Radiotherapy in Primary Liver Cancer (Hepatocellular Carcinoma, HCC)

1. Context & Rationale

Surgical resection, liver transplantation, and percutaneous ablation are curative modalities for early hepatocellular carcinoma (HCC), yet <25% of patients present with anatomically and functionally resectable disease. Historically, conventional external beam radiotherapy (EBRT) was limited by low whole‑liver tolerance (classic radiation-induced liver disease, RILD). Advances in image guidance, motion management, and conformal dose sculpting have expanded the therapeutic index, allowing high biologically effective doses (BED) to focal targets while preserving non-tumor parenchyma.

2. Patient Selection & Indications

| Indication | Role of Radiotherapy | Notes |
|———–|———————-|——-|
| Early-stage (ineligible for surgery/ablation) | Stereotactic ablative radiotherapy (SABR/SBRT) as alternative | Lesions typically ≤5 cm; proximity to GI tract influences fractionation |
| Intermediate-stage (BCLC B) | Bridge or downstaging to transplant; consolidation after TACE | Combine with TACE or Y-90 in selected cases |
| Portal vein tumor thrombus (PVTT) | Local control, potential survival benefit, enable systemic therapy | Hypofractionated or modulated plans to spare normal liver |
| Oligoprogression on systemic therapy | Focal control to maintain effective systemic regimen | Requires multidisciplinary review |
| Palliative (pain, mass effect) | Symptom relief | Lower dose/fraction schemes |

3. Planning Considerations

| Parameter | Considerations |
|———–|—————|
| Liver function | Child-Pugh class (A preferred; cautious in B; generally avoid in decompensated C unless palliative) |
| Tumor motion | 4D-CT, gating, breath-hold (DIBH), abdominal compression |
| Target delineation | Multiphasic contrast CT ± MRI fusion; exclude perfusion anomalies |
| Dose constraints | Mean liver dose (non-tumor), stomach/duodenum, bowel, spinal cord |
| Concomitant therapies | Timing with TACE/Y-90 to avoid compounded hepatic toxicity |

4. Techniques

| Technique | Description | Advantages | Limitations |
|———-|————-|————|————-|
| 3D-CRT | Forward planned beams shaped to target | Widely available | Less conformal; higher normal liver dose |
| IMRT/VMAT | Inverse planned modulation of intensity/arc delivery | Improved conformity & OAR sparing | Larger low-dose bath |
| SBRT (SABR) | High-dose per fraction (e.g., 3–5 fractions) | High BED, ablative local control | Requires precise motion management |
| IGRT | Daily image verification (CBCT, MR) | Setup & motion accuracy | Resource intensive |
| MR-guided RT | Real-time soft tissue visualization, adaptive | Adaptive replanning for organ shift | Limited availability |
| Particle therapy (Proton/Carbon) | Bragg peak reducing exit dose | Lower integral liver dose | Cost, access, motion sensitivity |
| Selective Internal Radiation Therapy (SIRT, Y-90) | Intra-arterial microsphere brachytherapy | Treats multifocal disease, spares parenchyma | Vascular mapping; nonuniform dose |

5. Dose & Fractionation (Illustrative)

| Clinical Scenario | Typical Regimen* | BED (α/β=10) Approx |
|——————-|——————|———————|
| Small peripheral lesion (SBRT) | 45–54 Gy / 3 fractions | 113–151 Gy |
| Central lesion (proximity GI) | 50–60 Gy / 5–6 fractions | 83–100 Gy |
| PVTT | 40–50 Gy / 15 fractions (IMRT) | 53–67 Gy |
| Palliative mass effect | 30 Gy / 10 fractions | 39 Gy |
| SIRT (Y-90) | Activity-based (partition model) | Variable focal BED |

*Regimens tailored to organ-at-risk (OAR) constraints and liver function.

6. Normal Liver & OAR Constraints (Conceptual)

| Structure | Example Constraint (SBRT context)** | Rationale |
|———-|———————————-|———–|
| Non-tumor liver (Gy) | Mean <15 Gy (for 3–5 fx) | Mitigate classic RILD |
| Spinal cord | Max point <18 Gy (3 fx) | Myelopathy prevention |
| Stomach/Duodenum | Max <30–32 Gy (5 fx) | Ulceration/fistula risk |
| Bowel (small/colon) | Max <30 Gy (5 fx) | Perforation risk |
| Kidney (bilateral mean) | Keep as low as achievable | Preserve function |

**Institutional protocols vary; follow published guidelines (e.g., AAPM TG‑101, NRG trials).

7. Outcomes

| Metric | SBRT Local Control | Notes |
|——–|——————–|——|
| 1-year | 80–95% for ≤5 cm lesions | Higher BED correlates with control |
| 2-year | 65–85% | Decline with larger volume, lower dose |
| Overall Survival Influence | Improved when used for early-stage or PVTT in multimodal approach | Dependent on liver function & systemic disease |

8. Toxicities

| Type | Presentation | Mitigation |
|——|————-|———–|
| Classic RILD | Anicteric hepatomegaly, ascites, elevated ALP (wks–mos) | Respect mean liver dose, spare ≥700 cc normal liver |
| Non-classic RILD | Jaundice, transaminase rise (in cirrhotics) | Child-Pugh risk stratification |
| GI toxicity | Ulceration, bleeding (central lesions) | Fractionation adjustment, spacer techniques (investigational) |
| Fatigue | Common, transient | Symptom management; assess anemia |
| Biliary stenosis | High-dose near hilum | Dose sculpting, MR-guidance potential |
| Radiation dermatitis | Rare (superficial lesions) | Skin dose optimization |

9. Integration with Other Modalities

| Combination | Rationale | Considerations |
|————|———-|—————-|
| RT + TACE | Synergistic ischemia + DNA damage | Sequence to allow hepatic recovery |
| RT + Systemic (TKIs, IO) | Potential radiosensitization, immune priming | Monitor hepatic & immune-related toxicity |
| SIRT followed by RT | Treat multifocal + focal dominant lesion ablatively | Cumulative liver dose modeling |
| Bridge to Transplant | Maintain local control awaiting graft | Timing relative to MELD changes |

10. Motion & Adaptive Strategies

• 4D-CT and internal target volume (ITV) creation for respiratory excursion.
• Breath-hold (DIBH) reduces target volume and liver dose.
• Daily cone beam CT or MR for interfraction position; online adaptive replanning emerging with MR-Linacs.

11. Special Situations

| Scenario | Approach |
|———-|———|
| Multifocal small lesions | Sequential or multifocal SBRT vs SIRT | Weigh cumulative liver dose |
| Child-Pugh B7–B8 | Consider reduced dose or fraction escalation | Enhanced monitoring |
| Tumor near stomach/duodenum | Use ≥5–8 fraction SBRT, tighter constraints | Consider spacer (trial) |
| PVTT extending to main portal vein | IMRT with simultaneous integrated boost (SIB) | Coordinate with systemic therapy |

12. Emerging Directions

| Innovation | Potential Benefit |
|———–|——————|
| MR-guided adaptive SBRT | Real-time gating, margin reduction |
| Radiogenomic biomarkers | Predict radiosensitivity & toxicity |
| Immunoradiotherapy sequencing | Enhance abscopal/systemic immune synergy |
| Particle therapy (scanned protons/carbon) | Better sparing for large/central lesions |
| Radiomics-based response prediction | Early adaptation of dose/fractionation |

13. Key Takeaways

• Modern conformal radiotherapy (SBRT, IMRT, image guidance) enables safe delivery of ablative doses in selected HCC patients historically deemed unsuitable for EBRT.
• Patient selection anchored in liver function (Child-Pugh/MELD), tumor burden, and proximity to critical GI structures is essential.
• Integration with locoregional (TACE, SIRT) and systemic (TKIs, immunotherapy) therapies can extend survival in a multidisciplinary framework.
• Rigorous dosimetric constraints and motion management mitigate risk of RILD and GI toxicity.
• Adaptive and biologically guided strategies represent the next frontier for precision liver radiotherapy.

Disclaimer: Educational synthesis; follow institutional and guideline-based protocols.