Chemoembolization For Hepatocellular Carcinoma › presentation › bb50 › ...Chemoembolization...
Transcript of Chemoembolization For Hepatocellular Carcinoma › presentation › bb50 › ...Chemoembolization...
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Chemoembolization For
Hepatocellular Carcinoma
Michael Meuse, M.D.
Vascular and Interventional
Radiology
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Hepatocellular Carcinoma
• Incidence 2.99 per 100,000 (~10,000 cases
per year)
• Most cases associated with cirrhosis
• Accounts for 65% of liver cancer in the U.S
• Between 1976 and 2000, incidence
increased by >90%
– Young white men had an increase of 432%
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase
in the incidence of hepatocellular carcinoma in the United States: an update.
Ann Intern Med 2003;139:817–23
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World Wide Mortality
Deaths per 100,000 people from HCC
El–Serag HB et al. Hepatocellular Carcinoma: Epidemiology and
Molecular Carcinogenesis Gastroenterology 2007; 132: 2557
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Therapy Options • Surgery
– Resection
– Transplantation
– Best therapy but < 30 % are candidates
• Systemic chemotherapy
– Sorafenib (oral multikinase inhibitor)
– Trial limited to Childs Class A/B
• External Beam Radiation
• Regional therapy
– Trans-arterial chemoembolization (TACE)
– Percutaneous tumor ablation
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Principles of Regional
Cancer Therapy
• Anatomically confined tumor
• Therapeutic advantage
• Technical feasibility
• Clinical benefit
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Transcatheter Therapy • Hepatic artery infusion chemotherapy
– single/multi-shot, port-a-cath, hypoxic
perfusion
– high response rate, no survival benefit
• Hepatic artery embolization
– effective for neuroendocrine tumors
• Lipiodol embolization
• Chemoembolization
– combination of oily HA embo and local
chemo
• Yttrium-90 glass microspheres
• Gene therapy
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TACE
• First described in 1982
• Injection of a 1:1 mixture of lipophilic chemotherapeutic agents and Lipidol into the hepatic artery branches supplying a HCC
• Lipiodol acts as a reservoir for the chemotherapy and slowly releases it (1month)
• Preferential uptake in tumor cells (Raoul 1988)
Konno T. Use of a lipid lymphographic agent, lipiodol, as a carrier of high molecular
weight antitumor agent, smancs, for hepatocellular carcinoma
Japanese Journal of Cancer & Chemotherapy. 1982; 9: 2005-15
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Chemoembolization Physiology
• Dual blood supply – Normal liver
• 75% portal vein
• 25% hepatic artery
– HCC • > 95% hepatic artery
• Hypervascular
• TACE leads to tumor ischemia and local drug concentrations 10-25x over systemic administration
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Chemoembolization
Hepatic artery embolization combined
with local infusion of chemotherapeutic
drugs emulsified in lipiodol
• Aim
– tumor ischemia necrosis
– tumor drug concentrations (10-25x)
– dwell time of drug (up to 1 month)
– systemic toxicity (85% retained in liver)
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Chemoembolic Agents
• Chemotherapeutic agents
– doxorubicin
– cisplatin
– mitomycin C
• Embolic agent
– lipiodol
– gelfoam - temporary embolic agent
– PVA particles - 150-250 micron
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Lipiodol PROPERTIES
• Iodinated ethyl esters of poppy seed oil
• Preferential uptake in tumor cells (Raoul
1988)
– penetrates tumor cells
• Plastic embolic agent
– enters portal venules
• Acts as a reservoir for anticancer drugs
– slow release of drugs from emulsion
• Selectivity for large arteries
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Patient Selection • Unresectable, liver-dominant tumor
• Contraindications
– to angiography
– to hepatic embolization
• encephalopathy
• >50% liver replaced by tumor
• AST > 100, LDH > 425, Bili >2
• biliary obstruction
• portal vein occlusion (relative)
– to chemotherapy
• severe leukopenia or thrombocytopenia
• renal or cardiac insufficiency
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Pretreatment Assessment
• Patient education (PES, complications,
etc)
• Cross-sectional imaging
– MRI or CT
• Labs
– CBC, PT/PTT, creat, LFT’s, tumor markers
• Diagnostic visceral arteriography
– portal vein patency, variant anatomy
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Technique
• Conventional Angiography
– Confirms diagnosis (if no biopsy performed or biopsy non-diagnostic)
– Map arteries for embolization
• Selective embolization
– Maximizes intra-tumoral concentration of chemotherapy
– Blocks small arterioles to promote tumor ischemia
– Minimizes embolization of normal liver
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Chemo-embolization
• 10-mL chemotherapy solution (cisplatin
100 mg [Bristol Myers Squibb, Princeton,
NJ], doxorubicin 50 mg [Adriamycin;
Pharmacia & Upjohn], and mitomycin C 10
mg [Bedford Laboratories, Bedford, OH])
dissolved in ionic contrast (Renografin)
• Mix in 1:1-2:1volume ratio with Lipiodol
(Savage Laboratories, Melville, NY)
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Selective Injection
Super-selective Injection
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Post TACE Angiogram
No tumor blush on post-treatment angiogram
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Hepatocellular Carcinoma
Pre-treatment CT
non-contrast contrast-enhanced
Typical findings of hepatocellular carcinoma (HCC)
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HCC Lipiodol Accumulation
2 months 8 months 18 months
Sequential non-contrast CTs
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Clinical Response to TACE
• There is a survival benefit in
selected patients with
unresectable hepatocellular
carcinoma (HCC) successfully
treated with TACE
• Careful patient selection,
technique, and follow-up are
important to the technical
success of TACE and in
achieving good outcomes
• Incomplete embolization is
associated with residual tumor
at follow-up imaging and poor
clinical results
Bruix J. Gastroenterology 2004; 127: s179
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Incomplete Embolization
• Associated with residual tumor at
follow-up
• More common when angiography
demonstrates:
– Complex arterial supply (e.g central
lesions)
– Lesions poorly visualized on angiography
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Causes of Incomplete
Embolization • Hypovascular lesions only seen on pre-
procedure MRI –May be difficult to identify at angiography
–Lesions may be atypical HCC (hypovascular) or mis-diagnosis
–Diagnostic Lipiodol injection with follow-up CT
• Hypervascular lesions with poor uptake of chemoembolization –Likely to have poor clinical response
• Lesions that are only visible on non-selective injections –Multiple vessel supply (common with central lesions)
–Insufficient contrast injection through
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Dyna CT
• Cone beam CT (CBCT) (Dyna CT,
Siemens Medical Solutions) improves
tumor visualization during diagnostic
angiography
• Helps the operator identify which vessels
are supplying a tumor
• Better defines the tumor embolization
endpoint by confirming Lipiodol uptake
prior to leaving procedure room
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Segment V-VIII HCC on MRI
56 y/o with Hepatitis C, cirrhosis and new hypervascular mass
Axial VIBE
Siemens Avanto
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Replaced Right Hepatic
Angiogram Demonstrates
Tumor Blush
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Segment VIII Arteriogram
Tumor blush not visible on conventional angiography
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Segment V Artery Dyna CT
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Segment VI Artery Dyna CT
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Segment VIII Large Volume
Dyna CT
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Incorporation of Dyna CT into
TACE Planning
• Celiac arteriogram
• Common hepatic angiogram in three views
• Selective right and left hepatic
angiography (3 views or Dyna Vision)
• Dyna CT of right or left hepatic artery
• Super-selective angiography
• Repeat Dyna CT of segmental arteries as
needed
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CBCT Sensitivity
• Forty-nine consecutive patients (52 suspicious lesions) were prospectively examined
• Conventional DSA plus CBCT was superior to DSA alone for identifying areas of tumor blush
• In 42 of the 52 lesions (81%), CBCT provided additional useful information for therapeutic decision making
Kakeda S. Usefulness of Cone-Beam Volume CT with Flat Panel Detectors
in Conjunction with Catheter Angiography for Transcatheter Arterial
Embolization. JVIR 2007; 18: 1508
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Follow-up CT Confirms Lipidol
Uptake
LV Dyna CT Multi-planar
reconstruction
Follow-up CT MPR
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Ethiodol uptake
• HCCs with complete uptake of iodized oil
after TACE are considered to be
completely necrotic
• HCCs with only partial uptake of iodized oil
after TACE may have residual viable
tumor
• We perform a post embolization Dyna CT
or LV Dyna CT on every case
Imaeda T, Yamawaki Y, Seki M, et al. Lipiodol retention and massive necrosis
after lipiodol-chemoembolization of hepatocellular carcinoma: correlation
between computed tomography and histopathology.
Cardiovasc Intervent Radiol. 1993;16:209-213.
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Gadolinium enhanced T1W axial image
50 y/o with HCC in Segment IV
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Selective Angiography
Left gastric angiogram demonstrates lesion
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Lesion identified on LV Dyna-CT
LV Dyna-CT confirms entire lesion fed by replaced
hepatic artery arising from the left gastric artery
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TACE Injection
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Post TACE LV Dyna CT
Density is provided by Lipiodol uptake
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Area of No Lipiodol Accumulation
Adjacent to Tumor
Area of hypo attenuation not identified at time of this study
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One Month CT Demonstrates
Residual Tumor Enhancement
Contrast enhancement-
Residual tumor
Lipiodol in tumor
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Repeat TACE
Complete filling of tumor with Lipiodol
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Repeat LV Dyna-CT
Complete left lobe lateral segment
opacification with Lipiodol Lipiodol uptake in the
tumor is improved
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CBCT Effect on Outcome
• Initial treatment of 265 tumors in 79 HCC
patients using CT-guided TACE
• Overall local recurrence-free rates after a
single TACE session at 6, 12, and 36
months were 67%, 49%, and 28%
• With complete lipiodol accumulation
confirmed by CBCT, the results were 82%,
68%, and 41%, respectively
Hayashi K. Local therapeutic results of computed tomography-guided
transcatheter arterial chemoembolization for hepatocellular carcinoma:
results of 265 tumors in 79 patients. CVIR 2007; 30: 1144.
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Post TACE Dyna-CT and
Conventional CT
Large volume Dyna-CT
immediately post embo Conventional unenhanced CT
4 weeks later
Incomplete uptake suggests poor outcome
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Chemoembolization COMPLICATIONS
• Major (3 - 4 %)
– hepatic insufficiency or infarction
– biliary necrosis
– hepatic abscess
– tumor rupture
– surgical cholecystitis
– nontarget embolization of gut
• Other ( ~ 1%)
– renal insufficiency
– anemia requiring transfusion
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Gallbladder Embolization
pre post
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Postprocedure / Follow up
• Posttreatment care
– manage post-embolization syndrome
(supportive)
– avg hospital stay:1-2 days, discharge
abx/meds
• Follow up
– repeat chemoembolizations at ~ monthly
intervals: avg 2-3 sessions
– assess response/recurrence at 1/3/6/12
months by lab tests and cross-sectional
imaging
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Hepatoma - Survival
• Untreated
– median survival 3-6 months
– 0% at 1 year
• Surgical resection
– 1/2/3 yr survival 60/50/40 %
• Systemic chemo
– 70 % response—tumor stablization
– Impact on survival similar to TACE
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Results of Chemoembolization HEPATOMA
• Response rate to chemoembolization
– AFP and/or tumor volume 60 - 83 %
• Cumulative survival (n=800)
1yr 72 % (55 - 76 %)
2yr 53 % (33 - 64 %)
3yr 40 % (15 - 51 %)
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Results of Chemoembolization HEPATOMA
• Bronwicki et al, Cancer 1994
• Simultaneous case-control study
1yr 64 % 18 %
2yr 38 % 6 %
3yr 27 % 5 %
4yr 27 % 0 %
survival chembo support
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RCT HONG KONG DATA
• 387 consecutive patients with HCC
– 108 patients sent for surgery
– 199 excluded (vascular, mets, poor function)
– 80 patients entered into study
• 40 control / 40 TACE
• TACE
– 192 courses of therapy (1 - 15, median 4.5)
– Cisplatinum/Lipiodol & 1mm gelatin-sponge
particles
– Median chemo volume 20 ml (2 - 60 ml)
– 38/40 had treatment stopped
• progressive dx/liver failure/death/refusal/AE/thrombosis
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RCT HONG KONG DATA
• Survival at 1, 2, & 3 years
– TACE 57%, 31%, and 26%
– Control 32%, 11%, and 3%
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RCT BARCELONA DATA
• Multicenter trial
• Strict selection with aggressive
retreatment
• Mild hepatic dysfunction (Okuda I, II)
• Primarily white patients with Hepatitis C
• Stopped after 4 years for statistically
significant results
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RCT BARCELONA DATA
• Evaluated 903 patients with newly
diagnosed HCC
– Excluded 791 patients
– Randomized 112
• 37 Bland embolization
• 40 TACE
• 35 Control
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RCT BARCELONA DATA
• Survival at 1, 2, & 3 years
– TACE 82%, 63%, & 29%
– Bland embo 75%, 50%, & 29%
– Control 63%, 27%, & 17%
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Percutaneous Tumor Ablation
• Advantages
– spares functioning liver tissue
– easily repeatable
– can treat multiple lesions
– outpatient procedure
– low cost (ethanol)
• Disadvantages
– size limitations
– tissue inhomogeneity
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Percutaneous Tumor Ablation
• Chemical
– ethanol injection
– acetic acid
– hot saline
• Thermal
– radiofrequency
– interstitial laser photocoagulation
– microwave coagulation
– cryotherapy
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Percutaneous Ethanol Injection
• Widely used to treat hepatoma, not
effective against colorectal mets
• Coagulation necrosis, fibrosis, cell death
• Prognostic factors
– solitary lesion < 3 cm
– Child class A
– initial AFP level < 200 mcg/L
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Percutaneous Ethanol Injection
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Percutaneous Ethanol Injection HEPATOMA SURVIVAL
• Livrahgi et al, Radiology 1995
• Lencioni et al, Radiology 1995
99 % 96 % 86 % 69 % 48 %
64 % 12 % 0 0 0
100 % _ 69 % _ 32 %
77 % _ 57 % _ 29 %
1yr 2yr 3yr 5yr 4yr
Child A <3cm
Child C <5cm
AFP<200
AFP>200
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Radiofrequency Ablation
• RF energy Ion agitation Friction
Heat Coagulation necrosis
• Procedure:
– Image-guided (US/CT/MR) percutaneous
electrode placement/real-time monitoring
– Percutaneous/laparoscopic/open
– Conscious sedation/anesthesia
– Prophylactic ABX
– Grounding pads
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Radiofrequency Ablation
• Various electrode designs
– monopolar/bipolar
– multiprobe arrays/ hooked arrays
– cluster probes/internally cooled electrodes
• Lesions > 4-5 cm: overlapping ablations
• Try to obtain 1cm margins
• Temp/impedance/time monitored depending on manufacturer
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RF Electrodes
Rita Radiotherapeutics Radionics
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Radiofrequency Ablation RESULTS
• Local recurrence 2-40% at 1 year
• Survival
– 1 yr 96%
– 3 yr 64%
– 5 yr 40%
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Dome lesions
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Follow-up
• CT or MR
• May get immediate CT/MR
• MR/CT at 1, 3, 6, mo
• Treat any evidence of recurrence or
residual disease
• Post Ablation syndrome
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Radiofrequency Ablation COMPLICATIONS
• De Baere et al, AJR 2003, n=350 – Total AE 10.6%, Mortality 1.4%
– Abscess n=7 (bilioenteric anastomosis)
– Pleural effusion n=5
– Skin burn n=5
– Pneumothorax n=3
– Subcapsular hematoma n=2
– Hemoperitoneum n=1
– ARF n=1
– Needle-tract seeding n=1
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Combination Therapy • Chemoembolization / perc. ethanol
injection
– Best for large solitary lesions
– Randomized trials: chembo/PEI vs repeat
chembo
• Tanaka et al, 1992. Bartolozzi et al, 1995
• significantly improved response and survival
• HA balloon occlusion or embo / RF
ablation
– Rossi et al, Radiology 2000
– Hepatoma nodules 3.5-8.5 cm
– 1 yr survival 87 %
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Dome Lesion Not Seen with US or CT
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TACE
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Conclusions
• Chemoembolization is effective and well
tolerated for palliation of hepatoma and
hypervascular metastases
• There are many unanswered questions
– optimal technique
– role in neoadjuvant therapy
– relative role to other treatment modalities
– role of ablation techniques/combination
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Conclusions
• Careful technique with thorough
embolization is essential to achieving
satisfactory results
• In high risk patients, super selective
embolization should be performed
• CBCT (Dyna CT) improves our ability to
localize and selectively embolize HCC
• Large volume Dyna CT improve the
diagnostic utility of the routine post TACE
CBCT
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Conclusions
• Percutaneous tumor ablation appears to
be efficacious for treatment of HCC and
mets <4-5cm
• Promising procedures evolving
– combination of embolization and ablation
– portal vein embolization
– radioembolization, gene therapy, ...
• Controlled studies are needed