What is an evidence note. Key points. Introduction. Health technology description

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1 In response to an enquiry from the National Cancer Waiting Times Delivery Group What is an evidence note Evidence notes are rapid reviews of published secondary clinical and cost-effectiveness evidence on health technologies under consideration by decision makers within NHSScotland. They are intended to provide information quickly to support time-sensitive decisions and are produced in an approximately 3 month period. Evidence notes are not comprehensive systematic reviews. They are based on the best evidence that Healthcare Improvement Scotland could identify and retrieve within the time available. The reports are subject to peer review but do not undergo external consultation. Evidence notes do not make recommendations for NHSScotland. Introduction This evidence note reviews the clinical and costeffectiveness evidence relating to radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). More specifically, two separate questions have been addressed: In patients with HCC suitable for surgery, how does RFA compare with surgical resection? In patients with HCC not suitable for surgery, how does RFA compare with other forms of ablation? Most evidence comes from secondary literature (ie systematic reviews and meta-analyses); however some good quality randomised controlled trials (RCTs) have also been considered. While there is some evidence relating to combined ablative therapies (eg RFA and percutaneous ethanol injection (PEI) versus PEI alone), this is outwith the scope of this evidence note. The literature was limited to publications since Health technology description For patients with HCC, treatment options include surgical resection (SRS), liver transplantation or local ablative therapies. In cases suitable for Key points Number 43 January 2012 Is radiofrequency ablation (RFA) treatment a suitable clinically and cost-effective treatment to be offered to patients with hepatocellular cancer in NHSScotland? The evidence on radiofrequency ablation as an alternative to surgical resection in patients with small hepatocellular carcinoma is inconclusive. While some reviews indicate that survival rates are similar with both therapies (particularly in tumours 3 cm), a recent randomised trial suggests that SRS provides better survival and lower recurrence rates. In some patients resection or transplantation is not possible, and so ablative methods, such as RFA, are employed. Evidence from good quality meta-analyses suggest that RFA is superior to PEI, an alternative ablative therapy, in terms of overall survival, cancer-free survival, complete necrosis and recurrence. There is insufficient evidence available to conclude whether RFA is superior to PAI, microwave ablation, thermal ablation or cryoablation. There is insufficient evidence to determine whether or not RFA would be considered cost effective for HCC at currently accepted thresholds in NHSScotland. transplantation, feasibility may be limited by the shortage of donor organs. Although SRS is regarded as the optimal therapy 1, the majority of patients are not eligible for this approach because of reduced hepatic function caused by coexisting cirrhosis or the presence of multiple tumours 2. Therefore ablative therapies, such as RFA, may be employed. RFA involves the local application of radiofrequency thermal energy to the tumour using a needle electrode 1. This produces heat in the target tissues, causing protein denaturation and cell death 3. The procedure is normally performed percutaneously with image guidance, though it can be done using an laparoscopic approach 3. It may not be apropriate to

2 2 use a percutaneous approach for tumours at the inferior edge of the liver if the stomach, duodenum, or transverse colon lies in close proximity to the tumour 4. Epidemiology HCC is the fifth most common cancer world wide 5, and in the United Kingdom (UK) it ranks 18th 6. A total of 341 diagnoses of liver cancer were made in Scotland in It is diagnosed more commonly in males (male:female ratio of 5:3), and 70% of cases are in people over the age of 65 years 6. Major risk factors are alcoholic cirrhosis and infection with hepatitis B and C 6. Prognosis is poor, and in Scotland the death rate has increased by 55% in the 10 years to Clinical effectiveness The clinical evidence identified relates to two main areas: RFA compared with SRS for small HCC; and RFA versus other ablative treatments for HCC. One review stated that there have been some small non-randomised studies assessing the use of RFA as a bridging therapy for people awaiting liver transplants, however there is a need for more robust evidence before conclusions can be drawn 10, and so it has not been discussed further in this evidence note. Radiofrequency ablation versus surgical resection Most of the evidence for this section comes from one good quality systematic review published in Four lower quality reviews and an RCT were also identified 15. It should be noted that all the reviews include observational studies which were probably affected by selection bias, with patients with worse prognosis being more likely to receive RFA 3. A good quality systematic review, by Xie et al., compared percutaneous RFA and SRS for early stage HCC 3. It included six studies (one RCT and five comparative cohort studies) on patients classified as Child-Pugh A or B, with tumour size <5 cm. The authors concluded that for Child- Pugh A patients for whom SRS and percutaneous RFA are available options, survival rates are similar following either procedure. This is based on the RCT (Chen et al., 2006) and pooled survival rates from the observational studies. The RCT reported that 1-, 2-, 3- and 4-year overall survival rates in the percutaneous RFA group and the SRS group, respectively, were very similar (94%, 80%, 69%, 66% versus 93%, 82%, 73%, 64%). The SRS group experienced more complications and had longer hospital stays. Based on the observational studies with Child-Pugh A patients, the pooled survival rates at 1 (98% versus 98%) and 3 (RFA 83% versus SRS 82%) years were not significantly different between the two groups. The authors of the review also pooled the survival rates from observational studies with a mixture of Child-Pugh A and B patients, and found that in this group, the 3- and 5-year survival rates were better in the SRS group (43% versus 62% at 3 years; and 25% versus 48% at 5 years) 3. With regards to recurrence and disease-free survival, the review was inconclusive. While the RCT shows comparable outcomes with both procedures at 3 years, the results of the cohort studies (especially those that include Child-Pugh A and B patients) appear to favour SRS 3. Four more systematic reviews (three of which included meta-analyses) were identified However, these all had methodological flaws such as inadequate literature searches, and failure to assess the quality of the included studies. One review by Zhou et al. 12 included the RCT by Chen et al. and nine non-randomised trials (four of which were included in the review by Xie et al. 3 ). Two of the studies used laparoscopic RFA, with the remaining using percutaneous RFA. It concluded that SRS was superior to RFA in the treatment of small HCC eligible for surgical intervention (particularly for tumours >3 cm) in terms of overall survival, local intrahepatic recurrence, and disease-free survival. However, the authors also noted that when the results for tumours 3 cm were considered separately (from three non-randomised trials) survival was not significantly different between those treated with RFA and SRS. Of the remaining three reviews (for which the included studies overlapped), two concluded that survival rates did not differ between SRS and RFA for HCC 5 cm 11,14 and one that they did not differ for HCC 3 cm 13. Two of the reviews suggested that recurrence of HCC may be lower in the SRS group 11,14. Finally, an RCT was recently published which included 230 patients who had either a single HCC 5 cm or up to three nodules each <3 cm 15. At 5 year follow up, overall survival for the RFA group was 54.8% and for the SRS group 75.7% (p=0.001); recurrence-free survival was 28.7% for the RFA group and 51.3% for the SRS group (p=0.017); and overall recurrence rate was 63.5% for the RFA group versus 41.7% for the SRS group (p=0.025). The authors concluded that SRS may provide better survival and lower recurrence rates than RFA for patients with small HCC 15.

3 3 Radiofrequency ablation versus other ablative treatments Four good quality meta-analyses were identified, which all compared RFA with PEI 2,8,9,16. PEI is a minimally invasive method for treating HCC, and involves the injection of 95% ethanol directly into the tumour 4. There was considerable overlap of the studies included, but overall the four metaanalyses concluded that RFA was a superior ablative therapy in terms of overall survival, cancer-free survival, complete necrosis and recurrence. The most recent meta-analyses 8 identified five studies comparing RFA with PEI. The authors reported that RFA was superior to PEI for survival (OR 0.52; 95% CI 0.35 to 0.78; p=0.001), resulted in complete nodule necrosis more frequently (OR 0.29; 95% CI 0.16 to 0.53; p<0.0001), and resulted in less local tumour recurrence (OR 0.27; 95% CI 0.16 to 0.45; p< ). With HCC 2 cm, there was no significant difference between RFA and PEI for the proportion dead at maximum follow up (OR 0.63; 95% CI 0.27 to 1.49; p=0.29) and local recurrence (OR 0.43; 95% CI 0.12 to 1.51; p=0.19). No significant differences were reported for adverse events (OR 1.21; 95% CI 0.89 to 1.63; p=0.22), and major complications (OR 2.00; 95% CI 0.72 to 5.53; p=0.18). These results are supported by the earlier three meta-analyses 2,9,16. However, Bouza et al. 9 reported that the overall rate of adverse events was higher with RFA (see safety section). The most recent meta-analysis also compares RFA with percutaneous acetic acid injection (PAI) 8. Only one RCT was identified, which compared RFA, PEI and PAI, and concluded that RFA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancerfree survival rates, but RFA caused more major complications 17. The authors of the meta-analysis combined these results with adjusted indirect estimates, and the pooled estimates suggested no significant difference in the proportion dead (OR 0.74; 95% CI 0.33 to 1.62; p=0.45), time to death (hazard ratio [HR] 0.65; 95% CI 0.37 to 1.13; p=0.13), de novo tumours (OR 0.94; 95% CI 0.49 to 1.82; p=0.86) or time to recurrence (HR 0.65; 95% CI 0.3 to 1.38; p=0.26). However, RFA resulted in less local recurrence (OR 0.29; 95% CI 0.15 to 0.55; p=0.0002). The authors of the meta-analysis also used the RCT data to conduct subgroup analysis by tumour size and demonstrated that with HCC 2 cm there was no significant difference in proportion dead or local recurrence. The results for tumours > 2 cm were also non-significant, although there was a trend favouring RFA for both proportion dead (OR 0.34; 95% CI 0.11 to 1.09; p=0.07) and local recurrence (OR 0.30; 95% CI 0.09 to 1.06; p=0.06) 8. It should be noted that headto-head comparisons are preferable to indirect comparisons, and so more research is required before robust conclusions can be drawn. Finally, one review reports on a small (n=72) RCT comparing microwave ablation (MWA) to RFA in patients with HCC <4 cm 4. This reported no statistically significant differences in complete response rate (89% versus 96% for MWA and RFA; p values not reported) or 2-year local recurrence rate (24% versus 12%). However the authors of the review highlight that this is a small trial without long-term survival data 4. Again, further research is required. No systematic review or RCT evidence was identified comparing RFA with other ablative therapies such as laser thermal ablation and cryoablation. Cost effectiveness One cost-effectiveness analysis was identified, which compared RFA with PEI for early HCC 18. The analysis was conducted for patients who had completed 1 year of follow up. The authors stated the perspective taken was that of the national health system in Italy. The effectiveness data were obtained from an RCT carried out on cirrhotic patients with 1 3 nodes of HCC and with lesions with a diameter <3 cm. The primary end-point was complete response (CR) 1 year after RFA. CR was defined as computed tomography/magnetic resonance detection of a non-enhanced area of necrosis/ scar at the site of every lesion defined as HCC at baseline. Statistical analysis was performed to detect the difference with confidence. The measure of effectiveness used was the proportion of patients with a sustained CR at 1 year. Costs included hospital costs related to the whole period of care; both inpatient and day care and were calculated for one or two cycles of treatment. Hospital costs were presented as Euros and based on the Diagnosis Related Group s (DRGs) tariffs, calculated by the Regional Information System for each year. The authors stated that due to DRGs not completely capturing the cost differences between PEI and RFA procedures, costs relating to the specific needles used for each patient were added to the patient s total costs.

4 4 The results showed that for an intention-to-treat analysis, 46/70 patients (65.7%) in the RFA arm achieved a CR, compared with 25/69 (36.2%) in the PEI arm, with an absolute difference of 29.5% (95% CI 12.9 to 43.9; p= ). In terms of overall survival, however, the difference was not sustained after a median follow up of over 26 months. The mean direct costs were 4,097 (approximately 3,413) for patients in the PEI group and 6,540 (approximately 5,449) for patients treated with RFA. The incremental costeffectiveness ratio of RFA relative to PEI was 8,286 (approximately 6,903 95% CI 2,284 to 17,424) per patient achieving a sustained complete response at 1 year. The authors therefore concluded that RFA was cost effective at 1 year but did question whether the extra costs of RFA were justified given that the survival advantage of RFA was not sustained (note: all reported costs converted to GBP using the exchange rate as at 25 January 2012). The authors reported that the analysis had several limitations, including that the PEI technique chosen was not representative of the most popular, a small sample size and the primary end-point being more technically relevant than clinical. This may limit the generalisability of results. Safety One review noted that major complications develop in % of patients receiving RFA, and procedural mortality is % 4. The authors refer to three case series, and describe the results of one. This series included 312 patients who underwent 350 sessions of RFA (124 intraoperative and 226 percutaneous) for the treatment of 582 tumours (115 HCC and 467 metastatic tumours). There were five deaths, due to liver failure, colon perforation or portal vein thrombosis. Portal vein thrombosis was significantly more common in cirrhotic (2/5) compared with noncirrhotic livers (0/54) after intraoperative RFA performed during a Pringle manoeuvre (clamping of the porta hepatis, thus interrupting hepatic arterial and portal venous flow to the liver). Non-fatal major complications (incidence 11%) included liver abscess, pleural effusion and skin burns, hypoxaemia during treatment, pneumothorax, subcapsular haematoma, acute renal insufficiency, haemoperitoneum and needle tract seeding. A review described an RCT comparing percutaneous RFA with SRS in HCC with a solitary tumour 5 cm. Major complications (eg liver failure, gastrointestinal bleeding, ascites and persistent jaundice) were significantly more frequent in the SRS group (55% versus 4%) than in the RFA group 3. In a well-conducted meta-analysis comparing RFA with PEI, no significant differences were reported for adverse events (odds ratio [OR] 1.21; 95% confidence interval [CI] 0.89 to 1.63; p=0.22), and major complications (OR 2.00; 95% CI 0.72 to 5.53; p=0.18) 8. However, another meta-analysis, by Bouza et al. 9, reported that the overall rate of adverse events across six studies was significantly higher with percutaneous RFA compared with PEI (19.2% versus 10.5%: relative risk [RR] 2.55; 95% CI 1.8 to 3.65; p<0.001). Complications reported included severe pain, fever, pleural effusion, subcapsular haematoma and haemothorax. There was no statistically significant difference in the proportion of patients with major complications which, based on four studies, was 4.1% in the RFA group and 2.7% in the PEI group (RR 1.85; 95% CI 0.68 to 5.01; p=0.22). Equality and diversity Healthcare Improvement Scotland is committed to equality and diversity in respect of the nine equality groups defined by age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race, religion, sex, and sexual orientation. The evidence note process has been assessed and no adverse impact across any of these groups is expected. The completed equality and diversity checklist is available on About evidence notes For further information about the evidence note process, see To propose a topic for an evidence note, evidencenotes.hcis@nhs.net References can be accessed via the internet (where addresses are provided), via the NHS Knowledge Network or by contacting your local library and information service.

5 5 Acknowledgements Healthcare Improvement Scotland would like to acknowledge the helpful contribution of the following, who gave advice on the content of this evidence note: Dr Hamish M Ireland, Consultant Radiologist, NHS Lothian Healthcare Improvement Scotland development team Joanna Kelly, Lead Author/Health Services Researcher Lisa Wilson, Author/Health Economist Carolyn Sleith, Information Scientist Susan Downie, Medical Writer Doreen Pedlar, Project Co-ordinator Marina Logan, Team Support Administrator Healthcare Improvement Scotland 2012 ISBN References 1. Abdalla EK, Stuart KE. Overview of treatment approaches for hepatocellular carcinoma [online] Jan 12 [cited 2010 Oct 19]; Available from: topic.do?topickey=gicancer/16848&selectedtitle=3%7e150&source=search_result 2. Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009;104(2): Xie X, Dendukuri N, McGregor M. Percutaneous radiofrequency ablation for the treatment of early stage hepatocellular carcinoma: a health technology assessment. Int J Technol Assess. 2010;26(4): Curley SA, Stuart KE, Schwartz JM, Carithers RL Jr. Nonsurgical therapies for localized hepatocellular carcinoma: radiofrequency ablation, percutaneous ethanol injection, thermal ablation, and cryoablation [online] [cited 2011 Mar 7]; Available from: 5. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399): Cancer Research UK. Liver cancer - UK incidence statistics [online] [cited 2012 Jan 30]; Available from: 7. ISD Scotland. Cancer Statistics: Liver Cancer [online] [cited 2012 Jan 30]; Available from: 8. Germani G, Pleguezuelo M, Gurusamy K, Meyer T, Isgro G, Burroughs AK. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar [sic hepatocellular] carcinoma: a meta-analysis. J Hepatol. 2010;52(3): Bouza C, Lopez-Cuadrado T, Alcazar R, Saz-Parkinson Z, Amate JM. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol. 2009;9:31.

6 6 References continued 10. Tsoulfas G, Curley SA, Abdalla EK, Barnett CC Jr, Hertl M. Liver transplantation for hepatocellular carcinoma [cited 2012 Jan 30]; Available from: com/contents/liver-transplantation-for-hepatocellular-carcinoma?source=search_result&selecte dtitle=1%7e150#h Liu JG, Wang YJ, Du Z. Radiofrequency ablation in the treatment of small hepatocellular carcinoma: a meta analysis. World J Gastroenterol. 2010;16 (27): Zhou Y, Zhao Y, Li B, Xu D, Yin Z, Xie F, et al. Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC Gastroenterol. 2010;10: Lau WY, Lai ECH. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg. 2009;249(1): Liu Z, Zhou Y, Zhang P, Qin H. Meta-analysis of the therapeutic effect of hepatectomy versus radiofrequency ablation for the treatment of hepatocellular carcinoma. Surg Laparo Endo Per. 2010;20(3): Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010;252(6): Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2009;49(2): Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percuraneous acetic acid injection to treat hepatocellular carcinoma of 3cm or less. Gut. 2005;54(8): Brunello F, Veltri A, Carucci P, Pagano E, Ciccone G, Moretto P, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled trial. Scand J Gastroentero. 2008;43(6):