What is the best treatment option for a woman with compensated hepatitis B virus (HBV) and metabolic-associated steatohepatitis-related liver disease (MASLD)-related cirrhosis, a history of smoking, and diabetes, who has multiple liver nodules with neoplastic vascular invasion and preserved liver function?

Systemic Treatment with Immunotherapy-Based Regimens is the First-Line Option

This patient requires systemic therapy as first-line treatment, with immunotherapy-based combinations (atezolizumab plus bevacizumab or lenvatinib plus pembrolizumab) as the preferred initial approach, given the presence of macrovascular invasion (neoplastic vascular invasion) which classifies her as advanced-stage HCC (BCLC-C). 1

Why Systemic Therapy is Mandatory

Macrovascular Invasion Excludes Locoregional Therapies

• The presence of neoplastic vascular invasion (Vp invasion) is an absolute contraindication to TACE, as it significantly increases the risk of post-procedural liver failure and provides no survival benefit. 1, 2
• TACE should not be used in patients with macroscopic vascular invasion or extrahepatic spread, regardless of liver function status. 1
• Surgical resection is not appropriate despite compensated liver function, as macrovascular invasion indicates advanced disease with high recurrence risk and poor prognosis even with complete resection. 1

Multifocal Disease Further Supports Systemic Approach

• The patient has four separate nodules across multiple liver segments, which exceeds the criteria for locoregional therapy even in the absence of vascular invasion. 1
• Patients with large-volume intrahepatic disease and intermediate-stage classification might be best served with systemic therapy as first-line treatment rather than TACE. 1

Recommended First-Line Systemic Therapy Options

Immunotherapy-Based Combinations are Standard of Care

Based on superior efficacy, atezolizumab plus bevacizumab is the first-choice standard of care for unresectable HCC. 1

• Patients need careful assessment for contraindications to either drug, particularly variceal bleeding risk with bevacizumab. 1
• Since the patient's last endoscopy in [YEAR] showed no varices and she has compensated cirrhosis (Child-Pugh A), she is an appropriate candidate for this regimen. 1

Alternative Immunotherapy Combination

• Lenvatinib plus pembrolizumab represents another immunotherapy-based first-line option for patients with unresectable HCC. 3
• The recommended lenvatinib dosage is based on body weight: 20 mg orally once daily (in combination with pembrolizumab) for most patients. 3

Tyrosine Kinase Inhibitor Monotherapy as Alternative

• For patients who have contraindications or decline intravenous therapy, sorafenib and lenvatinib are alternative first-line oral therapies. 1
• For HCC, lenvatinib monotherapy dosing is 12 mg orally once daily for patients ≥60 kg or 8 mg orally once daily for patients <60 kg. 3

Why Combined TACE Plus Systemic Therapy is Not Recommended

Despite promising early signals, there is insufficient evidence to recommend the combination of TACE with immune checkpoint inhibitors. 1

• TACE should not be combined with multikinase inhibitors based on current evidence. 1
• The presence of macrovascular invasion makes TACE inappropriate regardless of combination strategy. 1, 2

Critical Monitoring Considerations

HBV Management Must Continue

• All patients with decompensated or compensated cirrhosis and detectable HBV DNA should receive long-term antiviral therapy with entecavir or tenofovir. 1, 4
• Since this patient has been on treatment since [YEAR] with undetectable HBV DNA, continuation of her current antiviral regimen is mandatory throughout cancer treatment. 1, 4
• Interferon-based therapies are absolutely contraindicated in patients with cirrhosis receiving cancer treatment. 1

Systemic Therapy Toxicity Monitoring

• Monitor for hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal impairment, and proteinuria during lenvatinib treatment. 3
• Control blood pressure prior to treatment and withhold for Grade 3 hypertension despite optimal antihypertensive therapy. 3
• Monitor liver function prior to and periodically during treatment, withholding or discontinuing for Grade 3 or 4 hepatotoxicity. 3

Diabetes and Metabolic Management

• Screen and manage diabetes aggressively, as insulin therapy is the only evidence-based option for type 2 diabetes in patients with cirrhosis. 4
• Metformin is contraindicated due to lactic acidosis risk in cirrhosis. 4

Sequential Treatment Strategy

Systemic treatment should be proposed as first-line, with other options considered only based on response in a sequential manner. 1

• If the patient achieves significant tumor response with downstaging and resolution of vascular invasion, reassessment for potential locoregional consolidation could be considered. 1
• However, the primary goal is disease control with systemic therapy given the advanced stage at presentation. 1

Common Pitfalls to Avoid

• Do not attempt surgical resection in the presence of macrovascular invasion, as this provides no survival benefit and carries significant perioperative risk. 1
• Do not use TACE as first-line therapy when macrovascular invasion is present, as this significantly increases liver failure risk. 1, 2
• Do not discontinue HBV antiviral therapy during cancer treatment, as viral reactivation can cause hepatic decompensation. 1, 4
• Do not use combination TACE plus systemic therapy outside of clinical trials, as evidence is insufficient and macrovascular invasion contraindicates TACE. 1

Answer: D. Systemic treatment should be proposed as first line option to this patient, IO-based as first choice, considering other options only based on response in a sequential manner.