Upper GI and hepatobiliary cancers, hepatocellular carcinoma (screening, staging, transplant), gastric cancer (lymphadenectomy), pancreatic cancer (Whipple)

Epidemiology and Risk Factors

• HCC is one of the most common and lethal malignancies worldwide, with rising incidence in Western countries including Australia
• Risk factors include:
  • Hepatitis B virus (HBV) infection, including in non-cirrhotic liver
  • Hepatitis C virus (HCV) associated cirrhosis
  • Cirrhosis from any cause (present in approximately 90% of standard HCC cases)
  • Diabetes mellitus independently increases HCC risk
  • Metabolic syndrome and its components
  • Alcohol-related liver disease
  • Exposure to oral contraceptives, anabolic steroids, and certain chemotherapeutic agents
  • In children: Beckwith-Wiedemann syndrome, hemihypertrophy, von Gierke disease, Fanconi syndrome, hepatitis B

Fibrolamellar HCC: A Distinct Variant

• Fibrolamellar HCC carries a relatively better prognosis when resected but lymph node metastases predict worse outcome
• 5-year survival after complete resection is expected in approximately 50% to 75%, but recurrence is common, occurring in at least 80% of patients

Tumour Markers

• Alpha-fetoprotein (AFP) is the primary serum marker used in HCC surveillance and diagnosis
• AFP is elevated in approximately 80% of standard HCC cases, but only ~5% of fibrolamellar HCC
• AFP is not specific to HCC; elevated AFP can be seen with:
  • AFP-producing gastric cancers
  • AFP-producing non-germ cell tumours of the female genital tract
• Triple positive tumour markers (e.g. AFP, AFP-L3, des-gamma-carboxyprothrombin) are useful predictors of poor survival following resection or transplantation

Screening

• Screening targets high-risk populations: patients with cirrhosis, chronic HBV (even without cirrhosis), and other chronic liver disease populations
• Standard surveillance tool is ultrasound with or without AFP, performed at 6-monthly intervals in at-risk patients
• The rationale for screening is detection of early-stage HCC amenable to curative therapy (resection, ablation, or transplantation)
• Diagnosis of HCC in a cirrhotic liver with an arterially enhancing liver mass can often be made radiologically without biopsy, using characteristic imaging features (arterial enhancement with venous washout on dynamic contrast CT or MRI)

Staging Systems

Multiple staging systems exist; the most clinically relevant for surgical planning is the BCLC (Barcelona Clinic Liver Cancer) classification.

BCLC Staging

• The BCLC system incorporates tumour burden, liver functional reserve (Child-Pugh score), and performance status
• It provides both prognostic prediction and treatment strategy guidance
• Other staging systems used include CLIP score, JIS (Japan Integrated Staging) score, and AJCC TNM staging; modified JIS has been shown to perform well specifically in patients who have undergone hepatectomy

Hepatic Resection

Patient Selection

• Resection is the primary curative option for HCC in patients with preserved liver function and adequate future liver remnant (FLR)
• Key negative prognostic factors after resection include:
  • Tumour size (though size alone should not contraindicate resection)
  • Presence of cirrhosis
  • Infiltrative growth pattern
  • Vascular invasion (macro- or microvascular)
  • Intrahepatic metastases
  • Multifocal tumours
  • Lymph node metastases
  • Surgical margin less than 1 cm
  • Lack of a tumour capsule
• Best outcomes are seen in patients with single small tumours, but even large tumours (above 5 cm) should be considered for resection because size above 5 cm does not independently preclude long-term survival
• For patients with large tumours outside transplant criteria, resection may be the only therapeutic option with curative intent

Liver Functional Assessment Before Resection

• Child-Pugh score is the standard clinical measure of hepatic reserve
• Patients with Child-Pugh A are generally suitable for resection; Child-Pugh B/C significantly increases risk of post-hepatectomy liver failure
• Cirrhosis substantially increases operative risk: abdominal operations in cirrhotic patients carry markedly higher rates of liver-related complications, hepatic dysfunction or insufficiency, prolonged hospital stay, and 90-day mortality

Future Liver Remnant (FLR) and Portal Vein Embolisation (PVE)

• Measurement of liver volume and hepatic functional reserve is essential for decision-making before major hepatic resection
• The standardised FLR (sFLR) is calculated volumetrically:

$$\text{sFLR} = \frac{\text{FLR volume}}{\text{Total liver volume}} \times 100\%$$

• An sFLR that is inadequate (particularly when planned right hepatectomy leaves a very small remnant) necessitates portal vein embolisation (PVE) to induce hypertrophy of the FLR before surgery
• Example: sFLR of 12% pre-PVE rising to 22% post-PVE (10% degree of hypertrophy) after right PVE and segment IV embolisation, enabling safe extended right hepatectomy
• Post-hepatectomy liver failure risk rises steeply when the remnant volume is insufficient; modern surgical series emphasise FLR assessment to reduce this complication

Contraindications to Resection

• Extrahepatic metastases
• Major vascular invasion precluding safe resection
• Insufficient FLR (without the ability to augment via PVE or staged hepatectomy)
• Decompensated cirrhosis (Child-Pugh B/C with portal hypertension, ascites, encephalopathy)
• Performance status incompatible with major surgery

Microvascular Invasion and Margin

• Microvascular invasion (MVI) has been cited as a predictor of recurrence but evidence suggests it may not reliably predict long-term survival after resection in all series
• A surgical margin of at least 1 cm is associated with better outcomes; margins less than 1 cm are a recognised negative prognostic factor

Liver Transplantation

Milan Criteria (Standard Criteria)

• The Milan criteria define the widely accepted standard for transplant eligibility in HCC:
  • Single tumour up to 5 cm, OR
  • Up to 3 nodules, none exceeding 3 cm
  • No macrovascular invasion
  • No extrahepatic spread
• Patients meeting Milan criteria achieve outcomes after transplantation comparable to transplantation for non-malignant indications
• Transplantation treats both the tumour and the underlying cirrhosis, addressing the field defect that drives recurrence

Expanded Criteria

• Multiple centres have explored expanding beyond Milan criteria while maintaining acceptable post-transplant survival:
  • Various institutional criteria (e.g. UCSF criteria and Asian centre criteria) have been proposed
  • Living donor liver transplantation (LDLT) has facilitated expanded criteria at experienced Asian centres
  • Outcomes beyond Milan criteria are variable and centre-dependent
• Key principle: patients who benefit from transplantation are those where the survival benefit of transplant outweighs that of remaining on the waiting list or receiving alternative therapy

Transplant vs Resection Decision

• For patients with early HCC on a background of cirrhosis, transplantation addresses the underlying liver disease and offers lower recurrence rates compared to resection
• For patients with preserved liver function and no cirrhosis, resection is preferred as first-line curative therapy
• Transplant is preferred when:
  • Patient has cirrhosis with portal hypertension or compromised hepatic reserve
  • Tumour is within Milan criteria but not safely resectable
  • Tumour is within Milan criteria and resection would leave inadequate FLR

Pretransplant Oncological Assessment

• Pretransplant evaluation should include assessment of AFP, AFP-L3, and des-gamma-carboxyprothrombin as prognostic markers
• Bridging therapy (TACE, ablation) is used while awaiting transplantation to prevent tumour progression beyond Milan criteria
• Downstaging therapy is used to bring patients outside Milan criteria back within transplant eligibility

Locoregional and Systemic Therapy

Transarterial Chemoembolisation (TACE)

• First-line locoregional therapy for BCLC stage B (intermediate, unresectable, non-metastatic) HCC
• Randomised trials demonstrated that chemoembolisation improves survival in unresectable HCC compared to best supportive care
• HCC tumours are predominantly arterially supplied, allowing selective intra-arterial delivery of chemotherapy combined with embolisation

Ablative Therapy

• Percutaneous ablation (radiofrequency ablation, microwave ablation) is appropriate for small, unresectable HCC lesions (BCLC 0 and A not suitable for resection or transplant)
• Randomised trials support ablation as an effective local therapy for early-stage disease

Systemic Therapy: Sorafenib

• Sorafenib is a multikinase inhibitor targeting VEGFR-2, PDGFR, FLT3, Raf-1, Ret, and c-Kit
• Two landmark phase III randomised controlled trials:
  • SHARP trial (Western population): statistically significant improvement in overall survival of 2.8 months for advanced HCC
  • Asia-Pacific trial: overall survival improvement of 2.3 months
• Sorafenib is indicated for BCLC stage C (advanced) HCC
• Adjuvant sorafenib after resection has been studied and concluded to not be effective as adjuvant therapy

Cytotoxic Chemotherapy

• Cytotoxic chemotherapy has historically shown modest effects in HCC
• Better responses seen in patients with minimal underlying liver disease (no hepatitis or cirrhosis)
• Modified PIAF regimen (cisplatin, interferon alpha-2b, doxorubicin, 5-fluorouracil) has shown improved response rate, resectability, and survival in initially unresectable HCC patients without hepatitis or cirrhosis:
  • Cisplatin $20 \text{ mg/m}^2$ days 1-4
  • Interferon alpha-2b $4 \text{ MU/m}^2$ days 1-4
  • Doxorubicin $40 \text{ mg/m}^2$ day 1
  • 5-Fluorouracil $400 \text{ mg/m}^2$ bolus infusion days 1-4
• Standard PIAF uses cisplatin $20 \text{ mg/m}^2$ days 1-4, interferon alpha-2b $5 \text{ MU/m}^2$ days 1-4, doxorubicin $40 \text{ mg/m}^2$ day 1, and 5-FU $500 \text{ mg/m}^2$ over 24 hours days 1-4

Immunotherapy

• Immunotherapies for HCC are an evolving area, with checkpoint inhibitors being investigated as systemic options
• NASH (non-alcoholic steatohepatitis) as the underlying liver disease has been shown to limit anti-tumour immune surveillance in immunotherapy-treated HCC, potentially limiting efficacy in this population

Increasing Resectability in Large HCC

• For patients with large or otherwise unresectable HCC and adequate performance status, a number of strategies can convert unresectable to resectable disease:
  • Portal vein embolisation (PVE) to increase FLR volume before planned major hepatectomy
  • Neoadjuvant/downstaging systemic or locoregional therapy (TACE, modified PIAF in suitable patients)
  • Staged hepatectomy approaches
• Segment IV embolisation combined with right PVE can maximally hypertrophy the left lateral segments (I, II, III) prior to extended right hepatectomy

Key Clinical Pearls

• Tumour size above 5 cm does not independently preclude resection: long-term survival outcomes above 5 cm are driven more by vascular invasion and multifocality than by size per se
• Cirrhosis is present in 90% of standard HCC but only 5% of fibrolamellar HCC, fundamentally altering surgical strategy
• In cirrhotic patients, surgical risk is dominated by hepatic functional reserve, not just anatomical resectability
• AFP is non-specific: elevated AFP occurs in gastric cancer and gynaecological tumours, but in the correct clinical context (cirrhosis, hepatic mass), elevated AFP strongly supports HCC diagnosis
• The field defect of cirrhosis means resection carries high recurrence risk (at least 80% at 5 years) regardless of clear margins, favouring transplant when eligibility criteria are met
• BCLC staging remains the most clinically actionable system because it directly maps to treatment algorithms rather than simply providing a prognosis
• For patients with HCC outside transplant criteria and large tumours, resection may be the only option for cure and should be pursued aggressively if liver function and FLR allow