Management of hepatocellular carcinoma recurrence after liver surgery and thermal ablations: state of the art and future perspectives

Herrero, A., Toubert, C., Bedoya, J. U., Assenat, E., Guiu, B., Panaro, F., Bardol, T., & Cassese, G. (2024). Management of hepatocellular carcinoma recurrence after liver surgery and thermal ablations: state of the art and future perspectives. Hepatobiliary surgery and nutrition, 13(1), 71–88. https://doi.org/10.21037/hbsn-22-579IF: 7.8 Q1

Executive Summary

Hepatocellular carcinoma (HCC) recurrence remains the most significant challenge to improving long-term patient outcomes, with rates reaching as high as 70% after liver resection and 20% even after liver transplantation. The management of this recurrence is a complex issue influenced by the timing and location of the new tumor, the patient's underlying liver condition, and the initial treatment performed.

This document synthesizes the current state of knowledge regarding HCC recurrence, drawing from a comprehensive review of the field. Key takeaways include:

• Distinct Recurrence Patterns: Recurrence is categorized by timing and location, which correlate with different causes and prognoses. "Early" recurrence (<2 years, often <12 months) typically stems from micrometastases of the primary tumor and is associated with aggressive tumor biology. "Late" recurrence (>2 years) is often a de novo tumor arising from the cirrhotic liver.
• Lack of Adjuvant Therapy: At present, no adjuvant therapy is recommended after curative treatment for HCC. Systemic chemotherapy and sorafenib have failed to show efficacy in this setting. However, the future is promising, with several Phase III clinical trials investigating immunotherapy agents showing potential, and the IMBRAVE-050 trial recently reporting positive results.
• Aggressive Management is Critical: The primary strategy for managing recurrence is aggressive, timely treatment with curative intent. For intra-hepatic recurrence, repeat hepatectomy (RH) and thermal ablation (TA) are primary options, with evidence suggesting RH may offer better local control for larger tumors despite higher complication rates. Liver transplantation (LT) remains the ideal therapy for recurrent HCC after resection but is limited by organ shortages.
• The Future is Personalized Medicine: Advances in understanding HCC at a molecular level are paving the way for personalized treatment. Genomic analysis to identify molecular signatures of aggressiveness and the use of "liquid biopsies" to detect circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are emerging as powerful tools to predict recurrence, assess minimal residual disease, and ultimately guide therapeutic decisions.

Without effective adjuvant therapies, the current cornerstone of management is rigorous surveillance—especially within the first two years post-treatment—to diagnose recurrence at a curable stage.

--------------------------------------------------------------------------------

1. The Challenge and Scope of HCC Recurrence

Hepatocellular carcinoma is the seventh most-common cancer and the third leading cause of cancer-related death worldwide. While curative treatments like liver resection (LR), liver transplantation (LT), and thermal ablation (TA) can achieve 5-year overall survival rates of 50-70% in early stages, the high rate of tumor recurrence significantly undermines these outcomes.

• Recurrence Rate after Liver Resection (LR): Up to 70% of patients experience recurrence.
• Recurrence Rate after Liver Transplantation (LT): As high as 20% of patients experience recurrence.

The prevention and effective management of recurrence are the most important strategies for improving outcomes. The complexity of this challenge is magnified by the numerous variables involved, including the patient's underlying liver condition (most commonly cirrhosis), the shortage of donor organs for transplantation, and the diverse array of available therapies.

2. Understanding Recurrence: Patterns and Pathogenesis

HCC recurrence is not a uniform event. It is classified by its timing and location, which provide critical insights into its biological origin, risk factors, and prognosis.

Timing of Recurrence

There is a classical division between early and late recurrence, with a 12-month cutoff considered the most useful for standardization. A "very early" category has also been proposed.

Recurrence Type	Timeframe	Pathogenesis	Associated Risk Factors	Prognosis
Very Early	< 6 months	Occult micro-metastasis of the primary tumor	Treatment with ethanol, incomplete (R1) resection, vascular invasion, major blood loss (>1,692 mL).	Worse than both early and late recurrence. (Median OS of 20.4 months).
Early	< 2 years	Occult micro-metastasis of the primary tumor	Aggressive primary tumor characteristics: multinodular, large size, vascular invasion, satellite nodules, poor differentiation.	Poorer than late recurrence. More likely to be extra-hepatic and less likely to be treated with curative intent.
Late	> 2 years	De novo second primary HCC in the remnant cirrhotic liver.	Patient-related factors: sex, underlying cirrhosis, active hepatitis. Pathologic factors of tumor aggressiveness also remain important.	Better prognosis, as recurrence is more often intra-hepatic (90%) and amenable to curative treatment.

Location of Recurrence

Recurrence can be intra-hepatic (IH), extra-hepatic (EH), or both (I+EH).

• Intra-hepatic (IH): This is the most common pattern observed after surgery and carries the best prognosis due to the availability of effective local treatments like repeat surgery or ablation.
• Extra-hepatic (EH): Once EH disease occurs, overall survival is the same regardless of whether it appears after, with, or without IH recurrence. Treatment for EH disease is very limited, though immunotherapy is showing initial promise.

Correlation Between Timing and Location

Timing and location of recurrence are strongly linked. An international study of 1,004 patients found that early recurrence was significantly more likely to be extra-hepatic or combined I+EH (35.5% vs. 19.8%) compared to late recurrence. Conversely, a study by Xu et al. found that 90.1% of patients with late recurrence developed IH disease, with only 9.9% developing I+EH and no patients developing isolated EH late recurrence.

3. Predictive Factors for Recurrence

Identifying patients at high risk of recurrence is crucial for tailoring follow-up and considering future adjuvant therapies. These risk factors are related to the tumor, the patient, and the primary treatment.

Tumor and Patient-Related Factors

• For Early Recurrence: Factors indicating high tumor aggressiveness are the main predictors. These are often identified on post-resection pathology and include:
  • Vascular invasion (both macro- and micro-vascular)
  • Presence of satellite nodules
  • Large tumor size and multiple tumors
  • Poor cell differentiation and advanced pTNM stage
  • Macrotrabecular-massive (MTM) histological subtype
• Biomarkers: High preoperative levels of alpha-fetoprotein (AFP) (>400 ng/mL) and an elevated platelet-to-lymphocyte ratio (PLR) (>103.6) have been identified as independent predictors of early recurrence.
• For Late Recurrence: This is classically associated with patient-related factors driving de novo carcinogenesis, such as underlying cirrhosis and active hepatitis. However, multi-center studies confirm that factors of tumor aggressiveness (vascular invasion, multiple tumors) also remain important predictors for late recurrence.

Factors Related to Primary Treatment

The impact of surgical technique and resection margin on recurrence remains a subject of debate.

• Anatomical vs. Non-Anatomical Resection (AR vs. NAR): AR involves removing the entire hepatic tissue supplied by the portal vein draining the tumor, theoretically removing micro-metastases. Large studies show AR may improve disease-free survival (DFS) and reduce local recurrence, but often without a significant difference in overall survival (OS). This may be due to aggressive, curative-intent treatments for recurrence.
• Resection Margins:
  • Positive (R1) margins are associated with higher recurrence, often related to underlying venous invasion.
  • Studies have shown that for patients with high preoperative AFP levels, a surgical margin of <1 cm is associated with a significantly higher recurrence rate.
  • One study suggests that for NAR, a 0-mm negative margin is associated with less favorable survival, whereas for AR it may be acceptable.

4. Post-Treatment Monitoring and Surveillance

Close monitoring after curative treatment is essential for detecting recurrence at a treatable stage.

Imaging Modalities

• Frequency: International guidelines recommend surveillance 2 to 4 times a year for the first two years, followed by lifelong biannual monitoring.
• Techniques: Cross-sectional imaging with contrast (CT or MRI) is standard. Alternating between MRI and CT with chest sections is important to screen for both intra- and extra-hepatic recurrence.
• Response Assessment: Following thermal ablation, the mRECIST criteria are used to assess tumor viability. The Liver Imaging Reporting and Data System (LI-RADS) also provides an algorithm to assess treatment response (viable, equivocal, or non-viable), which has shown good inter-reader agreement and correlation with survival.
• PET-CT: The role of PET-CT is limited due to poor F18-FDG uptake by most HCCs, making it less sensitive than CT or MRI for initial diagnosis and follow-up, though it has good sensitivity for detecting extra-hepatic lesions (85.7%).

Role of Biomarkers

• Alpha-fetoprotein (AFP): Although not recommended for screening by all societies due to poor specificity, a high preoperative AFP level is a risk factor for early recurrence and MVI. Its progression can also be predictive of MVI.
• Other Markers: PIVKA-II (or DCP) appears to be more predictive of early recurrence than AFP. However, PIVKA-II and AFP-L3 are not currently recommended for routine monitoring.

5. The Role of Adjuvant Therapy

The high rate of recurrence highlights a major unmet need for effective adjuvant therapy.

Current Status and Investigated Therapies

• No Recommended Treatment: Currently, there is no effective or recommended adjuvant treatment after curative therapy for HCC. Randomized trials for systemic chemotherapy and sorafenib (STORM study) have failed to demonstrate a benefit.
• Intra-arterial Chemotherapy/TACE: Studies are discordant, though some suggest a benefit in selected patients at high risk (e.g., those with MVI). These results are limited by biases, particularly in studies on Asian patient populations.
• Stereotactic Body Radiotherapy (SBRT): Phase II and III trials suggest SBRT may improve DFS in patients with high-risk features (margins <1 cm and MVI), but further confirmation is needed.
• Managing Underlying Liver Disease: This is essential. Antiviral therapy for Hepatitis B (HBV) significantly reduces viral reactivation and can help prevent late recurrence. For Hepatitis C (HCV), direct-acting antivirals (DAAs) have not been shown to increase recurrence risk, and several meta-analyses suggest a positive effect on recurrence and survival.

Emerging Immunotherapies

Immunotherapy has revolutionized the treatment of advanced HCC and holds great promise in the adjuvant setting. Several international Phase III trials are ongoing for patients at high risk of recurrence.

Trial Name	Population	Immunotherapy Regimen	Target	Control Arm	Primary Outcome
CHECKMATE-9DX	High risk after resection/ablation	Nivolumab	PD-1	Placebo	RFS
KEYNOTE-937	Complete response after resection/ablation	Pembrolizumab	PD-1	Placebo	RFS, OS
EMERALD-2	High risk after resection/ablation	Durvalumab ± bevacizumab	PD-L1	Placebo	RFS
IMBRAVE-050	High risk after resection/ablation	Atezolizumab + bevacizumab	PD-L1	Active surveillance	RFS

The results of the IMBRAVE-050 trial have been declared positive, suggesting that the combination of atezolizumab and bevacizumab could become a new standard of care and represent a "real turning point in the management of curable HCC."

6. Management Strategies for Recurrent HCC

The guiding principle for treating recurrent HCC (in the absence of distant metastases) is that therapy must be radical and timely. Aggressive treatment of relapse can achieve long-term results similar to those of primary tumor treatment.

Repeat Hepatectomy (RH) vs. Thermal Ablations (TA)

For recurrent IH disease, RH and TA are the main curative options.

• Outcomes: A randomized trial found no significant difference in OS between RH and radiofrequency ablation (RFA), but RFA was associated with a higher incidence of local repeat recurrence (37.8% vs. 21.7%). In subgroup analysis, RFA was associated with worse OS for tumors >3 cm or with AFP >200 ng/mL. Another study using propensity score matching found significantly better 3-, 5-, and 10-year OS for RH compared to RFA.
• Complications: Surgery consistently has a higher complication rate than TA (e.g., 22.4% vs. 7.3% in one study).
• Minimally Invasive Surgery: Laparoscopic repeat hepatectomy has been shown to result in less blood loss with similar OS compared to open surgery, though it is typically used for patients with more favorable tumor characteristics.

The choice between RH and TA requires careful patient selection and multidisciplinary collaboration.

Liver Transplantation (LT)

LT is theoretically the best option as it removes the tumor and the underlying cirrhotic liver.

• De Principe vs. Salvage LT:
  • De Principe LT: Performing LT as the first treatment for patients with poor prognostic factors identified after an initial resection.
  • Salvage LT: Performing LT only at the time of recurrence.
  • Comparative studies show that the de principe strategy results in better survival outcomes (e.g., 5-year OS of 84.6% vs. 74.8% for salvage LT). Salvage LT is associated with higher operative mortality and risk of recurrence.
• Role of LR as a Bridge: While LR is still a primary option for small solitary HCC in compensated cirrhosis, the decision to resect or transplant upfront remains complex. For patients with high-risk features on pathology after resection, a de principe LT strategy has shown excellent survival.

Recurrence After Liver Transplantation

HCC recurs in 6-16% of patients after LT, presenting a significant challenge due to immunosuppression. Curative-intent LR is the first-line option for post-LT recurrence but is only feasible in up to 30% of patients.

7. Future Perspectives and Innovations

Improving survival in HCC requires a multi-pronged approach focused on better detection, neoadjuvant/adjuvant treatments, and personalized medicine.

Genomic Analysis and Molecular Signatures

HCC is a genomically heterogeneous disease. The goal of ongoing research is to use this information to predict prognosis and guide therapy.

• Key Genetic Alterations: Include the TERT promoter, Wnt/β-catenin pathway, P53, and RAS/RAF/MAP Kinase pathways.
• Prognostic Scores: While not yet used in clinical practice, a 5-gene score (KRT19, HN1, RAMP3, TAF9, RAN) has been shown to predict early tumor recurrence and death after resection, independent of classical clinical characteristics.

The Role of Liquid Biopsies

Liquid biopsies are non-invasive tests that detect circulating tumor biomarkers in body fluids, offering powerful insights into tumor biology.

• Biomarkers: Include Circulating Tumor Cells (CTCs), cell-free circulating tumor DNA (ctDNA), and extracellular vesicles.
• Prognostic Value: CTCs and ctDNA can provide information on tumor aggressiveness and micro-vascular invasion.
  • Meta-analyses have confirmed that the presence of CTCs is associated with significantly decreased recurrence-free survival (HR 3.03) and overall survival (HR 2.45).
  • Postoperative detection of CTCs or ctDNA has been shown to be an independent risk factor for HCC recurrence, indicating minimal residual disease.
• Surgical Impact: One study found that a "no-touch" anterior surgical approach lowered the dissemination risk of CTCs compared to a classical approach, improving both RFS and OS.