Transcript Postgastrectomy Syndromes

Joint Hospital Surgical Grand Round
Local Ablative Therapy for
Hepatocellular Carcinoma
Dr. Steven CY Law
Department of Surgery
Pamela Youde Nethersole Eastern Hospital
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 5:1208–36
Mazzaferro 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
P value
PEI
PAI
n
29
31
Local recurrence rate
38%
8%
<0.001
2-year survival rate
63%
92%
0.0017
 PAI better than PEI
Ohinishi et al. Hepatology 1998;27:67–72.
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
P value
PEI
PAI
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
 PEI is better than PAI
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):367-77
Pacella 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;85:1171–2
Pearson 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 Microwave
Coagulation 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;228:335-45
Lu 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 needle
Patterson 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):717–35
Shiina 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);670-4
Miao 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
P value
RFA
PMCT
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
Major complicaton: bile duct injury, abscess, hemorrhage
Ohmoto et al. J of Gastr & Hepatology. 24(2):223-7, 2009 Feb.
Energy Ablation
RFA ✔evidence in RCT
 Microwave
 Laser
Limited evidence but favor RFA vs PCMT
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;249:20-25
Lin et al. Gut 2005;54(8):1151–6
Shiina et al. Gastroenterology 2005; 129(1):122–30
Brunello 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;238:703-10
Chen 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;212-29
Choi 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
P value
RFA
Resection
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%
0.18
Comparable Results
Liang et al. Annals Surg Oncol 2008;15(12):3484-3493
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;198:396-406
Cho 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
0.0001
Lai & 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
P value
RFA
Resection
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;235:659-667
Cheung 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)


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. Ultrasonics Sonochemistry. 11(3-4):149-54, 2004
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