Systemic Therapy Eligibility in Primary Liver Cancer (Hepatocellular Carcinoma & Intrahepatic Cholangiocarcinoma)

1. Context

At diagnosis, a majority of hepatocellular carcinoma (HCC) patients present at intermediate or advanced Barcelona Clinic Liver Cancer (BCLC) stages, precluding curative resection or transplant. Systemic therapy (targeted agents, immune checkpoint inhibition, and selected cytotoxic regimens) complements or follows locoregional modalities when disease becomes unresectable, progresses after embolization/ablation, or exhibits extrahepatic spread. Eligibility hinges on hepatic reserve, performance status, tumor burden pattern, and hematologic/biochemical adequacy.

2. Core Eligibility Domains

| Domain | Key Parameters | Acceptable Thresholds (Typical) | Notes |
|——-|—————-|———————————|——|
| Histology / Diagnosis | HCC (imaging criteria or biopsy), ICC, mixed HCC-ICC | Confirmed per LI-RADS / pathology | Molecular profiling recommended in ICC |
| Performance Status | ECOG | 0–1 (preferred), selected 2 | ECOG ≥3 generally palliative care focus |
| Liver Function | Child-Pugh, ALBI | Child A; cautious Child B7–B8 | Child C: systemic therapy rarely appropriate |
| Hematologic | ANC, Platelets, Hemoglobin | ANC ≥1.5 ×10^9/L; Plt ≥60–75 ×10^9/L; Hb ≥8.5–10 g/dL | Platelet threshold may be lower in hypersplenism with caution |
| Renal | Creatinine, CrCl | Cr ≤1.5 × ULN; CrCl ≥50 mL/min | Dose modify renally cleared agents |
| Coagulation | INR (if not on anticoagulant) | Manageable / corrected | Variceal prophylaxis before antiangiogenic therapy |
| Disease Distribution | Intrahepatic vs extrahepatic | Extrahepatic permitted if organ function preserved | Macrovascular invasion influences regimen selection |

3. Indications for Initiating Systemic Therapy

| Indication Category | Clinical Scenario | Rationale |
|———————|——————|———–|
| Advanced Stage (BCLC C) | Macrovascular invasion (PVTT, HV/IVC), extrahepatic spread | Survival prolongation with systemic agents |
| Post-Locoregional Failure | Progression after TACE / ablation / SBRT not amenable to repeat | Switch early to preserve performance status |
| Unsuitable for Locoregional | Diffuse infiltrative pattern; vascular anatomy precludes TACE | Systemic control primary option |
| High-Risk Post-Intervention (select) | Positive margin, early recurrence risk features | Clinical trials / adjuvant strategies (evolving) |
| Bridge / Downstaging (Investigational) | Selected high tumor burden seeking transplant listing | Emerging data with IO combinations |

4. Contraindications (Absolute / Relative)

| Category | Absolute | Relative / Requires Optimization |
|———|———|——————————-|
| Performance | ECOG ≥3 | ECOG 2 (evaluate reversible factors) |
| Hepatic Reserve | Child-Pugh C decompensated (refractory ascites, encephalopathy) | Child-Pugh B ≥8–9 (selective, adjusted dosing) |
| Hematologic | ANC <1.0–1.5 ×10^9/L; Plt <50–60 ×10^9/L; Hb <8 g/dL | Borderline counts with supportive growth factors |
| Renal | CrCl <30–40 mL/min for renally cleared regimens | Moderate impairment → dose modify |
| Active Uncontrolled Infection | Sepsis, uncontrolled HBV replication (HBV DNA high) | Controlled HBV/HCV on antivirals |
| Cardiovascular | Unstable heart failure, recent significant ischemia | Controlled hypertension prior to VEGF blockade |
| Bleeding Risk | Active GI bleeding, untreated large varices | Variceal banding before antiangiogenic therapy |

5. Laboratory Threshold Guidance (Illustrative)

| Parameter | Standard Target | Notes |
|———-|—————-|——|
| Platelets | ≥60 ×10^9/L (≥75 for some trials) | Hypersplenism may allow cautious initiation below 75 |
| ANC | ≥1.5 ×10^9/L | Consider G-CSF if marginal for cytotoxic regimens |
| Bilirubin | ≤1.5 × ULN (IO/targeted); ≤2 × ULN some TKIs | Higher bilirubin increases TKI hepatotoxicity risk |
| AST/ALT | ≤5 × ULN (non-viral); ≤10 × ULN (viral flare exceptional) | Evaluate for active hepatitis flare |
| Albumin | ≥28–30 g/L | Low albumin correlates with poor tolerance |
| INR | <1.7 (if not anticoagulated) | Correct coagulopathy; evaluate synthetic failure |

6. Regimen Selection Considerations

| Clinical Feature | Preferred First-Line (Examples)* | Considerations |
|——————|———————————-|—————|
| Macrovascular invasion | Atezolizumab + Bevacizumab; Durvalumab + Tremelimumab; IO + TKI combinations (trial) | Assess bleeding risk before bevacizumab |
| High AFP | IO + anti-VEGF (e.g., Atez/Bev) | AFP decline prognostic |
| Autoimmune comorbidity | TKI (Lenvatinib, Sorafenib) | Weigh IO risk vs benefit |
| Child-Pugh B7 | Sorafenib (dose adjust) or cautious lenvatinib | Limited IO data; case-by-case |
| ICC (cholangiocarcinoma) | Gemcitabine + Cisplatin ± IO; FGFR2/IDH1 targeted agents (alteration+) | Baseline molecular profiling critical |

*Guideline-concordant options evolve; verify latest recommendations.

7. Decision Algorithm (Simplified)

1. Confirm diagnosis (imaging criteria vs biopsy) and stage (BCLC / AJCC).
2. Assess hepatic reserve (Child-Pugh, ALBI) & performance status.
3. Identify contraindications (bleeding varices, uncontrolled infection) → optimize first.
4. Stratify by macrovascular invasion / extrahepatic spread.
5. Select systemic backbone (IO combination vs TKI) aligned with risk profile and comorbidities.
6. Establish baseline labs, viral status, endoscopy (if anti‑VEGF considered).
7. Initiate therapy with early (4–6 week) response and toxicity assessment; adapt as needed.

8. Monitoring & Reassessment

| Interval | Assessment | Action Trigger |
|———|———–|—————|
| Baseline | CBC, CMP, coagulation, AFP, viral load | Optimize deficits |
| 2–4 weeks | LFTs, BP (if on anti-VEGF), symptom review | Grade ≥2 persistent toxicity → dose modify |
| Every 6–9 weeks | Imaging (CT/MRI) + AFP | RECIST/mRECIST progression or intolerable toxicity |
| Each Visit | Performance status, adherence | Decline to ECOG 3 → reassess goals of care |

9. Special Populations

| Population | Considerations |
|———–|—————|
| HBV-positive | Start antiviral (entecavir/tenofovir) before systemic therapy |
| HCV infection | Treat per guidelines; watch for transaminase fluctuations with IO |
| HIV coinfection | Drug–drug interactions with TKIs; coordinate with ID specialist |
| Post-transplant recurrence | IO risk of graft rejection—prefer TKIs initially |
| Elderly/frail | Geriatric assessment; start lower dose with early escalation |

10. De-escalation / Discontinuation Criteria

| Criterion | Action |
|———|——-|
| Radiologic progression (confirmed) | Switch line (consider trial) |
| Grade 3–4 unresolved hepatotoxicity | Hold; evaluate causality; switch class if recurs |
| Persistent ECOG ≥3 without reversible cause | Transition to best supportive care |
| Immune-mediated severe toxicity (Grade 4) | Permanently discontinue IO component |

11. Documentation Checklist

• Diagnosis modality & stage (BCLC, AJCC).
• Child-Pugh & ALBI grade baseline and on-treatment.
• Performance status each visit.
• Rationale for regimen selection (macrovascular invasion, biomarker status).
• Toxicity grading (CTCAE) and dose modifications.
• Shared decision-making summary (goals, expectations).

12. Key Takeaways

• Systemic therapy candidacy in liver cancer balances tumor biology with hepatic reserve and performance status; Child-Pugh and ECOG remain pivotal gatekeepers.
• Early initiation after locoregional failure prevents decline that would preclude effective regimens.
• Meticulous baseline optimization (viral suppression, variceal management, nutrition) improves tolerability and outcomes.
• Dynamic reassessment (lab trends, performance shifts, AFP kinetics) guides timely escalation, switch, or de-escalation.

Disclaimer: Educational synthesis; align decisions with evolving evidence-based guidelines and individualized patient context.