1. Joint Hospital Surgical Grand Round Radiofrequency Ablation of Hepatic Tumor (Factors affect local recurrence rate) Dr K Y Yuen United Christian Hospital

2. Introduction Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world Global annual incidence is one million new patients Global annual incidence is one million new patients 70% in Asia and 12% in Africa 70% in Asia and 12% in Africa

3. Introduction Surgery is the only known curative option for either primary or secondary hepatic carcinoma Surgery is the only known curative option for either primary or secondary hepatic carcinoma Resection or transplantation is the gold standard of treatment for liver tumor Resection or transplantation is the gold standard of treatment for liver tumor Only 20% to 37% of patients is suitable for hepatectomy Only 20% to 37% of patients is suitable for hepatectomy Fan et la, Annals of Surgery 1999

4. Introduction Factors limit the surgical intervention: multiple / diffuse tumors multiple / diffuse tumors tumor in unresectable locations (proximity of the tumors to major vascular and biliary structures) tumor in unresectable locations (proximity of the tumors to major vascular and biliary structures) Poor co-morbidity Poor co-morbidity inadequate liver reserve inadequate liver reserve significant portal hypertension significant portal hypertension 5- year survival rate for resectable HCC or liver metastasis is only 20 - 40 % Loco-regional therapies have been developed for the treatment of unresectable liver tumor

5. Nguyen et la, Clinical Gastroenterology 2005

6. Radio Frequency Ablation First described by Rossi et al in 1993 First described by Rossi et al in 1993 High-frequency (450- 500KHz) alternating RF current causes oscillatory movement of ions in tissue High-frequency (450- 500KHz) alternating RF current causes oscillatory movement of ions in tissue The mechanism of tissue heating is frictional heat caused by the motion from the ionic current The mechanism of tissue heating is frictional heat caused by the motion from the ionic current Cause coagulation necrosis at temperature between 50-80 o C Cause coagulation necrosis at temperature between 50-80 o C

8. Radio Frequency Ablation Indications: Alterative to surgery in poor liver function patient with primary or secondary liver tumor Alterative to surgery in poor liver function patient with primary or secondary liver tumor Supplementary to surgery in bilobal tumors Supplementary to surgery in bilobal tumors Liver transplant candidates (bridge) Liver transplant candidates (bridge) Some transplant surgeons are using percutaneous or laparoscopic RFA to treat HCCs detected in patients with cirrhosis on the transplant waiting list in an attempt to attain local control of tumor and prevent progression Robert Goldstein, MD, personal communication, April 2000

9. Radio Frequency Ablation Contraindications: –Child ’ C cirrhosis (gross ascites) –Excessive tumor burden –Extrahepatic diseases –Active infection –Renal insufficiency –Coagulopathy –Near major ductal confluence

10. Radio Frequency Ablation Complications (0-12%): Complications (0-12%): ● Abscess formation ● Bleeding(delayed bleeding into the ablated area, subcutaneous/ subcapsular haematoma) ● Needle tract seeding (up to 12.5%) ● Bile leakage ● Bile duct stricture ● hydropneumothrorax ● Liver failure ● Grounding pad burn ● Acute renal failure ● Mortality: 0 -1%

11. Radio Frequency Ablation RFA may be a superior option amount the locoreginal ablation therapy: RFA may be a superior option amount the locoreginal ablation therapy: Lower complication rate Less recurrence rate Shorter hospital stay R Poon et la, Annals of Surgery 1999

12. Radio Frequency Ablation Question to answer What determine the efficacy of RFA in liver tumor patient ? What determine the efficacy of RFA in liver tumor patient ? Local Recurrence is one of the important aspects Local Recurrence is one of the important aspects Local recurrence was defined as radiological (CT, MRI or contrast-enhanced ultrasound) and/or histological (tumor cells with intact mitochondrial enzyme staining) detection of residual or recurrent viable tumor at the site of the original tumor, during follow-up and after completion of all (one or more) sessions.

13. Pre OT Post OT 1 week Post OT 3 months Siperstein A et la, Annals of Surgical Oncology 2005

14. Local Recurrence After Hepatic Radiofrequency Coagulation Multivariate Meta-Analysis and Review of Contributing Factors Stefaan Mulier, MD, Yicheng Ni, PhD, Jacques Jamart, MD,Theo Ruers, PhD, Guy Marchal, PhD, and Luc Michel, MD Annals of Surgery, August 2005

15. Local Recurrence Local recurrence rate after RFA of liver tumors varies widely between 2% and 60% Local recurrence rate after RFA of liver tumors varies widely between 2% and 60% A local recurrence seriously jeopardizes the chances of cure A local recurrence seriously jeopardizes the chances of cure Re-treatment is often impossible or has a high risk of failure Re-treatment is often impossible or has a high risk of failure From Solbiati L et al 1999, only 55% recurrent tumors were re-treated and a complete coagulation was obtained in only cases 36%. From Solbiati L et al 1999, only 55% recurrent tumors were re-treated and a complete coagulation was obtained in only cases 36%. Reasons for not considering re-treatment: Reasons for not considering re-treatment: unfavorable geometry diffuse metastases

16. Local Recurrence Rate: Univariable Analysis of Contributing Factors 9 factors: 9 factors: Diameter (size) Pathology Proximity of major vessel Location Approach (surgery Vs percutaneous) Intentional Margin Vascular occlusion AnaethesiaImaging Physician ’ s experience

19. Diameter (Size) Current recommended tumor size <5cm Current recommended tumor size <5cm Nearly all authors agree tumor size determining local recurrence /efficacy Nearly all authors agree tumor size determining local recurrence /efficacy Goletti O et al, Montorsi M et al, Livraghi T et al, showed that complete tumor necrosis in 80% to 90% of HCCs smaller than 3 to 5 cm Goletti O et al, Montorsi M et al, Livraghi T et al, showed that complete tumor necrosis in 80% to 90% of HCCs smaller than 3 to 5 cm Livraghi T et al, complete ablation rate for larger tumors is less favorable: a study of RFA for 126 HCCs 3.1 to 9.5 cm (mean 5.4 cm) reported a complete necrosis rate of 48% with the use of a clustered electrode. Livraghi T et al, complete ablation rate for larger tumors is less favorable: a study of RFA for 126 HCCs 3.1 to 9.5 cm (mean 5.4 cm) reported a complete necrosis rate of 48% with the use of a clustered electrode.

20. Diameter (Size) Size of individual RFA is limited Single coagulation cannot cover a large lesion i.e.< 100% necrosis – higher risk of local recurrence Single coagulation cannot cover a large lesion i.e.< 100% necrosis – higher risk of local recurrence Adam R et la, Arch Surg 2002 For large tumors, overlapping coagulations is necessary, however, technically difficulty – Ultrasonogram is difficult to visualize the tumor after 1st coagulation – hyperechoeic microbubble cloud For large tumors, overlapping coagulations is necessary, however, technically difficulty – Ultrasonogram is difficult to visualize the tumor after 1st coagulation – hyperechoeic microbubble cloud R Poon et la, Annals of Surgery 2000

21. Diameter (Size) Large tumors have irregular borders and present satellite lesions Livraghi T et la, Radiology 2000 If the coagulation is restricted to the main tumor without safety margin, spiky irregular extensions and satellites will be left untreated. If the coagulation is restricted to the main tumor without safety margin, spiky irregular extensions and satellites will be left untreated.

22. Effect of Tumor Size on Outcome of RF Ablation Tumors 100% Necrosis <100% Necrosis p value 3.1-5.0 cm 49(61%)31(39%).001 >5cm11(24%)35(76%) Livraghi T et al. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology 2000; 214:761–768.

23. Diameter (Size) Conclusion There is no consensus for the optimal size for RFA There is no consensus for the optimal size for RFA Smaller tumor size ( < 3 cm diameter ), the better the outcome, the lesser the local recurrance rate Smaller tumor size ( < 3 cm diameter ), the better the outcome, the lesser the local recurrance rate Due the advancing technology, future electrode may tackle with larger tumor Due the advancing technology, future electrode may tackle with larger tumor

24. Approach Surgical (open / laparoscopic) Vs Percutaneous Surgical (open / laparoscopic) Vs Percutaneous Absence of RCT Absence of RCT No consensus No consensus

25. Surgical (open / laparoscopic) Vs Percutaneous From Steven A. Curley et la, complete ablations in the 65 HCCs treated during laparotomy or laparoscopy, however, 7.1% (6/84) incidence of incomplete RFA in the HCCs treated percutaneously. From Steven A. Curley et la, complete ablations in the 65 HCCs treated during laparotomy or laparoscopy, however, 7.1% (6/84) incidence of incomplete RFA in the HCCs treated percutaneously. From Rhim H et al, incomplete tumor destruction has been reported in up to 18% of liver cancers treated percutaneously with RFA From Rhim H et al, incomplete tumor destruction has been reported in up to 18% of liver cancers treated percutaneously with RFA

26. Surgical (open / laparoscopic) Vs Percutaneous One disadvantage to RFA is the difficulty in determine accurately the exact area that has been coagulated One disadvantage to RFA is the difficulty in determine accurately the exact area that has been coagulated Intraoperative or laparoscopic ultrasonography provides better resolution of the tumor and RFA treatment compared with transabdominal ultrasonography for percutaneous treatment Intraoperative or laparoscopic ultrasonography provides better resolution of the tumor and RFA treatment compared with transabdominal ultrasonography for percutaneous treatment Steven A. Curley et la, Annals of Surgery 2000

27. Surgical (open / laparoscopic) Vs Percutaneous Better tumor visualization compared with external ultrasound especially of tumors located in the superior right lobe of the liver Better tumor visualization compared with external ultrasound especially of tumors located in the superior right lobe of the liver ~30% increase in tumor detection rate by intraoperative ultrasound during laparoscopy or laparotomy compared with preoperative imaging ~30% increase in tumor detection rate by intraoperative ultrasound during laparoscopy or laparotomy compared with preoperative imaging Siperstein T et la, Annals of Surgical Oncology 2002 Siperstein T et la, Annals of Surgical Oncology 2002 Accurate tumor staging Accurate tumor staging K K-C Ng et la, Journal of Gastro-Hepatology 2003

28. Surgical (open / laparoscopic) Vs Percutaneous Easy access to tumors located in the superior right lobe of the liver Easy access to tumors located in the superior right lobe of the liver Improved visibility will lead to a more correct insertion of the electrodes and an increased chance of complete covering of the tumor, including its irregular margins, satellites, and a 1- cm safety margin Improved visibility will lead to a more correct insertion of the electrodes and an increased chance of complete covering of the tumor, including its irregular margins, satellites, and a 1- cm safety margin Mobilization of the liver allows larger degree of freedom for inserting the electrodes under an optimal angle Mobilization of the liver allows larger degree of freedom for inserting the electrodes under an optimal angle Rossi S et la, AJR AM J Roent-genol. 1996 Rossi S et la, AJR AM J Roent-genol. 1996

29. Surgical (open / laparoscopic) Vs Percutaneous Laparoscopic approach, pneumoperitoneum and the upward movement of the diaphragm, liver movement is minimal, facilitating precise electrode placement. Laparoscopic approach, pneumoperitoneum and the upward movement of the diaphragm, liver movement is minimal, facilitating precise electrode placement. Siperstein A et la, Surgical Endoscopy 2002 Surgical route, allows multiple parallel reinsertions of the electrode when overlapping coagulations are necessary Surgical route, allows multiple parallel reinsertions of the electrode when overlapping coagulations are necessary Rossi S et la, AJR AM J Roent-genol. 1996

30. Surgical (open / laparoscopic) Vs Percutaneous Intraoperative RFA allows the use of Pringle maneuver to minimize the “ heat sink ” effect of the hepatic vessels Intraoperative RFA allows the use of Pringle maneuver to minimize the “ heat sink ” effect of the hepatic vessels Mulier S et la, Eur J Surgical Oncology 2003 During laparoscopy, a 12-mm Hg pneumoperitoneum by itself causes a 40% decrease of portal vein flow During laparoscopy, a 12-mm Hg pneumoperitoneum by itself causes a 40% decrease of portal vein flow Smith MK et la, Surgical Endoscopy 2004

31. A 5-cm hepatocellular carcinoma at the dome of the liver (A,arrow) treated by intraoperative radiofrequency ablation using a clustered probe (B). R Poon et la, Annals of Surgery 2002

32. Intraoperative ultrasound provides guidance to positioning of the probe (C, arrow shows the tip of the probe) in the tumor before starting radiofrequency ablation, but the exact margin of ablation is obscured by hyperechoic shadow resulting from thermal changes in the tissue after starting the ablation (D, arrows). R Poon et la, Annals of Surgery 2002

33. Surgical (open / laparoscopic) Vs Percutaneous Intended safety margin of 1 cm, was used much less in the percutaneous approach than in the surgical approach Intended safety margin of 1 cm, was used much less in the percutaneous approach than in the surgical approach Subcapsular tumors are often undertreated by a percutaneous approach because of fear of burning adjacent organs, diaphragm, or the abdominal wall Subcapsular tumors are often undertreated by a percutaneous approach because of fear of burning adjacent organs, diaphragm, or the abdominal wall R Poon et la, Annals of Surgery 2002

34. Surgical (open / laparoscopic) Vs Percutaneous Approach No. of Cases No Margin 0.5 cm Margin 1 cm Margin p Percutaneous304688.4%(2692)5.4%(165)6.2%(189)<0.001 Surgical124828.8%(360)13.6%(170)57.55%(718)<0.001 Intentional Margin According to Approach tumor 10 mm Ablation zone

35. Surgical (open / laparoscopic) Vs Percutaneous Conclusion Laparoscopic or open approach is recommended in patients with a high risk of bleeding from severe coagulopathy, large HCCs (5 cm), superficial nodules adjacent to other visceral organs at risk of thermal injury, or deeply located lesions not accessible to percutaneous puncture Laparoscopic or open approach is recommended in patients with a high risk of bleeding from severe coagulopathy, large HCCs (5 cm), superficial nodules adjacent to other visceral organs at risk of thermal injury, or deeply located lesions not accessible to percutaneous puncture R Poon et la, Annals of Surgery 2002

36. Surgical (open / laparoscopic) Vs Percutaneous The percutaneous route remains valuable for certain indications: The percutaneous route remains valuable for certain indications: For patients that are too fragile to undergo laparoscopy or laparotomy. Tumors that are invisible on ultrasound imaging can be treated by a CT- or MRI- guided percutaneous procedure. May be performed as a day procedure

37. Surgical (open / laparoscopic) Vs Percutaneous 50.060.0>5 cm 21.725.93-5 cm 3.616.0<3 cm Laparoscopy/ Laparotomy (%) Percuteneous (%) Local Recurrence Rate According to Size and Approach

38. Conclusion Surgery remain the gold standard of treating liver tumor Surgery remain the gold standard of treating liver tumor RFA is superior option in treating unresectable primary and secondary RFA is superior option in treating unresectable primary and secondary Surgical approach have less local recurrance rate and better outcome when compared with percutaneous route Surgical approach have less local recurrance rate and better outcome when compared with percutaneous route Small size tumor have better outcome, however, advance technology may overcome this problem in future Small size tumor have better outcome, however, advance technology may overcome this problem in future

39. RFA Vs Cryoablation Local recurrence rate: Local recurrence rate: 2.2% Vs 13.6% 2.2% Vs 13.6% Treatment mortality: Treatment mortality: 0% Vs 2% 0% Vs 2% Complication rate: Complication rate: 3.3% Vs 40% 3.3% Vs 40% Pearson AS et al. Am. J. Surg. 1999

40. RFA Vs Microwave Coagulation Therapy Complete ablation: Complete ablation: 91% Vs 85% 91% Vs 85% Local recurrence Local recurrence 4%Vs 17% 4%Vs 17% Lencioni et al. Radiology 1999

41. RFA Vs PEI Complete necrosis : Complete necrosis : RFA Vs PEI – 90% Vs 80% RFA Vs PEI – 90% Vs 80% Treatment section: Treatment section: Mean 1.2 Vs 4.8 sessions Mean 1.2 Vs 4.8 sessions Complication rate: Complication rate: 12% Vs 0% 12% Vs 0% Livraghi T et al. Radiology 1999

42. RFA Vs TACE Complete control of tumor growth: Complete control of tumor growth: 50% Vs 30% 50% Vs 30% Mortality: Mortality: 0% Vs 4% 0% Vs 4% Livraghi et al. Radiology 2002

43. RFA Vs Resection Recurrence Recurrence 53% Vs 30% 53% Vs 30% Resection recurrence – distant recurrence Resection recurrence – distant recurrence RFA recurrence – local recurrence RFA recurrence – local recurrence Montorsi M et la, The Society for Surgery of the Alimentary Tract 2005 Resection is more effective, in terms of overall and disease-free survival, in Child ’ s A patient with a single tumour >3cm Resection is more effective, in terms of overall and disease-free survival, in Child ’ s A patient with a single tumour >3cm Vivarelli M et la, Annals of Surgery 2004 Vivarelli M et la, Annals of Surgery 2004

44. RFA – Bridge therapy Retrospective studyRetrospective study 14 cirrhotic patients with small HCC (  3.5cm)14 cirrhotic patients with small HCC (  3.5cm) RFA prior to transplanatationRFA prior to transplanatation Median follow-up: 16 monthsMedian follow-up: 16 months Histology :Histology : – complete necrosis: 71% – incomplete necrosis: 29% – tumour satellites < 1cm from main tumour: 57% No complication/ death/ recurrenceNo complication/ death/ recurrence