Is resection or transplant the only option for cure for patients with hepatocellular carcinoma (HCC)? Or, with advances in technology, are less invasive options appropriate, and if so, for which patients?
HCC is the sixth most common cancer and third leading cause of cancer death worldwide.1 Unlike Asia, where endemic hepatitis B (HBV) is the leading cause of HCC, in the U.S., the most common risk factors include alcoholic liver disease, hepatitis C infection, and nonalcoholic steatohepatitis. HCC in these types of patients typically arises in the background of cirrhosis, although the exact mechanism of carcinogenesis is not understood. Therefore, in addition to patient and tumor factors, HCC therapy must address the functional capacity of the liver.
Figure 1. BCLC staging system for HCC and treatment strategy depending on tumor factors, Child-Pugh classification, and patient performance status
The Barcelona Clinic Liver Cancer (BCLC) group has proposed and validated a therapeutic staging system to optimize treatment of HCC (see Figure 1).2 While resection and transplantation have demonstrated the highest survivals for HCC, most patients are ineligible for these modalities due to advanced liver disease and limited organ availability.
Thermal ablation, which was limited to use in unresectable disease, has now been used more frequently in early stage disease. Its use as potentially curative therapy in early stage tumors has reported outcomes nearly equivalent to hepatectomy in retrospective studies.3,4 As its use by both liver surgeons and interventional radiologists increases, the role of ablation in HCC needs to be more rigorously studied to identify which population derives the most benefit. The decision on modality should be based on patient and disease factors and not influenced by referral pattern or the door through which the patient entered the hospital system.
Techniques
Figure 2. Laparoscopic microwave ablation of 1.5-centimeter HCC in segment seven in a patient with hepatitis C cirrhosis
Panel A demonstrates the view from the laparoscope with the probe in position under ultrasound guidance. Panel B shows the probe through the tumor during ablation procedure.
The most common types of thermal ablation are radiofrequency (RFA) and microwave (MWA). RFA uses an alternating current, whereas MWA uses electromagnetic radiation to generate frictional heat in tissues. However, when applied close to large blood vessels, that energy can be absorbed and diverted away from tumor cells as a heat sink. Both RFA and MWA can be delivered percutaneously, with laparoscopic assistance, or during open surgery. Ultrasound guidance is typically used for probe placement (see Figure 2). The percutaneous approach avoids the risks of laparotomy with faster recovery. However, tumors on the capsule near the diaphragm, peritoneum, or bowel cannot be safely treated through this route. Laparoscopy allows for liver mobilization to ablate lesions in those locations while limiting surgical morbidity. However, tumors in the hilum or hepatic vein confluence cannot be ablated thermally due to the potential for injury to biliary and vascular pedicles. In addition, incomplete ablation can occur in larger lesions, and ablation is typically not recommended for lesions greater than 3 centimeters.
Trials
Only two randomized controlled trials (RCT) on thermal ablation and resection in HCC have been reported in literature published in the U.S., both conducted in China. The first RCT compared 180 patients with a single tumor smaller than 5 centimeters and Child’s A cirrhosis between percutaneous RFA or open resection.5 The groups were evenly matched with respect to tumor size, alpha-fetoprotein, liver function, and indocyanine green clearance. However, 19 patients from the RFA group crossed over to the surgery group.
No difference was found in overall or disease-specific survival in the intention-to-treat analysis between groups, but resection was associated with one death and more complications (55 percent versus 4 percent, p<0.05) than RFA. The second trial compared 230 patients with HCC within Milan criteria with percutaneous RFA or open resection.6 The groups consisted predominantly of HBV patients with Child’s A and B cirrhosis and were evenly distributed, with the exception of slightly larger tumors in the RFA group.
A total of 25 patients were lost to follow-up (seven RFA, 18 surgery), and seven patients in the RFA group crossed over to the surgical group. The tumor recurrence rate was higher in the RFA group compared with the surgery group (69 percent vs. 52 percent, p<0.02), although the majority of recurrences were in the liver away from the ablation site. The five-year overall and disease-free survival rates were significantly higher in the surgery group (75 percent and 51 percent) than the RFA group (54 percent and 28 percent, p<0.001). No hospital deaths occurred, but more complications arose in the surgery cohort than in RFA (28 percent versus 2 percent, p<0.05), resulting in a longer length of stay. Both trials had significant shortcomings, including problems with group allocations, number of patients with cirrhosis, small sample size, and short follow-up.
Additional research
Given the paucity of level I evidence and the discrepancy in the methodology and results from existing RCTs, thermal ablation as treatment for early HCC clearly requires further investigation. Clinical trials performed via U.S. cooperative groups are sorely needed, as the HCC population is significantly smaller and different from the one in Asia. With the continued evolution and evaluation of this technology, it may be possible for thermal ablation to become the first-line option for very early HCC (BCLC 0). In the meantime, resection remains the gold standard for small HCC in eligible patients, reserving ablation for those with impaired liver function who are not candidates for transplantation, preferably after discussion at a multidisciplinary liver tumor board.
References
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
- Forner A, Llovet J, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245-1255.
- Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, Bartolozzi C. Early-stage hepatocellular carcinoma in patients with cirrhosis: Long-term results of percutaneous image-guided radiofrequency ablation. Radiology. 2005;234(3):961-967.
- Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complication rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008;47(1):82-89.
- Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, Lin XJ, Lau WY. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243(3):321-328.
- Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J, Xu Y, Zeng Y. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010;252(6):903-912.
