~10%)
• FBC: anaemia
• HbA1c: new diabetes screening
• Coagulation (INR): may be deranged (vitamin K malabsorption in obstructive jaundice)

Imaging

• CT thorax/abdomen/pelvis (pancreatic protocol): triple-phase (arterial, portal, delayed); gold standard for diagnosis and resectability assessment; assesses vascular involvement (SMA, coeliac, portal vein, SMV)
  • Resectability: resectable (no vascular involvement), borderline resectable (vascular contact <180°), locally advanced unresectable (>180° arterial encasement), metastatic
• MRCP: biliary and pancreatic duct assessment
• EUS ± FNA: tissue diagnosis (if CT inconclusive or tissue confirmation needed for oncological treatment); staging
• PET-CT: assess for occult metastases in borderline resectable disease
• Staging laparoscopy: identify occult peritoneal disease (changes management in ~15%)

Special Tests

• Molecular profiling: KRAS, BRCA1/2 (for olaparib eligibility — POLO trial), MSI/dMMR status
• Germline testing: BRCA2, PALB2 if family history or young onset
• Biliary stenting (ERCP): for palliation of jaundice or pre-operative biliary drainage (controversial — mainly if jaundice severe or delayed surgery)

Non-pharmacological

• HPB MDT discussion: all cases
• Nutritional support: dietitian, PERT (CREON), manage diabetes
• Biliary drainage: ERCP + metal stent for palliation of jaundice; plastic stent as temporary bridge in resectable disease
• Psychological support: cancer nurse specialist

Pharmacological

• Adjuvant (post-resection):
  • Modified FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) × 12 cycles: current standard (PRODIGE 24/CCTG PA.6 trial — median DFS 21.6 vs 12.8 months)
  • Gemcitabine + capecitabine: alternative if FOLFIRINOX not tolerated (ESPAC-4 trial)
• Neoadjuvant: increasingly used for borderline resectable — FOLFIRINOX or gemcitabine/nab-paclitaxel; aims to downstage and improve R0 resection rate
• Palliative chemotherapy (advanced/metastatic):
  • FOLFIRINOX (fit patients — median OS 11.1 months, ACCORD 11 trial)
  • Gemcitabine + nab-paclitaxel (median OS 8.5 months, MPACT trial)
  • Gemcitabine monotherapy (if unfit)
• Targeted: olaparib maintenance for BRCA-mutated PDAC after platinum chemotherapy (POLO trial)
• Pain management: WHO analgesic ladder; pregabalin/amitriptyline as adjuvants; EUS-guided coeliac plexus neurolysis for severe pain

Surgical/Interventional

• Pancreaticoduodenectomy (Whipple): for head/uncinate tumours; ~5% perioperative mortality at high-volume centres
• Distal pancreatectomy + splenectomy: for body/tail tumours
• Total pancreatectomy: for multifocal disease or positive resection margin
• Vascular resection/reconstruction: in borderline resectable disease at specialist centres
• Palliative procedures: biliary stenting (ERCP/PTC), gastrojejunostomy (duodenal obstruction), coeliac plexus neurolysis (pain)

Referral Criteria

• 2WW referral per NICE NG12
• All confirmed cases to HPB MDT
• Specialist HPB centre for surgery (centralised service)
• Genetics referral if family history or BRCA/PALB2 mutation carriers
• Palliative care early involvement for advanced disease

Overall 5-year survival <10% (~7%). Resectable disease (15-20% at diagnosis): median survival 20-24 months with adjuvant mFOLFIRINOX; 5-year survival ~20-30% after R0 resection. Locally advanced unresectable: median survival ~12-15 months. Metastatic: median survival ~6-11 months. FOLFIRINOX improved outcomes significantly compared to gemcitabine alone. Perioperative mortality at high-volume centres is ~3-5%. Poor prognostic factors: positive margin (R1), node-positive, high CA19-9, poor differentiation.

Resectability Classification

Key Trials