Ablative therapy for HCC

Locoregional therapies have been the primary approach for treating early-stage non-surgical hepatocellular carcinoma (HCC), mainly utilizing radiofrequency ablation (RFA) and Microwave ablation (MWA), and for intermediate-stage HCC, using transarterial chemoembolization (TACE). 

Keypoints:

  1. Ablation margin of 0.5 –  1.0 cm is considered optimal to achieve complete tumor destruction.
  2. Protective Techniques used to prevent adjacent organ damage include – hydro dissection, carbon dioxide, balloon inflation, elective pneumothorax/pleural effusion, and cooled biliary perfusion
  3. RFA is superior to PEI in terms of less number of sittings and better OS
  4. Hepatic resection is considered superior to RFA in terms of decreased local recurrence. 
  5. The best results for hyperthermic ablative therapy like RFA and MWA are with early-stage disease (lesion size < 3 cm), however many authors have successful ablation of lesions up to 5 cm. Cryoablation can successfully create an ablation zone larger than 5 cm, however, there is an increased risk for complications like cryoshock
  6.  Patients with a pacemaker and other cardiac devices need special attention as RFA and MWA can interfere with their working, even if placed more than 15 cm away from cardiac leads, and can cause reset if ablation probes are within 5 cm of the cardiac device.
  7. Milan criteria – Single HCC  < 5 cm in size or upto 3 HCC s all < 3 cm , liver transplant shows better outcome.
  8. UCSF criteria – Single HCC  < 6.5 cm in size or up to 3 HCC s all < 4.5 cm, liver transplant shows better outcome.

Various research and publications:

Publication/ResearchResultsAuthor's conclusion
RF vs PEI vs PAI
Lencioni, R. A. et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228, 235–240 (2003)OS at 1 and 2 year (p =.138)
RF group = 100% and 98%
PEI group = 96% and 88%
Local recurrence free survival rates at 1 and 2 year (p =.002)
RF group = 98% and 96%
PEI group = 83% and 62%
Event-free survival rates at 1 and 2 year (p =.012)
RF group = 86% and 64%
PEI group = 77% and 43%		RF ablation is superior to PEI with respect to local recurrence-free survival rates
Lin, S. M., Lin, C. J., Lin, C. C., Hsu, C. W. & Chen, Y. C. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 54, 1151–1156 (2005).OS at 1, 2 and 3 year (RF vs PEI p =.031) (RF vs PAI p =.038)
RF group = 93%, 81% and 74%
PEI group = 88%, 66% and 51%
PAI group = 90%, 67%, and 53%
Local recurrence rates at 1, 2 and 3 year (RF vs PEI p =.012) (RF vs PAI p =.017)
RF group = 10%, 14% and 14%
PEI group = 16%, 34% and 34%
PAI group = 14%, 31% and 31%
Cancer-free survival rates at 1, 2 and 3 year (RF vs PEI p =.038) (RF vs PAI p =.041)
RF group = 74%, 60% and 43%
PEI group = 70%, 41%, and 21%
PAI group = 71%, 43%, and 23%		RF group was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.
Shiina, S. et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129, 122–130 (2005).Number of treatment sessions (P < .0001)
RF group = 2.1
PEI group = 6.4
Four-year survival rate
RF group = 74% (95% CI: 65%-84%)
PEI group = 57% (95% CI: 45%-71%)

Radiofrequency ablation had a 46% smaller risk of death (adjusted relative risk, 0.54 [95% CI: 0.33-0.89], P = .02), a 43% smaller risk of overall recurrence (adjusted relative risk 0.57 [95% CI: 0.41-0.80], P = .0009), and an 88% smaller risk of local tumor progression (relative risk, 0.12 [95% CI: 0.03-0.55], P = .006) than ethanol injection.		Higher survival but similar adverse events, radiofrequency ablation is superior to ethanol injection for small hepatocellular carcinoma.
Giorgio, A. et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma compared to percutaneous ethanol injection in treatment of cirrhotic patients: an Italian randomized controlled trial. Anticancer. Res. 31, 2291–2295 (2011).OS at 3 and 5 year (p =n.s)
RF group = 74% and 68%
PEI group = 79% and 70%
Local recurrence rates at 3 and 5 year (p =n.s)
RF group = 7.8% and 11.7%
PEI group = 9.4% and 12.8%
Percutaneous ethanol injection and radiofrequency ablation conferred similar 5-year survival. Feasibility is not the same for both procedures. Percutaneous ethanol injection is much cheaper than radiofrequency ablation and should be considered whether in poor and rich countries.
RF vs MWA
Lu MD, Xu HX, Xie XY et al. Percutaneous microwave and radiofrequency ablation for hepatocellular carcinoma: A retrospective comparative study. J Gastroenterol 2005;40:1054–1060.OS at 1, 2, 3 and 4 year (p =.12)
RF group = 71.7%, 47.2%, 37.6%, and 24.2%
MWA group = 81.6%, 61.2%, 50.5%, and 36.8%
Local recurrence rates (p =.12)
RF group = 20.9%
MWA group = 11.8%
Disease-free survival rates at 1, 2, 3 and 4 year (p =.53)
RF group = 37.2%, 20.7%, and 15.5% (1, 2 and 3 years)
MWA group = 45.9%, 26.9%, 26.9%, and 13.4%		Percutaneous microwave ablation and radiofrequency ablation are both effective methods in treating hepatocellular carcinomas. The local tumor control, complications related to treatment, and long-term survivals were equivalent for the two modalities.
Simo KA, Sereika SE, Newton KN et al. Laparoscopic‐assisted microwave ablation for hepatocellular carcinoma: Safety and efficacy in comparison with radiofrequency ablation. J Surg Oncol 2011;104:822–829.1. Mean follow-up was 19 months in Lap RFA group = 50% alive without evidence of disease, 9% alive with disease, 36% deceased and 5% lost to follow-up.
2. Mean follow-up in the Lap-MWA group was 7 months - 54% alive without evidence of disease, 31% alive with disease and 15% deceased.		Lap-MWA is a safe and efficacious locoregional therapy for HCC which achieves outcomes comparable to Lap-RFA. Shorter operative times were realized with this modality and complete coagulative necrosis was confirmed histologically on explanted livers.
Ohmoto K, Yoshioka N, Tomiyama Y et al. Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas. J Gastroenterol Hepatol 2009;24:223–227. 1. Fewer treatment sessions (P < 0.001) RFA>MWA
2. Larger necrotic area (P < 0.001) RFA>MWA
3. Lower local recurrence rate (P < 0.031) RFA>MWA
4. Overall Survival (P < 0.018) RFA>MWA
5. Pain, Bile duct injury, pleural effusion, ascites and fever MWA>RFA		RFA is more useful than PMCT for the treatment of small HCC because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.
Thornton LM, Cabrera R, Kapp M et al. Radiofrequency vs microwave ablation after neoadjuvant transarterial bland and drug‐eluting microsphere chembolization for the treatment of hepatocellular carcinoma. Curr Probl Diagn Radiol 2017;46:402–409.Complete response (p = 0.29)
RF + TAE/TACE = 80%
MWA + TAE/TACE = 95%
Local recurrence
RF + TAE/TACE = 30%
MWA + TAE/TACE = 0%

Local disease control for duration of the study, demonstrated a significant difference in favor of MWA (p value 0.0091)		MWA and RFA when combined with neoadjuvant TAE or TACE have similar safety and efficacy in the treatment of early stage HCC. MWA provided more durable disease control in this study, however, prospective data remains necessary to evaluate superiority of either modality.
Abdelaziz AO, Abdelmaksoud AH, Nabeel MM et al. Transarterial chemoembolization combined with either radiofrequency or microwave ablation in management of hepatocellular carcinoma. Asian Pac J Cancer Prev 2017;18:189–194TACE-MWA showed a higher tendency to provide complete response rates than TACE-RFA (P 0.06)
Recurrence-free survival rates at 1, 2, and 3 year (p =.1)
RF-TACE group = 70%, 42% and 14%
MWA-TACE group = 81.2%, 65.1% and 65.1% 		TACE-MWA led to better response rates than TACE-RFA with tumors 3-5 cm, with no difference in survival rates.
Yu, Jie et al. “Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial.” Gut vol. 66,6 (2017): 1172-1173. doi:10.1136/gutjnl-2016-312629OS at 1, 3 and 5 year (p=0.91)
RF group = 95.9%, 81.4% and 72.7%
MWA group = 96.4%, 81.9% and 67.3%
Local tumour progression rates at 1, 3 and 5 year (p=0.11)
RF group = 2.1%, 5.8%, 19.7%
MWA group = 1.1%, 4.3%, 11.4%
Intrahepatic metastatic rates at 1, 3 and 5 year (p=0.30)
RF group = 3.8%, 23.2% and 67.8%
MWA group = 3.5%, 22.9% and 58.7%
Extrahepatic metastatic rates at 1, 3 and 5 year (p=0.30)
RF group = 2.2%, 11.2% and 19.3%
MWA group = 1.6%, 5.9% and 13.2%
Disease free survival rates at 1, 3 and 5 year (p=0.07)
RF group = 93.8%, 66.0% and 24.1%
MWA group = 94.0%, 70.6% and 36.7%
Complication Rate
RF group = 2.5%
MWA group = 3.4%		Findings in this large-sample RCT study suggest that both MWA and RFA are suitable options for early-stage HCC, with better prospects for MWA due to its higher thermal efficiency.
RFA vs Resection
Park, Eun Kyu et al. “A comparison between surgical resection and radiofrequency ablation in the treatment of hepatocellular carcinoma.” Annals of surgical treatment and research vol. 87,2 (2014): 72-80. doi:10.4174/astr.2014.87.2.72OS at 1, 3 and 5 year (p=0.725)
RF group = 94.4%, 74.0%, and 74.0%
Resection group = 91.3%, 78.8%, and 64.9%
Disease free survival rates at 1, and 3 year (p=0.015)
RF group = 65.2% and 24.7%
Resection group = 70.0% and 53.0%

Multivariate analysis identified that recurrence (P = 0.036) and portal hypertension (P = 0.036) were associated with OS and that portal hypertension (P = 0.048) and increased serum α-FP (P = 0.008) were the factors significantly associated with DFS		HCC within Milan criteria should consider hepatectomy as the primary treatment if the patient's liver function and general conditions are good enough to undergo surgical operation. But in that RFA revealed similar overall survival to HR, RFA can be an alternative therapy for patients who are eligible for surgical resection.
Chen, Min-Shan et al. “A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma.” Annals of surgery vol. 243,3 (2006): 321-8. doi:10.1097/01.sla.0000201480.65519.b8OS at 1, 2, 3 and 4 year
RF group = 95.8%, 82.1%, 71.4%, 67.9%
Resection group = 93.3%, 82.3%, 73.4%, 64.0%
Disease free survival rates at 1, 2, 3 and 4 year
RF group = 85.9%, 69.3%, 64.1%, 46.4%
Resection group = 86.6%, 76.8%, 69%, 51.6%,
PLAT was as effective as surgical resection in the treatment of solitary and small HCC. PLAT had the advantage over surgical resection in being less invasive.
Huang, Jiwei et al. “A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria.” Annals of surgery vol. 252,6 (2010): 903-12. doi:10.1097/SLA.0b013e3181efc656OS at 1, 2, 3, 4 and 5 year (P = 0.001)
RF group = 86.96%, 76.52%, 69.57%, 66.09%, 54.78%
Resection group = 98.26%, 96.52%, 92.17%, 82.60%, 75.65%,
Recurrence free survival rates at 1, 2, 3, 4 and 5 year (P = 0.017)
RF group = 81.74%, 59.13%, 46.08%, 33.91%, 28.69%
Resection group = 85.22%, 73.92%, 60.87%, 54.78%, 51.30%,
Overall recurrence free survival rates at 1, 2, 3, 4 and 5 year (P = 0.024)
RF group = 16.52%, 38.26%, 49.57%, 59.13%, and 63.48%
Resection group = 12.17%, 22.60%, 33.91%, 39.13%, and 41.74%		Surgical resection may provide better survival and lower recurrence rates than RFA for patients with HCC to the Milan criteria.
Ueno, Shinichi et al. “Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria.” Journal of hepato-biliary-pancreatic surgery vol. 16,3 (2009): 359-66. doi:10.1007/s00534-009-0069-7group that underwent hepatic resection showed a trend towards better survival (P = 0.06) and showed significantly better disease-free survival (P = 0.02) compared with the RFA group, although differences in liver functional reserve existed. In patients with small HCCs within the Milan criteria, hepatic resection should still be employed for those patients with a single tumor and well-preserved liver function. RFA should be chosen for patients with an unresectable single tumor or those with multinodular tumors, regardless of the grade of liver damage. In order to increase long-term oncological control, surgical RFA seems preferable to percutaneous RFA, if the patient's condition allows them to tolerate surgery.
Feng, Kai et al. “A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma.” Journal of hepatology vol. 57,4 (2012): 794-802. doi:10.1016/j.jhep.2012.05.00OS at 1, 3 and 5 year (p=0.342)
RF group = 93.1%, 83.1%, 67.2%
Resection group = 96.0%, 87.6%, 74.8%
Recurrence free survival rates at 1, 3 and 5 year (p=0.122)
RF group = 86.2%, 66.6%, 49.6%
Resection group = 90.6%, 76.7%, 61.1%
In patients with small hepatocellular carcinomas, percutaneous RFA may provide therapeutic effects similar to those of RES. However, percutaneous RFA is more likely to be incomplete for the treatment of small HCCs located at specific sites of the liver, and open or laparoscopic surgery may be the better choice.
RFA vs Cryoablation
Wang, Chunping et al. “Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma.” Hepatology (Baltimore, Md.) vol. 61,5 (2015): 1579-90. doi:10.1002/hep.27548OS at 1, 3 and 5 year (P = 0.747)
RF group = 97%, 66%, and 38%
Cryoablation group = 97%, 67%, and 40%
Local tumor progression rates rates at 1, 2, and 3 year (P = 0.043)
RF group = 9%, 11%, and 11%
Cryoablation group = 3%, 7%, and 7%
Tumor-free survival rates at 1, 3 and 5 year (P = 0.628)
RF group = 84%, 50%, and 34%
Cryoablation group = 89%, 54%, and 35%

For lesions >3 cm in diameter, the local tumor progression rate was significantly lower in the cryoablation group versus the RFA group (7.7% versus 18.2%, P = 0.041)
Major complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P = 0.776).		Cryoablation resulted in a significantly lower local tumor progression than RFA, although both cryoablation and RFA were equally safe and effective, with similar 5-year survival rates

RF/RFA = Radiofrequency Ablation, PEI = percutaneous ethanol injection, PAI = Percutaneous acetic acid injection, OS = Overall survival, MWA = Microwave ablation, PLAT = Percutaneous Local ablative therapy, HCC = hepatocellular carcinoma

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