Local Ablative Therapy for Hepatocellular

Carcinoma

Dr. Steven CY Law

Department of Surgery

Pamela Youde Nethersole Eastern Hospital

Joint Hospital Surgical Grand Round

Introduction

Hepatocellular carcinoma is the fifth most common cancer worldwide

Associated with high mortality

Surgical resection and liver transplantation offers the best chance of cure but is only applicable to minority of patients

Surgical resection being limited by the reduced liver reserve from underlying cirrhosis

Organ donor shortage is a major concern limiting availability of transplantation, with the progression of tumor while awaiting organ

Parkin et al. Cancer Journal for Clinicians 2005;55(2):74–108

Ries et al. SEER cancer statistics 2007

Local Ablative Therapy Evolving in clinical practice for past three decades

Minimally invasive approach Preserve uninvolved liver parenchyma Avoid morbidity of major hepatic surgery

Aim at adequate local control of the target lesions with complete tumor necrosis

A treatment option for patients with small HCC with poor liver function who are not suitable for liver resection or transplantation

Bruix Hepatology 2005; Vol. 42, issue 5:1208–36Mazzaferro et al. New England Journal of Medicine

1996;334:693–9

Modality Injection of damaging agent

Chemicals: ethanol, acetic acid

Application of energy source Thermal ablation

Radiofrequency Microwave Interstitial laser photocoagulation

Cryoablation

Injection Therapy

Percutaneous Ethanol Injection Therapy (PEI)

First introduced in in the 1980s

Mechanism: non-selective protein denaturation and cellular dehydration, small vessel thrombosis from chemical vasculitis, leading to necrosis

95% absolute ethanol injected into tumor with USG/CT guidance

Usually repeated twice a week for up to four to six sessions

Commonly used probably related to its simplicity, cost effectiveness and repeatability

Shiina et al. Eur J Ultrasound 2001;13(2):95-106

Percutaneous Acetic Acid Injection (PAI)

First introduced in 1996

A viable alternative to percutaneous ethanol injection

Diffuse better than ethanol in tumor

Ohnishi et al. Hepatology 1996;24:1379-85

PEI vs PAI Only two randomised trials in literature comparing PEI vs PAI

on survival outcome

Ohinishi et al. Prospective RCT 1998 Subject: 60 patients, 1-4 HCCs, <3 cm size, absence of

vascular invasion or extrahepatic metastasis, Child’s A/B Mean FU 29 months

PAI better than PEIOhinishi et al. Hepatology 1998;27:67–72.

PEI PAI P value

n 29 31

Local recurrence rate 38% 8% <0.001

2-year survival rate 63% 92% 0.0017

PEI vs PAI Lin et al. 2005. Prospective RCT

Subject: 125 patients, 1-3 HCC, ≤ 3 cm in size, absence of vascular invasion or extrahepatic metastasis, Child’s A/B

Mean FU 35 months

PEI is better than PAI

PEI PAI P value

N 62 63

Local recurrence rate 34.5% 29% 0.015

3-year overall survival rate

51% 53% NS

3-year disease-free survival

21% 23% NS

Lin et al. Gut. 2005;54(8):1151–6..

PEI or PAI?

Meta-analysis Only 2 RCT in literature addressing PEI vs PAI

on local recurrence and survival

Combining the data: No significant difference in overall survival and recurrence-free survival between PEI and PAI

Schoppmeyer et al. Cochrane Database of Systematic Review 2009,

Issue 3. Art No: CD006745

Energy Ablation

Laser

Microwave

Cyroablation

RFA

Interstitial Laser Photocoagulation

Mechanism: conversion of absorbed Nd:YAG neodymium:yttrium-aluminum-garnet light with a wavelength of 1064 nm by tissue into heat

laser light is emitted from the tip of thin (0.2–0.6 mm in diameter) fibers with an effective distance up to 1.5cm

Most published literature only assess the short term tumor necrosis rate only

currently still experimental and pending data on local recurrence rate and survival rate

Vogl et al. Radiology 2002;225(2):367-77Pacella et al. Radiology 2001;219(3)181-8

Cryoablation Mechanism: employs liquid nitrogen at -196oC

delivered through a closed triple-lumen probe for rapid freezing of cell below -35oC, result in intracellular crystals leading to destruction of cellular structure, vessel injury and delayed hypoxia and necrosis

Suggested benefit: tumor freezing facilitates mapping of margins of ablation which is a key to reduction of local recurrence

Kohli et al. British Journal of Surgery 1998;85:1171–2Pearson et al. The American Journal of Surgery

1999;178(6):592–9.

Evidence for Cryoablation

No randomised trial in literature

Previous studies have demonstrated non-ignorable complication up to 50% and mortality 4% (massive hemorrhage), cryoshock syndrome 1%

Pearson et al. The American Journal of Surgery 1999;178(6):592–9

Adam et al. Archives of Surgery 2002;137(12):1332–9

Cochrane Review 2009 There is insufficient evidence to determine the

benefits of cryotherapy in treatment of HCC, as outweighted by its associated complications Awad et al. Cochrane Database of Systematic

Reviews 2009, issue 4. Art. No: CDD007611

Percutaneous MicrowaveCoagulation Therapy (PMCT)

Mechanism: use of a microwave coagulator with electromagnetic frequency above 900kHz that generates and transmits microwave energy to a monopolar-type needle electrode inserted into the liver tumor

The energy causes molecular vibration of dipoles, especially water molecules in tissue, and produces dielectric heat and thermal coagulation around the electrode

Limited literature data, mostly case report and retrospective small size study

Goldberg et al. Radiology 2003;228:335-45Lu et al. Radiology 2001;221:167-72

Radiofrequency Ablation

First described by Rossi et al. in 1993

Mechanism: alternating current from electrode tip into surrounding tissue causing electron vibration at high frequency resulting heat generation directly in tissue leading to coagulation necrosis

Using a needle electrode (15–18G) with an insulated shaft and a noninsulated distal tip that is inserted into a lesion under image guidance

Temperature is maintained at 55-100oC throughout entire target volume for 6-12 minutes

Can be applied percutaneously, laparoscopically or open

Rossi S et al. J Interv Radiol 1993; 8:97–103.

Limitations of RFA Problem of ‘heat sink effect’: close proximity <1cm

from structures with a large volume of blood flow, such as the heart and major blood vessels, the heat generated by radiofrequency will be carried away by the blood and make the treatment less effective

peripheral lesions that abut organs such as the gallbladder, large bowel, or stomach can be damaged

Increase impedence from tissue charring limited effect

Tumor seeding Risk factor: subcapsular location, poor

differentiation, and high baseline AFP performing thermocoagulation of the needle

track while removing the needlePatterson et al. Ann Surg 1998;227(4):559-65

Radiofrequency Ablation

Different RCT have shown its safety and efficacy in treatment of early HCC: irresectable HCC up to 5cm without vascular invasion or extrahepatic metastasis, Child’s A or B

Brunello et al. Scandi J of Gastr 2008;43(6):717–35Shiina et al. Gastroenterology 2005; 129(1):122–30.

Lencioni et al. Radiology 2003;228(1):235–40.Siperstein et al. Surg Endosc 2000:14(4):400-5.

Goldberg et al. Acad Radiol 1995;2(8);670-4Miao et al. J Surg Res 1997;71(1):19-24

RFA vs PMCT Only one randomised trial in literature comparing RFA and PMCT

Shibata et al. RCT: 72 patients with 94 HCC. Mean FU 18 months

Subject: solitary HCC <4cm, Or HCC ≤ 3 in number and ≤ 3 cm. Exclusion criteria not mentioned

Data was based on tumor nodules, NOT on individual patients

No data on survival

RFA PMCT P value

Local recurrence rate 12% 24% 0.20

Morbidity rate 3% 11% 0.36

Shibata et al. Radiology 2002;223:331–7

RFA vs PMCT Ohmoto et al. Retrospective study: 83 patients,

lesion ≤ 2cm, no exclusion criteria (Child’s C patient included)

Mean FU time 33.5 months

RFA PMCT P value

n 34 49

3-year local recurrence rate 9% 19% 0.031

3-year overall survival rate 70% 49% 0.018

Morbidity rate 5.8% 24% 0.025

Ohmoto et al. J of Gastr & Hepatology. 24(2):223-7, 2009

Feb.

Major complicaton: bile duct injury, abscess,

hemorrhage

Energy Ablation

RFA ✔evidence in RCT

Microwave Limited evidence but favor RFA vs PCMT

Laser Limited evidence

Cyroablation Limited evidence, high morbidity

Injection therapy vs RFA

Meta-analysis: RFA vs PEI

Bouza et al. BMC Gastroenterol 2009; 9: 31

RFA vs PEI RFA is superior to PEI in terms of recurrence-

free survival and overall survival Subgroup analysis also suggest fewer

sessions required in RFA group to achieve complete tumor necrosis

Bouza et al. BMC Gastroenterol 2009; 9: 31

Base on current evidence, RFA is more effective than other ablative therapies in treatment of unresectable small HCC within Milan Criteria, if location of tumor is technically feasible

Further Application of RFA

Recurrent HCC

First line treatment for operable small HCC

as a bridge to liver transplantation

Lau et al. Ann Surg 2009;249:20-25Lin et al. Gut 2005;54(8):1151–6

Shiina et al. Gastroenterology 2005; 129(1):122–30Brunello et al. Scan J Gastroenterology 2008;43(6):717–35.

Recurrent HCC

Repeated hepatectomy is an effective treatment for intrahepatic HCC recurrences with a 5 year survival of 19-56%

However repeated hepatectomy can only be carried out in small proportion of patient with recurrence ranging 10.4-31% Poor functional reserve after initial hepatectomy Multifocal recurrence

RFA has emerged its role for small HCC recurrence <5cm

Minagawa et al Ann Surg 2003;238:703-10Chen et al. Chin J Clin Oncol 2003;2:2-9

Nagasue et al. Br J Surg 1996;83:127-31

RFA in Recurrent HCC

Studies have demonstrated safety and efficacy for recurrent HCC

3 year survival to be 62-68%, comparable to surgical resection

Choi et al with 102 patients using RFA in recurrent HCC after hepatectomy as first-line treatment Mean tumor diameter 2cm Complete tumor necrosis rate 93.3% Major complication 1% (liver abscess) Survival rate at 1, 3, 5 years were 93%, 65%

and 51%Poon et al. Ann Surg 2002;235:466-86

Elias et al Br J Surg 2002;212-29Choi et al Radiology 2004;230:135-141

RFA vs Surgical Resection

in Recurrent HCC Studies have demonstrated similar effectiveness of RFA

and repeated hepatectomy for recurrent HCC < 5cm

Liang et al. Retrospective study for longterm results of RFA vs repeated hepatectomy recurrent tumor <5 cm, no extrahepatic

metastasis, Child’s A/B

Liang et al. Annals Surg Oncol 2008;15(12):3484-3493

RFA Resection P value

n 66 44

5-year survival rate post recurrent treatment

38.6% 39.9% 0.72

5-year survival rate post initial hepatectomy

55.6% 58.7% 0.18Comparable

Results

RFA as first-line treatment for resectable

small HCC

RFA as first-line treatment for Resectable

small HCC The annual average size of newly

diagnosed HCC has decreased over years from 2.6cm in 1999 to 1.9cm in 2011, due to better imaging technique and resolution

More patients are being detected at early stage, which is feasible for RFA treatment

Molinari et al. Am J Surg 2009;198:396-406Cho et al. Hepatology 2010;51:1284-1290

Wang et al J Hepatol 2012;20:130-40

RFA as First-line Treatment

Retrospective anaylsis of 100 patients with HCC ≤ 2cm, Child’s A, operable

5-year overall survival rate was 68%

Livraghi et al. Hepatology 2008,47:82-89

Longterm Results for RFA as First Line Treatment

Kim et al. 1305 patients with small HCC using RFA as first-line treatment Overall survival rates 32.3% at 10 years

Kim et al. J Hepatology 2012;58:89-97

Shiina et al 1170 patients Overall survival rates 27.3% at 10 years

Shiina et al. Am J Gastroenterol 2012;107:569-577

Surgical Resection vs RFA in Operable Small HCC

Retrospective nonrandomised comparative study of RFA vs surgical resection as first-line treatment of small HCC within Milan Criteria (Surgery, PYNEH)

RFA Resection

P value

n 31 80

5-year overall survival rate 84% 71% 0.166

5-year disease-free survival rate

40% 60% 0.037

Morbidity rate 3.2% 25% 0.006

Mortality rate 0% 3.8% 0.262

Mean Operative Time (min) 67 177 0.005

Mean Hospital Stay (day) 3.8 6.8 0.0001Lai & Tang et al. International Journal Of Surgery.

11(1):77-80, 2013

RCT: Surgical Resection vs RFA

in Operable Small HCC Solitary HCC ≤ 5cm, suitable for surgical resection, no previous treatment of HCC

RFA is as effective as surgical resection

RFA Resection

P value

n 71 90

4-year overall survival 67.9% 64% NS

4-year disease-free survival 46.6% 51.6% NS

Mean hospital stay (day) 9 19 <0.05

Chen et al. Ann Surg 2006, 243:321-328

RCT: Surgical Resection vs RFA

in Operable Small HCC Single HCC ≤ 5cm or up to 3 nodules each < 3cm, suitable for

surgical resection, no previous HCC treatment

Surgical resection offer better survival and lower recurrence than RFA

RFA Resection

P value

n 115 115

5-year overall survival 54.7% 75.6% 0.001

5-year disease-free survival 28.6% 51.3% 0.017

5-year overall recurrence 63.4% 41.7% 0.024

Huang et al. Ann Surg 2010, 252:903-912

Meta-analysis Surgical Resection vs RFA

in Operable Small HCC

patients with early HCC (conforming to Milan Criteria single HCC ≤ 5cm or up to 3 lesions ≤ 3cm)

1223 surgical resection, 1302 RFA

Surgical resection significantly Improve overall 5 year survival lower overall recurrence rate

Xu et al. World Journal of Surgical Oncology 2012, 10:163

Conclusion

RFA is currently the main modality of local ablative therapy

RFA is more effective than other ablative therapies for unresectable small HCC conforming to Milan Criteria

Percutaneous ethanol injection has a role if location of tumor is not suitable for RFA

Surgical resection is still superior to RFA as first-line treatment of newly diagnosed small HCC, however RFA has less morbidity and is repeatable

Thank You

Percutaneous Injection Therapy (PEI and PAI)

Indication: for early irresectable HCC Solitary size < 5cm Multicentric ≤ 3 in number, ≤ 3 cm in size

Contraindication Child’s C cirrhosis Uncontrollable coagulopathy Gross ascites Portal vein thrombosis

Ohnishi et al. Hepato-Gastroenterology 1998;45:1254–8

Meloni et al. Eur J Ultrasound 2001;13(2);107-115

High-Intensity Focused Ultrasound Ablation

(HIFU) New, totally extracorporeal non-invasive ablation using

focused ultrasound energy

Mechanism: utilize frequency of ultrasound wave 0.8-3.5 MHz which is focused at a distance from therapeutic transducer, accumulated energy at the focused region induces necrosis of target lesion by temperature > 60C

Temperature outside focus point remains static as particle oscillation is minimal→little collateral damage beyond target lesion

Presence of gross ascites favour energy transmission

Skin puncture is not required, Guided by USG or MRI

Wu et al. Radiology 2005;235:659-667Cheung et al. World J Surg 2012;36:2420-27

Evidence for HIFU Wu et al. reported safety and efficacy of HIFU in 1038 patients

with 4 year FU (include HCC, osteosarcinoma, breast cancer) Wu et al. Ultrasonics Sonochemistry. 11(3-4):149-54, 2004

A second trial specifically on HCC demonstrates the safety, efficacy and feasibility of extracorporeal HIFU 55 patients with HCC <5 foci, Child’s A/B, no extrahepatic

metastasis, not fit for surgical resection Tumor size range 4-14cm (mean 8cm) Survival rate at 18 month: 35.3% No major complication (minor complication skin burn,

fever) Wu et al. Annals of Surgical Oncology. 11(12):1061-9, 2004

Feasibility of HIFU in difficult location (tumor adjacent <1cm to a main blood vessel, the heart, the gallbladder and bile ducts, the bowel, or the stomach) 6 HCC, 17 liver metastasis. FU time 12 months

Zhang et al. American Journal of Roentgenology. 195(3):W245-52, 2010

Evidence for HIFU Safety & Feasibility in HCC

100 patients, tumor < 5cm (new and recurrent) Not fit for surgical resection/transplant/RFA 84 Child’s A, 15 Child’s B, 1 Child’s C Complete ablation with single treatment: 87% Overall complication 18% (Clavien classification

3 or above is 4%) Cheung et al. Hepatobiliary & Pancreatic Dis Int.

11(5):542-4, 2012

Bridging therapy for transplant in a patient with extremely low platelet (20x109/L)

Cheung et al. World Journal of Surgery. 36(10):2420-7, 2012

General Consideration

Patient’s factor gross ascites favor intraperitoneal bleeding coagulopathy that cannot be corrected obstructive jaundice with risk of bile peritonitis

Tumor factor Tumor located at superior part of segment 4, 7,

8 Multiple tumor > 3 (need for repeated puncture) Tumor located at surface of liver, risk of

intraperitoneal bleeding or seeding