Key Facts

Pancreatic cancer is one of the most aggressive malignancies with few effective treatments. Research into early detection and novel therapies is a priority.

Epidemiology

• ~10,500 new cases/year in the UK
• ~9,800 deaths/year (almost equal incidence and mortality — reflects poor prognosis)
• Median age: 72 years
• Incidence increasing slightly
• 5-year survival: approximately 7%

Aetiology

• Smoking: most important modifiable risk factor (2× risk; 25% of cases)
• Chronic pancreatitis: 10-15× risk
• Diabetes mellitus: 2× risk (and new-onset diabetes can be an early sign)
• Obesity: 1.5× risk
• Family history: 5-10% have hereditary predisposition (BRCA2, PALB2, CDKN2A, Lynch syndrome, Peutz-Jeghers)
• Alcohol: indirect risk via chronic pancreatitis

Pathophysiology

• KRAS mutation: present in >90% (constitutive activation of RAS-MAPK pathway)
• TP53, CDKN2A, SMAD4 loss: common tumour suppressor mutations
• Dense desmoplastic stroma: creates hypoxic, immunosuppressive microenvironment (contributes to treatment resistance)
• 60-70% arise in the head of the pancreas
• Early perineural invasion and lymphatic spread
• Metastases: liver (most common), peritoneum, lung

Head of Pancreas (60-70%)

• Painless obstructive jaundice: progressive, dark urine, pale stools, pruritus
• Courvoisier's sign (palpable, non-tender gallbladder)
• Weight loss
• New-onset diabetes (may precede cancer diagnosis by 1-2 years)

Body/Tail of Pancreas (30-40%)

• Epigastric pain radiating to the back (often worse at night, relieved by leaning forward)
• Weight loss
• Often presents later (no jaundice)

Advanced Disease

• Ascites (peritoneal carcinomatosis)
• Hepatomegaly (liver metastases)
• Gastric outlet obstruction (nausea, vomiting)
• Trousseau's syndrome (migratory thrombophlebitis)
• Depression (may precede diagnosis)

Red Flags

• Painless jaundice in adults >40
• New-onset diabetes >50 with weight loss
• Epigastric pain radiating to back with weight loss
• Unexplained acute pancreatitis >60
• Courvoisier's sign

Bedside

• Abdominal examination (jaundice, palpable gallbladder, hepatomegaly, ascites)
• Urine dipstick (bilirubin)

Bloods

• LFTs (obstructive pattern: raised ALP, GGT, bilirubin)
• CA 19-9: elevated in 80% (also raised in obstructive jaundice without cancer; not suitable for screening)
• FBC, U&Es, coagulation (vitamin K deficiency from obstructive jaundice)
• HbA1c (new-onset diabetes)

Imaging

• CT pancreas protocol (triple-phase contrast-enhanced CT): investigation of choice for diagnosis and resectability assessment
• MRCP: biliary anatomy, alternative if CT indeterminate
• EUS with FNA: tissue diagnosis; best for small lesions and locoregional staging
• PET-CT: detect occult metastases in potentially resectable disease
• Staging laparoscopy: mandatory before resection (peritoneal disease missed by CT in 10-20%)

Special Tests

• EUS-guided FNA/biopsy: tissue confirmation (especially before neoadjuvant chemo or if unresectable)
• ERCP with stenting: for biliary decompression pre-operatively (only if delayed surgery or cholangitis)
• Germline testing: all patients with pancreatic cancer (BRCA2, PALB2, Lynch — guides PARP inhibitor use)
• Faecal elastase if exocrine insufficiency suspected

Non-pharmacological

• MDT discussion mandatory
• Nutritional support (PERT — pancreatic enzyme replacement: Creon)
• Psychological support
• Specialist palliative care involvement early

Pharmacological

• Resectable: adjuvant modified FOLFIRINOX (mFOLFIRINOX) × 12 cycles (PRODIGE-24 trial) or gemcitabine + capecitabine (ESPAC-4)
• Borderline resectable: neoadjuvant mFOLFIRINOX or gemcitabine + nab-paclitaxel then surgery
• Locally advanced unresectable: mFOLFIRINOX or gemcitabine + nab-paclitaxel (MPACT trial)
• Metastatic (good PS): mFOLFIRINOX (PRODIGE-4/ACCORD 11) or gemcitabine + nab-paclitaxel
• Metastatic (poor PS): gemcitabine monotherapy
• BRCA-mutated: olaparib maintenance after platinum-based chemo (POLO trial)
• PERT (Creon): pancreatic enzyme replacement for exocrine insufficiency (50,000 units lipase with main meals)

Surgical/Interventional

• Pancreaticoduodenectomy (Whipple procedure): for resectable head of pancreas tumours; includes distal gastrectomy, duodenum, head of pancreas, CBD, gallbladder
• Distal pancreatectomy + splenectomy: for body/tail tumours
• Biliary stenting (ERCP or PTC): palliative for jaundice in unresectable disease
• Gastrojejunostomy: bypass for gastric outlet obstruction
• Coeliac plexus block: for pain management in advanced disease

Referral Criteria

• Suspected pancreatic cancer: urgent CT and 2-week wait HPB referral
• All confirmed cancers: HPB cancer MDT
• BRCA/Lynch carriers: genetics referral
• Palliative care: early referral recommended (NICE)

• Resectable with adjuvant chemo: median survival 28-54 months (mFOLFIRINOX adjuvant: median OS 54 months — PRODIGE-24)
• Locally advanced: median survival 12-18 months
• Metastatic (mFOLFIRINOX): median survival 11 months
• Metastatic (gemcitabine alone): median survival 6-7 months
• Overall 5-year survival: approximately 7%
• Only 10-20% are resectable at diagnosis
• 5-year survival after Whipple + adjuvant chemo: 20-30%
• Operative mortality for Whipple: 2-5% in high-volume centres

Resectability Criteria

Key Trials