Role of Interventional
Radiology in a Gastrointestinal
Tumor Service
Anastasia Balius, MD
Interventional Radiology
UTMCK
October 23, 2011
Hepatocellular Carcinoma
• Approximately 24,120 persons diagnosed
with liver or intrahepatic bile duct cancer in
the US in 20101
• 18,910 deaths from those cancers during
that year1
• Incidence has risen significantly in
developed countries in the past two
decades2
– Increased prevalence of hepatitis B and C
1American
2Ince
.
Cancer Society. Statistics last revised 7/7/10
N, Wands JR. The increasing incidence of heaptocellular carcinoma. N Engl J Med 1999;340:798-799.
Risk Factors
•
•
•
•
•
•
•
Same as those for Cirrhosis
Hepatitis B/C
Inherited errors of metabolism
Autoimmune hepatits
Non -alcoholic steatohepatitis [NASH]
Excessive alcohol intake
Environmental exposure to aflatoxin
3
Hepatocellular Carcinoma
(HCC)
• With definitive treatment 5 year survival is
over 50%1
• For all stages combined, 5 year survival is
approximately 10%1
• Only 10-15% of patients are candidates for
curative therapy2,3
– Surgical resection or transplant
1American
Cancer Society. Statistics last revised 8/16/10
JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol. 2004;7:431-441
3Kanematsu T, Furui J, Yanaga K, et al. A 16-year experience in performing hepatic resection in 303 patients
with hepatocellular carcinoma. J Vasc Interv Radiol 1995; 6:71–74.
2Llovet
Metastatic Colorectal Cancer
(mCRC)
• 5 year survival for stage IV colorectal cancer is 6%1
• Liver is most frequent site of metastases
– Approximately 60% of patients with mCRC will
eventually have liver as predominant site of disease2
• Surgical resection is treatment of choice
– 5 year survival rates after resection >50%3,4
– Feasible in <20% of patients2
1American
Cancer Society. Statistics last revised 3/2/2011
AR, Sigurdson ER. Surgical treatment of liver metastases. Semin Oncol. 2002;29:107-118
3Choti MA, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235:759-766.
4Pawlik TM, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg.
2005;241:715-722, discussion 722-714.
2Sasson
NCCN Categories of evidence
• Category 1: The recommendation is based on high-level
evidence (eg randomized controlled trials) and there is
uniform NCCN consensus
• Category 2A: The recommendation is based on lowerlevel evidence and there is uniform NCCN consensus
• Category 2B: The recommendation is based on lowerlevel evidence and there is non uniform NCCN
consensus (but no major disagreement)
• Category 3: The recommendation is based on any level
of evidence but reflects major disagreement
• All recommendations are Category 2A unless
otherwise noted
Treatment of HCC
HCC
confirmed
•Multidisciplinary Evaluation
•H+P
•Hepatitis Panel
•Bilirubin, transaminases,
alk phos, LDH
•PT /INR, albumin, protein,
BUN, Cr
•CBC, platelets
•AFP
•Chest imaging
•Bone scan as indicated
Potentially resectable or
transplantable, operable
by performace status or
comorbidity
Metastatic disease
Inoperable by
performance status or
comorbidity, local
disease only
Unresectable
Treatment of HCC
For patients with an estimated FLR/total liver
volume ratio below recommended values
who are otherwise suitable candidates for
liver resection, pre-operative portal vein
embolization (PVE) should be considered
NCCN Practice Guidelines in Oncology – v.2.2011, Hepatobiliary Cancers.
Treatment of HCC
Clinical presentation
Potentially
resectable or
transplantable
Surgical Assessment
•Child’s A, B
•No portal hypertension
•Suitable tumor location
•Adequate liver reserve
•Suitable liver remnant
•UNOS criteria
•Patient has a tumor <5 cm in dm or 23 tumors < 3 cm each
•No macrovascular involvement
•No extrahepatic disease
•These patients may be resected if
transplantation not feasible
Treatment
Resection, if
feasible
(preferred)
or locoregional
therapy
Liver
Transplant
Child-Pugh Score
Clinical/Biochemical Parameters
Points for Increasing Abnormality
1
2
3
Encephalopathy (grade)
None
1-2
3-4
Ascites
None
Slight
Moderate
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
Prothrombin time
Prolonged (sec)
1-4
4-6
>6
Bilirubin (mg/dL)
- for primary biliary
cirrhosis
1-2
1-4
2-3
4-10
>3
>10
Class A = 5-6 points; Class B = 7 -9 points; Class C = 10-15 points
Treatment of HCC
Clinical Presentation
Inoperable by performance
status or comorbity, local
disease only
Metastatic disease
Treatment
Options:
Sorafenib (Child-Pugh Class A [Category 1] or B)
Clinical Trial
Locoregional Therapy
RT (conformal or sterotactic) (category 2B)
Supportive Care
Sorafenib (Child-Pugh Class A [Category 1] or B)
Or
Supportive Care
Or
Clinical trial
Locoregional Therapy
Ablation
Embolization
• Tumor and margin of
• Arterial blood supply to the
normal tissue should be
tumor must be able to be
treated
isolated without non-target
embolization
• Tumors < 3 cm; lesions
between 3-5 cm should be • Relatively contraindicated
treated in combination with
with bilirubin >3 mg/dL
embolization
• Contraindicated with main
PV thrombosis (relative) or
Child-Pugh Class C
(absolute)
Treatment of HCC
•Inadequate
hepatic
reserve
•Tumor
location
Transplant
Meets
UNOS
criteria?
Not a transplant
candidate
Unresectable
Extensive
liver tumor
burden
Options:
Sorafenib (Child-Pugh Class A [Category 1] or B)
Chemotherapy + RT only in the context of a clinical
trial
Clinical trial
Locoregional therapy
RT (conformal or sterotactic) (category 2B)
Supportive care
Systemic or intra-arterial chemotherapy in clinical
trial
Treatment of mCRC
When hepatic disease is not optimally
resectable based on insufficient remnant
liver volume, approaches utilizing
preoperative portal vein embolization1 or
staged liver resection can be considered
NCCN Practice Guidelines in Oncology – v.3.2011, Colon Cancer
1Covey
AM, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for
resectable hepatic colorectal metastases. Ann Surg. 2008 Mar;247(3):451-5.
Treatment of mCRC
• Ablative techniques may be considered alone or
in conjuction with resection. All original sites of
disease need to be amenable to ablation or
resection.
• Some institutions use arterially directed embolic
therapy in highly select patients with
chemotherapy resistant/refractory disease
without obvious systemic disease, with
predominent hepatic metastases (category 3)
Interventional Radiology’s
Role
1. Supportive procedures for the
oncology patient
2. Determination of disease
3. Facilitation of definitive surgical
treatment
4. Treatment of non-surgical
candidates
Determination of Disease
• AFP and ultrasound are used as screening
for HCC
• Additional imaging is indicated in the
setting of a rising serum AFP or
identification of a liver mass nodule on US
Determination of Disease
• Three different modalities
– Triphasic helical CT
– Triphasic dynamic contrast enhanced MRI
– Contrast enhanced U/S
Determination of Disease
• Nodules 1 to 2 cm in size need to demonstrate
classic arterial enhancement with two different
diagnostic techniques
• Nodules > 2 cm need demonstrate classic
arterial enhancement with only one diagnostic
technique
• Nodules < 1 cm should be re-evaluated every 3
to 4 months until fit into a size criteria
• If nodules are non-diagnostic on imaging, tissue
sampling is needed
Facilitation of Definitive Surgical
Treatment
Portal Vein Embolization
Transplant “Bridge”
Portal Vein Embolization (PVE)
• In primary or secondary hepatic malignancy,
extended hepatectomies provide a chance of
cure1
• Morbidity and mortality of such procedures are
considerable2
• Volume and function of the liver remnant is a
major risk factor for perioperative complications3,4
1Vauthey
JN, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Annals of Surgery. 2004 May; 239(5):72230; discussion 30-2
2Jarnagin WR, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the
past decade. Annals of Surgery. 2002 Oct;236(4):397-406; discussion-7..
3Abdalla EK, et al. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein
embolization. Arch Surg. 2002 Jun:137(6):675-80; discussion 80-1
4Vauthey JN, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and
clinical associations. Surgery. 2000 May;127(5):512-9
Portal Vein Embolization
• PVE induces hypertrophy in the nonembolized liver segments
• Increase in volume and function of future
liver remnant (FLR)
• Decreases risk of post-operative hepatic
insufficiency
Abdalla EK, et al. Portal vein embolization: rationale, technique and future
prospects. The British Journal of Surgery. 2001 Feb;88(2):165-75
Makuuchi M, et al. Preoperative portal embolization to increase safety of major
hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990
May;107(5):521-7
PVE
• Normal underlying liver1
– FLR should be 20-25% of total liver volume
(TLV)
• Chemotherapy induced liver injury2
– FLR should be >30% of TLV
• Chronic liver disease (cirrhosis or severe
fibrosis)2
– FLR should be >40%
1Abdalla
EK, et al. Extended hepatectomy in patients with hepatobiliary malignancies with and without
preoperative portal vein embolization. Arch Surg. 2002 Jun;137(6):675-80; discussion 80-1.
2Azoulay D, et al. Percutaneous portal vein embolization increases the feasibility and safety of major
liver resection for hepatocellular carcinoma in injured liver. Annals of Surgery. 2000 Nov;232(5):117681.
PVE Contraindications
•
•
•
•
•
•
•
Extrahepatic metastases
Overt portal hypertension
Tumor invasion of the portal vein
Tumor invasion of the FLR
Biliary obstruction
Renal insufficiency
Uncorrectable coagulopathy
Couinaud Classificiation
Hepatic Anatomy
Hepatic Anatomy
PVE
• Performed under conscious sedation
• 2 standard approaches
– Percutaneous ipsilateral
– Percutaneous contralateral
• Wide array of embolic agents
– Coils, amplatzer plugs
– Particles
– Absolute alcohol
– Fibrin glue
– N-BCA (n-butyl cyanoacrylate)
Complications
• Migration of embolic
material (0.2-5.3%)
• Portal vein thrombosis of
FLR (<1%)
• Portal vein dissection
• Intraparenchymal injury
• Transient liver failure
(3.2%)
•
•
•
•
•
Bleeding (0.2 – 1/6%)
Pneumothorax
Sepsis
Liver abscess (0.3%)
Portal hypertension
resulting in esophageal
variceal hemorrhage
Di Stefano DR, et al. Preoperative percutaneous portal vein embolization: evaluation of adverse
events in 188 patients. Radiology. 1993 Jul;188(1):73-7
Kodama Y, et al. Complications of percutaneous transhepatic portal vein embolization. J Vasc
Interv Radiol. 2002 Dec;13(12):1233-7
Outcomes
• Average expected growth of FLR = 8-27%1
• 75% of growth occurs in first 3 weeks postPVE2
• Failure to hypertrophy >5% following PVE
is associated with a significantly higher risk
of major complications, hepatic
insufficiency, and increased 90-day
mortality2
1Abulkhir A,
et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008
Jan;247(1):49-57
2Ribero D, et al. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability, and
outcome. The British Journal of Surgery. 2007 Nov;94(11): 1386-94
Facilitation of Definitive Surgical
Treatment
• Locoregional treatment of HCC as a
“bridge” to liver transplantation1,2
– Radiofrequency ablation3,4
– Chemoembolization5
– Radioembolization
1Bruix
J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236
JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698-711.
3Pompili M, et al. Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted for liver
transplantation: assessment of efficacy at explant analysis and of safety for tumor recurrence. Liver Transpl. 2005;11:11171126.
4Mazzaferro V, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver
transplantation: a prospective study. Ann Surg. 2004;240:900-909.
5Richard HM, 3rd, et al. Hepatic arterial complications in liver transplant recipients treated with pretransplantation
chemoembolization for hepatocellular carcinoma. Radiology. 2000;214:775-779.
2Llover
Treatment of Nonsurgical Candidates
• Ablative techniques
– Radiofrequency ablation
– Microwave ablation
– Alcohol ablation
• Arterial embolization
– Trans-arterial embolization (TAE)
– Trans-arterial chemoembolization (TACE)
– Trans-arterial radioembolization or Selective
Internal Radiation Therapy (SIRT)
• Combination therapy
Patient Work-up
• Laboratory studies
– CBC, Chem 7, PT/PTT, liver function tests,
tumor markers
• Cross-sectional imaging (CT/MRI)
• Childs class
• Performance status
– ECOG/Karnofsky
• Staging
• Consent with emphasis on palliation and
management of expectations
Alcohol versus RFA
• RFA was shown to be superior to PEI with
respect to complete response rate1
• RFA demostrated a lower rate of
recurrence2,3
• Overall survival higher for RFA2,3
• Fewer treatment sessions for RFA3
1Brunello
F, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A
randomized controlled trial. Scand J Gastroenterol. 2008;43:727-735
2Lin SM, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular
carcinoma <4 cm. Gastroenterology. 2004;127:1714-1723
3Shiina S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small
hepatocellular carcinoma. Gastroenterology. 2005;129:122-130.
RFA vs. Ethanol Injection
Survival rate
Author
Treatment
Complete
Resonse
2-yr local
progression
2 yr
3 yr
Lencioni ,
20031
PEI (n=50)
82%
38%*
88%
NA
RFA (n=52)
95%
4%*
96%
NA
88%
45%
61%
50%
PEI, high dose
(n=52)
92%
33%
63%
55%
RFA (n=52)
96%
18%
82%
74%
PEI (n=114)
100%
11%
82%
63%
RFA (n=118)
100%
2%
90%
80%
Lin, 20042 PEI, low dose
(n=52)
Shiina,
20053
1Lencioni
P
NS
<.05
<.05
R, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency ablation versus percutaneous ethanol injection. Radiology 2003;228:235-240.
SM, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology 2004;127:1714-1723.
3Shiina S, et al. A randomized controlled trial of radiofrequency ablation versus ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129:122-130.
2Lin
Local recurrence rates for HCC
• More recent study found <3% of patients
with single HCC tumor < 2 cm had
recurrent disease at 31 months after
repeated application of RFA1
1Livraghi
T, et al. Sustained complete response and complications rates after radiofrequency ablation
of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice?
Hepatology. 2008;47:82-89.
18
Long-Term Survival
Survival Rate (%)
Author and Year
Patient Characteristics
Pt # 1 yr
3 yr
5 yr
Lencioni, 2005
Child A, 1 HCC <5cm or 3 <3cm
144
100
76
51
Child A, 1 HCC <5 cm
116
100
89
61
Child B, 1 HCC <5 cm or 3 <3 cm
43
89
46
31
Naive patients
319
95
78
54
Non-naïve patients
345
92
62
38
59
94
65
43
Child A, 1 HCC <5cm or 3 <3 cm
359
NA
78
64
Child B, 1 HCC <5cm or 3 <3 cm
160
NA
49
38
Tateishi, 2005
Cabassa, 2006
Choi, 2007
Lencioni R, et al. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous image-guided
radiofrequency ablation. Radiology 2005;234:961-967
Tateishi R, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. Cancer 2005;103:1201-1209
Cabassa P, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term experience with expandable needle
electrodes. AJR 2006;185:S316-321
Choi D, et al. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment:
long-term results and prognostic factors in a large singe-institution series. Eur Radiol 2007;17:684-692.
Radiofrequency Ablation vs.
Resection
• RFA compared to liver resection in a
prospective randomized controlled study
• Patients with solitary HCC <5 cm in dm
• No differences in recurrence-free survival
or overall survival were found when
treatment arms were compared.
Chen MS, et al. A prospective randomized trial comparing percutaneous
local ablative therapy and partial hepatectomy for small hepatocellular
carcinoma. Ann Surg. 2006;243:321-328.
Microwave Ablation
• In moderately or poorly differentiated HCC,
overall survival was significantly better than with
PEI1
• In study of 234 pts, 3 yr and 5 yr survival rates
were 73% and 57%2
• In the one randomized trial comparing microwave
and radiofrequency ablation, no statistically
significant differences were observed in the
efficacy of the two techniques3
1Seki
T, et al. Percutaneous microwave coagulation therapy for patients with small hepatocellular carcinoma: comparison with
percutaneous ethanol therapy. Cancer 1999;85:1694-1702
2Dong B, et al. Percutaneous sonographically guided microwave coagulation therapy for hepatocellular carcinoma: results in 234
patients. AJR 2003;180:1547-1541.
3Shibata T, et al. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave
coagulation therapy. Radiology 2002;223:331-337.
RFA for mCRC
Author
Patients
Metastases
Size (cm)
Local contol
Survival
Solbiati
20011
117
179
0.9-9.6;
61%
3 yr: 46%
Gillams
20042
167
354
1-12; mean, 74.9%
3.9
5 yr: 26%
Jakobs
20063
68
183
0.5-5.0;
mean, 2.2
82%
3 yr: 68%
Lencioni
20054
423
543
0.5-5.0;
mean 2.7
85.4%
3 yr: 47%
5 yr: 24%
Sorensen
20075
102
332
1Solbiati
3 yr: 64%
5 yr: 44%
L, et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117
patients. Radiology 2001 Oct;221(1):159-66.
2Gillams AR, Lees WR. Radio-frequency ablation of colorectal metastases in 167 patients. Eur Radiol 2004;14:2261-2267.
3Jakobs TF, et al. Radiofrequency ablation of colorectal liver metastases: mid-term results in 68 patients. Anti-cancer Res
2006;26:671-680.
4Lencioni R, et al. Percutaneous radiofrequency ablation of hepatic colorectal metastases: technique, indications, results and new
promises. Invest Radiol 2004;39:689-697.
5Sorensen SM, et al. Radiofrequency ablation of colorectal liver metastases: long-term survival. Acta Radiol 2007;48:253-258.
RFA versus resection of mCRC
• A number of retrospective studies have compared RFA
and liver resection in the tx of liver mets1-3, although RFA
has not been well studied in this setting
• In retrospective studies comparing RFA and liver
resection in liver mets RFA has been inferior to resection
with respect to rates of local recurrence and 5-year
overall survival4
• Patient selection bias, technological limitations of RFA or
both?2
1Hur
H, et al. Comparative study of resection and radiofrequency ablation in the treatment of solitary colorectal liver metastases. Amer
J Surg. 2009;197:728-736.
2Gleisner AL, et al. Colorectal liver metastases: recurrence and survival following hepatic resection, radiofrequency ablation, and
combined resection-radiofrequency ablation. Arch Surg. 2008;143:1204-1212.
3Reuter NP, et al. Radiofrequency ablation vs. resection for hepatic colorectal metastasis: therapeutically equivalent? J Gastrointest
Surg. 2009;13:486-91.
4Abdalla EK. Commentary: Radiofrequency ablation for colorectal liver metastases: do not blame the biology when it is the technology.
Amer J Surg. 2009;197:737-739.
Radiofrequency Ablation
• Electrode probes deliver an alternating
high-frequency electrical current (460
to 500 kHz)
• Ion agitation is converted by friction
into heat
• Tissue temperature is increased
• Cellular death occurs via thermal
coagulation necrosis
Technique
• Re-identify lesion under CT or US
• Choose appropriate access site
• Plan approach
• Place probes
• 12 to 16 minute ablation
• Tract ablation
Considerations
• “Heat sink” effects
• Compromised sphincter of Oddi
– Levaquin and flagyl prep
• Adjacent structures
– Diaphragm
– Abdominal wall
– Capsule
– Bowel
• Size
Development of Ablated Region
• After 24 to 48 hours, necrotic lesion forms
reaching maximum size by 7 days
• Ablated lesion may exhibit an increase in size up
to 3 months post ablation1
• Ablated tissue will be replaced by scar or
reabsorbed
• Treated area will not enhance on follow up
imaging2
• Most residual viable tumor is evident at 1-3
months after ablation3
1McDougal
WS, et al; J Urol 2005; 174:61-63
2Kawamoto, et al; Radiographics 2007; 27:343-355
3Gervais, et al; AJR 2005; 185:64-71
Complications
• Hemorrhage1
– Hemoperitoneum
– Hemothorax
– Hemobilia
•
•
•
•
Pneumo/Hydrothorax
Abscess
Sepsis
Liver Failure2
• Tumor seeding
• Skin Burn
• Damage to surrounding
structures
• Pain in a dermatomal/
diaphragmatic
distribution
• Post ablation syndrome
1Goto
E et al. J Clin Gastroenterol 2009 Oct 3 [Epub ahead of print}
2Kong WT, et al. World J Gastroenterol 2009 Jun 7; 15(21):2651-6
11
Complication Rate
• Mortality rate ranges from 0.1% to 0.5%
– Most common causes of death were sepsis and hepatic
failure
• Major complication rate ranges from 2.2% to 3.1%
• Minor complication rate ranges from 5% to 8.9%
– Most common complications were intraperitoneal
bleeding, hepatic abscess, bile duct injury, hepatic
decompensation, and grounding pad burns
Rhim H. Complications of radiofrequency ablation in hepatocellular carcinoma. Abdom Imaging 2005 Jul-Aug; 30 (4): 409-18
Livraghi T, et al. Treatment of focal liver tumors with percutaneous radiofrequency ablation: complications encountered in a multicenter
study. Radiology 2003;26:441-451.
De Baere T, et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. AJR 2003;181:695-700.
Bleicher RJ, et al. Radiofrequency ablation in 447 complex unresectable liver tumors: lessions learned. Ann Surg Oncol 2003;10:5258.
12
Tumor seeding
• Uncommon late complication
• Subcapsular location and poor degree of
differentiation seem to be at a higher risk1
• Incidence of 0.5% in HCC patients in both
a multicenter and single institution series2,3
• Tract ablation used routinely to prevent
1Llovet
JM, et al. Barcelona Clinic Liver Cancer (BCLC) Group. Increased risk of tumor seeding after percutaneous
radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001;33:1124-1129.
2Livraghi T, et al. Treatment of focal liver tumors with percutaneous radiofrequency ablation: complications
encountered in a multicenter study. Radiology 2003;26:441-451.
3Lencioni R, et al. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous imageguided radiofrequency ablation. Radiology 2005;234:961-967.
Post RFA Syndrome
• Analagous to post embolization syndrome
• Defined as low grade fever and flu-like
symptoms within the first 24-48 hours
lasting approximately one week
• Fever usually peaks on day 3
• Flu-like symptoms peak on day 5
14
Post RFA Syndrome
• Incidence of 37% in liver ablation
• 95% of patients had symptoms but not
complete syndrome
• Size of treated lesion doesn’t correlate with
incidence or severity
• Number of ablations (>3) correlates with
increased symptoms
Wah, et al; Radiology 2005; 237:1097-1102
15
Overall RFA Complication
Rates
Tissue
# patients
Complications
Mortality rates
Liver
2300 [1]
2.2%
0.3%
382 [2]
8%
0.1%
Kidney
54 sessions [3]
7%
0%
Bone
43 [4]
7%
0%
Lung
26 [5]
10%
0%
1. Livraghi T et al. Treatment of Focal Liver Tumors with Percutaneous Radiofrequency Ablation: complications encountered in a multicenter study.
Radiology 2003; 226: 441-451
2. Curley S et al. Early and late Complications after Radiofrequency Ablation of malignant Liver Tumors in 608 Patients. Annals of Surgery, Vol 239,
No4 April 2004
3. Gervais DA et al, renal Cell Carcinoma: Clinical Experience and Technical Success with Radio-frequency Ablation of 42 tumors. Vascular and
Interventional Radiology
4. Goetz et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multi center study. J Clin Oncol. 2004 Jan
15;22 (2):300-6
5. Lee et al. Percutaneous Radiofrequency Ablation for inoperable NSC Lung Cancer and matastases: Preliminary report. Radiology, January 2004
Follow-up imaging
Post ablation hypoattenuation is greater than original lesion initially,
then a decrease in size will be seen
HCC
• Contrasted CT or MRI in 1
month
• CT/MRI every 3 months
until one year
• Enhancement in HCC pt =
residual
disease/recurrence
1Akhurst
mCRC
• Contrasted CT or MRI in 1
month to detect new
lesions
• CT/MRI every 3 months
with tumor markers
• PET may be useful in
detecting residual tumor or
relapse1,2,3
T, et al. Positron emission tomography imaging of colorectal cancer. Semin Oncol 1999;26:577-583
Y, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001
consecutive cases. Ann Surg 1999;230:309-321
3Anderson GS, et al. FCG positron emission tomography in the surveillance of hepatic tumors treated with radiofrequency ablation. Clin
Nucl Med 2003;28*:192-197
2Fong
Intra-arterial therapy
HCC
• The panel recommends that patients with
unresectable/inoperable disease who are eligible
to undergo embolization therapy and have tumor
lesions > 5 cm should be treated using arterial
embolic approaches (chemoembolization, bland
embolization, radioembolization)
• Those patients with lesions 3-5 cm can be
considered for combination therapy with ablation
and arterial embolization
NCCN Practice Guidelines in Oncology – v.1.2011, Hepatobiliary Cancers
Intra-arterial Therapy
mCRC
• Arterially-directed embolic therapy is considered
category 3
• Specifically, highly select patients with
chemotherapy resistant/refractory disease,
without obvious systemic disease, with
predominant hepatic metastases
• Radioembolization with yttrium-90 microspheres
is the only technique specifically mentioned
NCCN Practice Guidelines in Oncology – v.3.2011, Colon Cancer
Intra-arterial Therapy Options
At this point, institution and physician preference
determines technique(s) preferred
Catheter is
placed via a
transfemoral
approach with
tip within the
selected
hepatic artery
Intra-arterial administration exploits the
dual blood supply of the liver
• Tumors receive 80100% of their blood
supply from hepatic
artery
• Normal liver receives
> 75% of its blood
supply from portal
vein
Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol. 1954;30:969-977.
Bland Embolization of HCC
• Retrospective analysis
• 1-, 2-, and 3-year survival rates of 66%,
46%, and 33% were observed
• Survival rates increased to 84%, 66% and
51% when only the subgroup of patients
w/o extrahepatic spread or portal vein
involvement by tumor was considered1
1Maluccio
MA, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable
hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19:862-869
Bland Embolization of HCC
• Predictors of poor prognosis on
multivariate analysis
– Tumor size >5 cm
– 5 or more tumors
– Extrahepatic disease
• Portal vein occlusion was not found to be
an independent predictor of survival
Maluccio MA, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable
hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19:862-869
Bland vs. Chemo-embolization
of HCC
• Only one study directly comparing the two
therapies
– Pt randomized to TAE, TACE, supportive care
• This was stopped early when a demonstrable
benefit was shown between chemoembolization
and supportive care arms
• Due to early termination, lack of power to detect
a difference in TACE and TAE
Llovet JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable
hepatocellular carcinoma: a randomixed controlled trial. Lancet 2002;359((9319):1734-9.
Chemoembolization
of
HCC
Barcelona Multicenter
Study1
• 112 patients with
unresectable HCC
• 85% had hepatitis C
• Randomized to
blandembolization,
chemoembolizaiton, or
conservative management
• Primary endpoint was
survival
1Llovet
Hong Kong (Single Center)
Study2
• 80 patients with
unresectable HCC
• 80% had hepatitis B
• Randomized to
chemoembolization or
conservative management
• Primary endpoint was
survival
JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with
unresectable hepatocellular carcinoma: a randomixed controlled trial. Lancet 2002;359((9319):1734-9.
2Lo CM, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable
hepatocellular carcinoma. Hepatology 2002;35(5):1164-71
Chemoembolization of HCC
Barcelona Study
Hong Kong Study
• Survival in CE group
• Survival in CE group
1 yr = 82%
1 yr = 57%
2 yr = 63%
2 yr = 31%
• Survival in bland
embolization group
• Survival in conservative
therapy group
1 yr = 75%
1 yr = 32%
2 yr = 50%
2 yr = 11%
• Survival in conservative
therapy group
1 yr = 63%
2 yr = 27%
Chemoembolization of HCC
• In both studies, patients in the
chemoembolization group were half as
likely to die during the trial than patients in
the conservative therapy group
– For the Barcelona study:
• OR = 0.45
• 95% CI 0.25 – 0.81
– For the Hong Kong study:
• OR = 0.5
• 95% CI 0.31 – 0.81
Chemoembolization of HCC
• Survival rates in both the CE and control
groups were lower in the Hong Kong study
than in the Barcelona study
– Higher proportion of Okunda stage II disease
– Patients with portal vein invasion not excluded
Chemoembolization of HCC
• Only independent predictor of survival was
treatment allocation1
• Benefit of chemoembolization was
independent of tumor size, stage or
presenting symptom2
– When portal vein invasion present, however, no
benefit to chemoembolization seen
1Llovet
JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with
unresectable hepatocellular carcinoma: a randomixed controlled trial. Lancet 2002;359((9319):1734-9.
2Lo CM, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable
hepatocellular carcinoma. Hepatology 2002;35(5):1164-71
Bland/Chemo-embolization of
mCRC
Randomized study comparing TAE with
TACE demonstrated no advantage of one
technique over the other
Salman HS, et al. Randomized phase II trial of embolization therapy versus
chemoembolization therapy in previously treated patients with colorectal carcinoma
metastatic to the liver. Clin Colorectal Cancer 2002;2:173-179.
Drug eluting beads in HCC
• Objective response rate by imaging (EASL
criteria) ranged from 60 to 90%1,2
• Survival rates appear improved over those
with conventional TACE3
– 93% at 6 months to 89% at 2 years1,2
• Significantly lower serum levels of
chemotherapy drug4
1Kettenbach
J, et al. Drug-loaded microspheres for the treatment of liver cancer: review of current results. Cardiovasc Intervent Radiol 2008;31:468476.
2Malagari K, et al. Transarterial chemoembolization of unresectable heptaocellular carcinoma with drug eluting beads: Results of an open-label study
of 62 patients. Cardiovasc Intervent Radiol 2008;31:269-280.
3Dhanasekaran R, et al. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting
beads (DEB) for unresectable hepatocelluar carcinoma (HCC) J. Surg. Oncol. 2010; 101:476-480
4Varela M, et al. Chemoembolization of Hepatocellular carcinoma with drug eluting beads: Efficacy and doxorubicin pharmcokinetics. J Hepatol
2007;46:747-787.
DEB for mCRC
• In study of 55 patients, survival rate of 78%
at 18 months1
• Patients thought to have less side effects
from the beads than from traditional TACE
• Easier to infuse
• More study is needed
1Martin
RCG, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the
treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report. World
Journal of Surgical Oncology 2009, 7:80
Chemoembolization Pt Selection
• Is patient eligible for hepatic resection?
• Is patient eligible for ablation?
• Liver dominant disease
– Hepatocellular carcinoma
– Metastatic colorectal carcinoma
– Intrahepatic cholangiocarcinoma
– Metastatic neuroendocrine tumors
– Rarely, ocular melanoma, sarcoma, pancreas,
breast, lung
Chemoembolization Work-up
• Cross-sectional imaging (MR/CT)
• Assessment of performance status (ECOG
or Karnofsky)
• Childs class
• Tumor stage
• Laboratory studies (CBC, Chem 7,
PT/PTT, liver function tests, tumor
markers)
Relative Contraindications
• Biliary obstruction
– High risk of infection of obstructed segments1
• Without intact sphincter of Oddi
– Increased risk of abscess2
• Portal vein occlusion
– Liver infarction
• Elevated bilirubin
– Liver failure
11Song
SY, et al. Liver abscess after transcatheter oily chemoembolization for hepatic tumors: incidence, predisposing factors
and clinical outcome. J Vasc Interv Radiol 2001;12:313-320.
2Kim W, Clark TWI, Baum RA, et al. Risk factors for liver abscess formation after hepatic chemoembolization. J Vasc Interv
Radiol 2001; 12:965–968.
Relative Contraindications
• Biliary obstruction
– Percutaneous catheter drainage1
• Without intact sphincter of Oddi
– Night before bowel prep and prophylactic antibiotics2
• Portal vein occlusion
– Segmental or subsegmental embolization
– Limit chemotherapy3
– Document sufficient hepatic collaterol flow4
• Elevated bilirubin
– Superselective embolization
1Song
SY, et al. Liver abscess after transcatheter oily chemoembolization for hepatic tumors: incidence, predisposing factors and
clinical outcome. J Vasc Interv Radiol 2001;12:313-320.
2Geschwind JF, Kaushik S, Ramsey DE, et al. Influence of a new prophylactic antibiotic therapy on the incidence of liver abscesses
after chemoembolization treatment of liver tumors. J Vasc Interv Radiol 2002; 13:1163–1166.
3Kiely JM, et al. Chemoembolization in patients at high risk: results and complications. J Vasc Interv Radiol 2006;17:47-53.
4Pentecost MJ, et al. Hepatic chemoembolization: safety with portal vein thrombosis. J Vasc Interv Radiol 1993;4:347-351.
Prep for Sphincter of Oddi
disfunction
• Oral levaquin 500 mg daily two days
before and for seven days following
the procedure
• Oral Flagyl 500 mg twice daily two
days before and for seven days
following the procedure
High risk of acute hepatic failure
and post procedural mortality post
TACE
• >50% of liver volume
replaced by tumor
• LDH >425 IU/L
• AST (SGOT) > 100
IU/L
• Bilirubin >2 mg/dL
• Individual
abnormalities of these
four parameters have
not been shown to
predict adverse
outcomes of
chemoembolization
Charnsangavej, C. Chemoembolization of liver tumors.
Semin Invest Radiol 1993;10:150-160.
Berger DH, Carrasco CH, Hohn DC, et al. Hepatic artery
chemoembolization or embolization for primary and
metastatic liver tumors: post-treatment management and
complications. J Surg Oncol 1995; 60:116 –121.
Brown DB, Fundakowski CE, LiskerMelman M, et al. Comparison of
MELD and Child-Pugh scores to predict
survival after chemoembolization
for hepatocellular carcinoma. J Vasc Interv
Radiol 2004; 15:1209 –1218.
Side effects
• Post embolization syndrome in 80-90% of
patients
• Pain, fever, nausea, vomitting
• Severity varies
• PCA and liberal use of antiemetics as well
as good pre-procedure medication regimen
Leung DA, Goin JE, Sickles C, et al. Determinants of postembolization syndrome after hepatic chemoembolization.
J Vasc Interv Radiol 2001; 12:321–326.
Complications
Serious event = 3-7%
Other complications (<1%
incidence each)
• Hepatic
• Renal insufficiency
insufficiency/infarction
• anemia
• Hepatic abscess
• Tumor rupture
30 day mortality
• Chemical cholecystitis
ranges from 1 – 4%
• Non-target embolization to
the bowel
Sakamoto I, et al. Complications associated with transcatheter embolization for hepatic tumors. Radiographics 1998;18:605-619
Gates J, et al. Chemoembolization of hepatic neoplasms: safety, complications and when to worry. Radiographics 1999;19:399414.
Major complications
Specific Major Complication
Reported Rate (%))
Liver failure
2.3
Abscess with functional sphincter of Oddi
<1
Post-embolization syndrome requiring extended stay or
readmission
4.6
Abscess with biliary-enteric anastamosis/biliary
stent/sphincterotomy
25
Surgical cholecystitis
<1
Biloma requiring perutaneous drainage
<1
Pulmonary arterial oil embolus
<1
Gastrointestinal hemorrhage/ulceration
<1
Iatrogenic dissection preventing treatemtn
<1
Daniel B. Brown,
al. Quality
Embolization, and
Death
withinet 30
daysImprovement Guidelines for Transhepatic Arterial Chemoembolization,
1
Chemotherapeutic Infusion for Hepatic Malignancy. J Vasc Interv Radiology July 2009 ;20(7) Supplement:S219S226.e10
Pre-procedure orders
• IV normal saline 500 cc bolus then
200cc/hr
• Rocephin 1 gm IV
• Diphenhydramine 50 mg IV
• Dexamethazone 10 mg IV
• Ondansetron 24 mg IV
• Pepcid 20 mg IV
• Dilaudid PCA
Post procedure orders
•
•
•
•
Patient controlled anesthesia
Ondansetron 8 mg q8h IV, PRN nausea
Tylenol 650 mg q4h po, PRN fever
Augmentin 875mg one PO BID x seven
days. or if allergic to PCN: Cipro 500mg
one PO bid x seven days.
Follow up
• Labs in three weeks to assess for
continued eligibility
• Repeat CT or repeat treatment in 4
weeks
Discharge
• Augmentin or Ciprofloxacin
• Fevers < 103o are normal in the first
week and do not require cultures
Radioembolization or
Selective Internal Radiation Therapy
(SIRT)
This technique selectively targets a very high
radiation dose to all tumors (average dose of
280-380 Gy) within the liver, regardless of their
cell of origin, number, size or location while at
the same time maintaining a low radiation dose
to the normal liver tissue (<40 Gy)
Radiation in HCC
• Traditional radiation therapy in
management of unresectable HCC
demonstrated palliation of symptoms in
>50% of patients and 20% signficant tumor
shrinkage
• Risk of radiation induced liver toxicity after
uniform whole liver radiation to 30 Gy
(<dose required to eradicate tumor)
delivered over 3 weeks was 5%
Sakamoto I, et al. Complications associated with transcatheter embolization for hepatic tumors. Radiographics 1998;18:605-619
Gates J, et al. Chemoembolization of hepatic neoplasms: safety, complications and when to worry. Radiographics 1999;19:399-414.
SIR-Sphere size is small enough to gain entry
into tumor nodules but too large to pass
through the end capillary bed into the venous
circulation
Tumor vessels 25μm -75μm
End arterioles 8 μm
SIR-Spheres mean diameter 35 μm
Regulatory Status
• In US, regulated under the pre-market
approval regulations (21 CFR Part 814)
– FDA approval March 2002
– Unresectable metastatic liver tumors from primary
colorectal cancer together with adjuvant intrahepatic chemotherapy with FUDR
• In Europe and UK, Europe and UK
regulated under the Active Implantable
Medical Device Directive (90/385/EEC)
– CE Mark approval October 2002
– Primary and secondary (metastatic) liver cancer
Radioembolization in HCC
• Partial response rate of 42.2% in phase 2
study of 108 patients with unresectable
HCC with/without portal vein thrombosis
• More study is needed
Kulick LM, et al. Safety and efficacy of 90Y radiotherapy for
hepatocellular carcinoma with and without portal vein
thrombosis. Hepatology. 2008;47:71-81
Patient Selection
Unresectable primary hepatic
malignancy:
Hepatoma
Unresectable metastatic disease:
Colorectal
Breast
Pancreatic
Carcinoid
Neuroendocrine
Cholangiocarcinoma
Patient Selection
• Tumor board/ multidisciplinary team
determination that patient has
unresectable liver tumor with a life
expectancy > 3 months
• ECOG 0,1,2
• Karnofsky score of 60% or higher
Patient Work-up
1) CT/MRI/PET imaging to confirm
– liver dominant disease + no CNS mets
– tumoral/nontumoral volume
– patent portal vein
2) Adequate synthetic and excretory liver function
– Total bilirubin < 2.0mg/dL
– Serum albumin > 3.0g/dL
3) Patient may be on systemic chemotherapy except
except Capecitabine, Avastin, Erbitux
– Trials in progress to determine safety in
conjunction with Capecitabine, Avastin, Erbitux
4) No history of external beam radiation to the liver
Patient Work-up
• Two absolute contraindications
– reflux into arteries that supply the
gastroduodenal region
• can result in gastritis, pancreatitis, gastric ulceration
– exaggerated hepatopulmonary shunting (lung
shunt > 20%)
• can result in radiation pneumonitis
• To address these issues, a pre-treatment
diagnostic hepatic angiogram is performed
Ability to coil embolize
GDA and RGA and
others as necessary to
prevent reflux into
arteries in the
gastroduodenal region
Pre-treatment
hepatic
arteriogram
Hepatic Arteries
Right Gastric Artery
Gastroduodenal Artery
After coil
embolization,
injection of 5-6 mCi
of Tc-99m labeled
MAA as a
microsphere
surrogate into the
hepatic arterial
territory to assess
extent of
hepatopulmonary
shunting
19
Reduce implanted activity for
lung shunting > 10%
Lung shunt fraction
Reduce implanted activity by
0 – 10%
No reduction required
11 – 15%
Reduce by 20%
16 – 20%
Reduce by 40%
> 20%
Do not treat
Implanted activity calculation for a whole
liver treatment from the proper hepatic
artery
– 1) Activity (GBq) = BSA*-0.2 +
Tumor volume
Tumor volume + normal liver volume
– 2) Reduce implanted activity for lung shunting as
described
– 3) Reduce implanted activity for special cases
• CRLMs – heavy pre-treatment with systemic
chemotherapy
• HCC - cirrhosis
*BSA = Body Surface Area
SIR-Spheres Meds
• Rocephin 1gm IV pre procedure. No home
antibiotics.
• PPI or any H2 blocker one week before
and for 4 weeks after.
• Medrol dose pack if not diabetic (script
written at discharge).
• Ketorolac 10mg PO q 4-6 hours PRN pain
x 5 days after treatment.
• Ondansetron 8mg PO q 8 hours PRN N/V.
or Promethazine 25mg tablets, one PO q
6hours PRN N/V.
Radiation Safety
• Exposure
– Bremsstrahlung is typically 15 uSv per Gbq
at 15cm from the patient’s right side
(initially)
• Ward
– Outpatient procedure
– No pregnant women, children (‘three feet
for three days’)
– Nursing from left hand side of patient
– Shielding unnecessary
– No special handling required for blood,
body fluids, urine
Complications to be aware of…
•
Postembolization syndrome – may occur in as many as 50%
pts; not as severe as that observed with TACE and is usually
dominated by fatigue and constitutional symptoms
•
Gastrointestinal ulceration – incidence minimized with coil
embolization of right gastric, etc.
•
Pancreatitis – incidence minimized with coil embolization of
gastro-duodenal artery
•
Radiation pneumonitis – incidence practically zero with routine
work-up and Tc99 lung shunt study
•
Radiation hepatitis (RILD) – increased risk in patients with
cirrhosis and reduced liver reserve
•
Radiation Cholecystitis – clinically relevant radiation
cholecystitis requiring cholecystectomy is not common but does
occur
Questions?
Anastasia Balius, MD
Interventional Radiology
abalius@mc.utmck.edu
865-242-1496