Justin McWilliams, MD     Assistant ProfessorInterventional Radiology                  UCLA
Justin McWilliams, MD     Assistant ProfessorInterventional Radiology                  UCLA
   Minimally invasive treatments for HCC       Description of techniques       Review of the evidence       What is be...
“Resection with wide                                                              “OLT is the best available   margins is ...
Percutaneous ethanol injection (PEI)Radiofrequency ablation (RFA)Microwave ablation (MWA)Transarterial chemoembolization (...
Percutaneous ablation   PEI   Radiofrequency ablation   Microwave ablationTransarterial chemoembolizationYttrum-90 radioem...
   Ethanol injection causes vessel    thrombosis and protein denaturation     • Complete necrosis of small (<2 cm) HCC   ...
   RF current induces thermal coagulation    necrosis around an electrode       •    Complete ablation rates >80% for sma...
     Three RCTs and two meta-analyses      confirm superiority of RFA over PEI      for small HCC         • 5-year surviv...
    Next-generation RF ablation electrodes     are available       •    Internal cooling       •    Saline injection     ...
      Microwave creates a field of electromagnetic energy       and thermal coagulation around an antenna         • Activ...
“Local ablation is safe and effective therapy for patients   who cannot undergo resection, or as a bridge to   transplanta...
Percutaneous ablationTransarterial chemoembolization   Conventional TACE (cTACE)   Drug-eluting beads (DEB-TACE)   Pushing...
   HCC takes its blood supply almost    exclusively from the hepatic artery   Surrounding normal liver has dual    blood...
1. Select tumor-bearing artery2. Embolize to near-stasis or stasis   • Chemotherapy     (doxorubicin, cisplatin, mitomycin...
   6 randomized trials in 1990s    showed no benefit of TACE for    unresectable HCC    • Selection criteria not stringen...
   RCT of TACE vs. symptomatic treatment for unresectable HCC   Llovet: 112 patients     •   Mostly Hepatitis C     •   ...
   RCT of TACE vs. symptomatic treatment for unresectable HCC   Llovet: 112 patients        3-year survival:        29% ...
    Meta analysis of cTACE        • TACE reduced 2-year mortality (OR 0.54) compared to symptomatic             treatment...
 Cohort                     study of 8510 patients having cTACE       • Initial treatment       • Unresectable HCC       ...
   AFP                                                   Child class                                              Max t...
“TACE is first-line non-curative therapy fornon-surgical patients with large or multifocalHCC who do not have vascular inv...
   Chemotherapy in lipiodol washes out    of tumor quickly    • Less effective tumor kill    • More systemic side effects...
   RCT vs. bland embo                                                          Mid-term survival data     •   41 DEB-TAC...
   212 patients randomized to DEB-TACE with LC beads    vs. cTACE with doxorubicin     •   Child A and B, ECOG 0 or 1    ...
   Expandable microspheres made of    sodium acrylate/vinyl alcohol    copolymer   Ionically binds doxorubicin   Arrive...
   Single-arm trial of 50 patients     • Child A     • Exclusion criteria        Tumor size >10 cm, Portal vein invasion...
   281 consecutive patients with PV      164 patients with segmental or              125 patients with main PV    invas...
   Retrospective study of >1000    patients     • 843 patients <70 compared to 197       patients >70     • Elderly patie...
Percutaneous ablationTransarterial chemoembolizationYttrium-90 radioembolization
   Transarterial administration of radioactive    microspheres (Yttrium-90)     • Half-life 64 hours; decays into stable ...
   Liver-only or liver-dominant tumor, not suitable    for radical therapy     • Resection     • Liver transplantation   ...
1. Superior mesenteric angiogram    •   Detect hepatic arterial variations    •   Determine patency of portal vein and hep...
1. 2 weeks after mesenteric   mapping, patient returns for Y90   administration2. Repeat celiac/hepatic angiography    • E...
   108 patients with unresectable                   291 patients with unresectable intermediate    intermediate or advan...
   8-center study of 325 patients with    unresectable intermediate or advanced    HCC     •   82% Child A, 18% Child B  ...
   Y90 expected to be better tolerated than TACE    in patients with PV invasion     •   Y-90 is less embolic; therefore ...
Resection vs. TACEResection vs. ablation   Ablation vs. TACE       TACE vs. Y90
   185 patients with resectable early-      419 patients with resectable HCC    stage HCC and Child A cirrhosis         ...
   3225 patients with HCC                    87 patients with resectable HCC    retrospectively grouped by clinical     ...
   115 RFA vs. 115 surgery                      180 patients with solitary HCC <5 cm     •   HCC within Milan criteria  ...
   5317 American patients with HCC   7185 patients with HCC (3 tumors up to 3          •   Median tumor size 6 cm    cm)...
   91 patients with unresectable HCC (up to 3 nodules, each up to    5 cm)                                               ...
   790 patients with unresectable                                                        intermediate-stage HCC +/- PVT ...
   73 comparable patients with unresectable    HCC, ~35% with vascular invasion      •   Segmental PV occlusion could hav...
TACE + ablationTACE + sorafenib
   37 patients with solitary HCC 3.1-5.0    cm                                                          89 patients with...
What have we learned?
   Interventional radiology plays a key role (maybe the    key role!) in liver cancer treatment    • Percutaneous ablatio...
TS                65 y/o female             Hepatitis B cirrhosis Routine screening US and CT demonstrated          two ad...
MRI 2/25/2010: No residual tumor.Patient downstaged, exception points          awarded for OLT                            ...
TACE #3 11/18/2010                                               75 mg doxorubicin on                                     ...
MRI 12/20/2010: Minimal residual tumorSuccessful OLT 1/22/2011 (1 year after first               intervention)  Now almost...
YO            58 y/o male      Hepatitis B and C and HIV    Abdominal pain prompted CT      7 cm biopsy-proven HCCNot a su...
MRI 1 month later –100 mg doxorubicin on      mass mostly      LC beads           devascularized
Follow-up MRI –  Percutaneous       complete necrosis, nomicrowave ablation    recurrence at 4 mos
TG               39 y/o female    Fibrolamellar HCC diagnosed in 2001Left lobe resection of 9 x 11 cm mass in 2001  Recurr...
TACE 5/3/2010   100 mg doxorubicin on                      LC beads                                        2 weeks later, ...
CT 5/19/2010: near- complete       tumor necrosis                               Prolonged     CT 8/6/2010: Biloma    Percu...
August 2009 –present                                                 100 patients with HCC referred for                   ...
Liver transplantation   Indications and outcomes   MELD   Downstaging   BridgingSurgical resectionPercutaneous ablationTra...
   Treatment with TACE or RFA can downstage    tumors into Milan criteria   UCSF criteria for downstaging     • One lesi...
   Patients with tumors exceeding Milan do well with    transplant after downstaging     • Success of downstaging 24-90% ...
   Systematic review of downstaging    for HCC beyond Milan criteria   8 studies, 720 patients   Successful downstaging...
 “Downstaging with a subsequent interval of observation to assess biologic aggressiveness should be considered for patien...
   Natural history of patients with    HCC within Milan criteria, at 1    year    • 70% will have tumor growth    • 20% w...
   87 patients listed for OLT              52 patients listed for OLT     • 43 non-TACE and 22 TACE                • Bri...
 “Bridgingtherapy with TACE and RFA have low morbidity, favorable HCC response, and probably reduce drop-out for patients...
 “OLT  is the preferred treatment for patients with cirrhosis and HCC meeting Milan criteria” “OLTshould be considered o...
Liver transplantationSurgical resection   Indications and outcomes   Portal vein embolizationPercutaneous ablationTransart...
 Standard treatment for resectable HCC in patients without cirrhosis Only~5% of HCC patients in the Western world qualif...
   Advantages    • No restrictions on tumor size or number (within a lobe)    • Macrovascular invasion acceptable    • No...
   Overall 5-year survival for hepatic resection in HCC is 25-50%     • If solitary tumor and non-cirrhotic liver, 5-year...
   Liver resection is often limited due to inadequate    volume of the future liver remnant     • Normal patients can sur...
     Technical considerations           •   Access ipsilateral (into tumor bearing lobe)           •   5F sheath and pigt...
   “Resection with wide margins is the treatment of    choice for HCC in patients without cirrhosis”   “Resection is acc...
Liver grand rounds 2012
Liver grand rounds 2012
Liver grand rounds 2012
Liver grand rounds 2012
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Liver grand rounds 2012

  1. 1. Justin McWilliams, MD Assistant ProfessorInterventional Radiology UCLA
  2. 2. Justin McWilliams, MD Assistant ProfessorInterventional Radiology UCLA
  3. 3.  Minimally invasive treatments for HCC  Description of techniques  Review of the evidence  What is best? IR as adjunctive treatment  Bridging and downstaging to OLT  Portal vein embolization Case examples: successes and failures My practice – the first 2.5 years, by the numbers
  4. 4. “Resection with wide “OLT is the best available margins is the treatment of curative treatment for HCC choice for HCC in patients in cirrhotic livers” without cirrhosis”Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  5. 5. Percutaneous ethanol injection (PEI)Radiofrequency ablation (RFA)Microwave ablation (MWA)Transarterial chemoembolization (TACE)Yttrium-90 radioembolization (Y-90)
  6. 6. Percutaneous ablation PEI Radiofrequency ablation Microwave ablationTransarterial chemoembolizationYttrum-90 radioembolization
  7. 7.  Ethanol injection causes vessel thrombosis and protein denaturation • Complete necrosis of small (<2 cm) HCC can be achieved • Tumors near sensitive organs can be treated; no heat sink effect 5-year survival of 32-38% Disadvantages • Multiple treatment sessions needed • Uncertain ablation zone • High local recurrence rate (17-38%)
  8. 8.  RF current induces thermal coagulation necrosis around an electrode • Complete ablation rates >80% for small to medium HCC • Local recurrence uncommon (1-12%) 5-year survival of 40-58% Disadvantages • Relies on thermal conduction (limited ablation size)  Best for tumors <3 cm  Increasing technical failure and local recurrence for tumors >3 cm • Heat sink effect • SlowMcWilliams J, et al. Percutaneous ablation of hepatocellular carcinoma: current status. J Vasc Interv Radiol 2010;21:S204-S213.Hinshaw J. The role of image-guided tumor ablation in the management of liver cancer. Cancer News review article.
  9. 9.  Three RCTs and two meta-analyses confirm superiority of RFA over PEI for small HCC • 5-year survival about 15% better for RFA versus PEI PEI: 5-year RFA: 5-year survival 35% survival 50% • Less local tumor recurrence for RFA • 3x fewer treatment sessions for RFA PEI still useful for tumors in sensitive locationsShiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma.Gastroenterology 2005; 129:122–130.Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellularcarcinoma or 4 cm. Gastroenterology 2004; 127:1714–1723.Lencioni RA, Allgaler HP, Cloni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablationversus percutaneous ethanol injection. Radiology 2003; 228:235–240.
  10. 10.  Next-generation RF ablation electrodes are available • Internal cooling • Saline injection • Expandable tines Ablation zones of 4-7 cm are achievable McWilliams J, et al. Percutaneous ablation of hepatocellular carcinoma: current status. J Vasc Interv Radiol 2010;21:S204-S213.
  11. 11.  Microwave creates a field of electromagnetic energy and thermal coagulation around an antenna • Active heating not reliant on conduction (faster, larger ablation zones) • Less heat-sink effect • Multiple antennae can be activated simultaneously 5-year survival of ???? Next-generation 2450 MHz MW ablation devices now available • 17-gauge antennae • CO2 based internal cooling • High power (140 watts) • Large ablation zones (3.5 x 5 cm) McWilliams J, et al. Percutaneous ablation of hepatocellular carcinoma: current status. J Vasc Interv Radiol 2010;21:S204-S213.
  12. 12. “Local ablation is safe and effective therapy for patients who cannot undergo resection, or as a bridge to transplantation.”American Association for Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL).
  13. 13. Percutaneous ablationTransarterial chemoembolization Conventional TACE (cTACE) Drug-eluting beads (DEB-TACE) Pushing the envelopeYttrium-90 radioembolization
  14. 14.  HCC takes its blood supply almost exclusively from the hepatic artery Surrounding normal liver has dual blood supply (with portal vein) Chemotherapy + embolic agent administered into hepatic artery should selectively kill tumor while sparing normal liver
  15. 15. 1. Select tumor-bearing artery2. Embolize to near-stasis or stasis • Chemotherapy (doxorubicin, cisplatin, mitomycin C) • Lipiodol vehicle; selectively retained by HCC  Causes ischemia  Extends contact of chemotherapy with tumor • Finish embolization with gelfoam or particles
  16. 16.  6 randomized trials in 1990s showed no benefit of TACE for unresectable HCC • Selection criteria not stringent  Severe underlying liver disease • Many patients not aggressively re-treated  Objective responses to TACE are not maintained with time • Nonselective embolization often used
  17. 17.  RCT of TACE vs. symptomatic treatment for unresectable HCC Llovet: 112 patients • Mostly Hepatitis C • 75% had multinodular tumor • Mean diameter of main nodule was ~5 cm • About 75% Child A, 25% Child B • Repeated Doxorubicin/Ethiodol TACE (mean 3 treatments/patient) Lo: 80 patients • Mostly Hepatitis B • 60% had multifocal tumor • Mean diameter of main nodule was ~7 cm • ~25% had right or left PV obstruction • Repeated Cisplatin/Ethiodol TACE (mean 4.5 treatments/patient)
  18. 18.  RCT of TACE vs. symptomatic treatment for unresectable HCC Llovet: 112 patients 3-year survival: 29% with TACE 17% with supportive care Lo: 80 patients 3-year survival: 26% with TACE 3% with supportive care
  19. 19.  Meta analysis of cTACE • TACE reduced 2-year mortality (OR 0.54) compared to symptomatic treatment Camma C, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002.
  20. 20.  Cohort study of 8510 patients having cTACE • Initial treatment • Unresectable HCC • No extrahepatic disease • 5-year survival 26%Takayasu K, et al. Prospective Cohort Study of Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma in 8510 Patients. Gastroenterology 2006.
  21. 21.  AFP  Child class  Max tumor size • <20 = 34% • A = 33% • <=2 cm = 39% • 21-200 = 27% • B = 21% • 2.1-3 cm = 28% • 201-1000 = 19% • C = 8% • 3.1 – 5 cm = 23% • >1000 = 15% • >5 cm = 16%  # of lesions  PV invasion • 1 = 33% • None = 28% • 2-3 = 24% • Peripheral branch = 12% • 4 or more = 16% • Left or right = 11% • Main = 0%Takayasu K, et al. Prospective Cohort Study of Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma in 8510 Patients. Gastroenterology 2006.
  22. 22. “TACE is first-line non-curative therapy fornon-surgical patients with large or multifocalHCC who do not have vascular invasion orextrahepatic spread (level I evidence).”American Association for Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL).
  23. 23.  Chemotherapy in lipiodol washes out of tumor quickly • Less effective tumor kill • More systemic side effects Chemotherapy loaded onto a particle can be eluted slowly • LC beads: Size-calibrated spherical hydrogel particle which can be loaded with doxorubicin • Chemotherapeutic elutes gradually over weeks, though tumor necrosis greatest at 7- 14 days
  24. 24.  RCT vs. bland embo  Mid-term survival data • 41 DEB-TACE vs. 43 bland embo • 71 patients • Child A and B, ECOG 0 or 1 • Child A and B, ECOG 0 or 1 • Procedures q2 months up to 3; 100-300 and • Exclusion criteria: Creatinine >2, Portosystemic 300-500 micron LC beads shunt, Hepatofugal blood flow, Main portal vein thrombus, extrahepatic disease DEB-TACE: • 1-4 procedures, q3 months as needed. 100- • Higher complete response rate at 6 months 300 and 300-500 micron LC beads with 150 (27 vs 18%) mg doxorubicin per treatment. • Lower recurrence rate at 12 months (46% vs 78%)  88% survival at 30 months (better • Longer time to progression (42 vs 36 weeks) than historical cTACE)
  25. 25.  212 patients randomized to DEB-TACE with LC beads vs. cTACE with doxorubicin • Child A and B, ECOG 0 or 1 • Exclusion criteria: Bili >3, Vascular invasion, >50% tumor, extrahepatic spread, AST or ALT >5x normal • 1 vial 300-500, 1 vial 500-700 micron LC beads, 75 mg doxo/vial vs. 150 mg doxo in Ethiodol with operator choice embolic • Treatments q2 months up to 3 treatments; tumor response evaluated at 6 months Tendency toward better response with DEB-TACE (52 vs. 44%) Significant reduction in liver toxicity and side effects with DEB-TACE Survival was not an endpoint (too short f/u)
  26. 26.  Expandable microspheres made of sodium acrylate/vinyl alcohol copolymer Ionically binds doxorubicin Arrive dehydrated; when placed in saline or contrast, they increase in volume (50-100 micron goes to 150-300 micron) Soft and deformable, conform to vessel wall
  27. 27.  Single-arm trial of 50 patients • Child A • Exclusion criteria  Tumor size >10 cm, Portal vein invasion, Extrahepatic disease • 50 mg doxo or epirubicin per treatment, repeated “on demand” ? Survival ? • 6-month results: ? Durable effect ?  CR in 52%  PR in 26%  PD in 23% ? Comparison to LC  Only 31/50 followed up beads or cTACE ? “Safe, well-tolerated and efficient agent to produce tumor necrosis”
  28. 28.  281 consecutive patients with PV  164 patients with segmental or  125 patients with main PV invasion studied retrospectively major PV invasion invasion • 84 treated with TACE vs. 80 with • 83 treated with superselective supportive care TACE vs. 42 with supportive care Aggressive repeated TACE was • 1-year survival 31% vs. 4% • Repeated TACE showed survival well tolerated and showed • 2-year survival 9% vs. 0% benefit (5.6 vs. 2.2 months) significant survival benefits • Significant advantage for TACE in • 29% morbidity rate (similar to (median survival 10 vs 2 months) both segmental and major PV supportive care), no mortality invasion • No procedure-related mortality
  29. 29.  Retrospective study of >1000 patients • 843 patients <70 compared to 197 patients >70 • Elderly patients had more comorbid disease (64 vs 33%) but had earlier stage of HCC • Overall survival better for the elderly  14 vs. 8 months  TACE tolerated equally well TACE is good for young and old alike
  30. 30. Percutaneous ablationTransarterial chemoembolizationYttrium-90 radioembolization
  31. 31.  Transarterial administration of radioactive microspheres (Yttrium-90) • Half-life 64 hours; decays into stable zirconium-90 • Beta-emitter with path length of 2.5 mm • Particles lodge in the tumor, producing very high local radiation dose (100-1000 Gy or more) • Not dependent on flow occlusion TheraSpheres • FDA approved under Humanitarian Device Exemption for use in treatment of HCC • Glass particle, 15-35 micron diameter • 1.2-8 million spheres per vial (3GBq) • Minimally embolic Two scenarios must be avoided with Y90 • Shunting into lung (radiation pneumonitis) • Nontarget embolization of GI tract (ulceration)
  32. 32.  Liver-only or liver-dominant tumor, not suitable for radical therapy • Resection • Liver transplantation • Ablation Preserved functional status • ECOG 0-2 Preserved hepatic function • Total bili <= 2.0 • Albumin >= 3.0 • No ascites or other clinical signs of liver failure Low risk of pulmonary effects • <20% hepatopulmonary shunt • <30 Gy expected dose delivery to lungs (<50 Gy for multiple infusions)
  33. 33. 1. Superior mesenteric angiogram • Detect hepatic arterial variations • Determine patency of portal vein and hepatopetal flow2. Complete celiac angiography • Map arterial anatomy • Detect extrahepatic supply to tumor • Det3. Prophylactic embolization of any vessel in the treatment zone which does not lead to liver • GDA • Right gastric • Accessory left gastric • Falciform • Supraduodenal • Cystic4. Place microcatheter at site of expected Y90 treatmentand administer 4 mCi Tc-99m MAA • Similar size particles to TheraSpheres • Perform MAA scan to see distribution of particles • Measure lung-shunt fraction (must be <20%) • Detect any mesenteric flow
  34. 34. 1. 2 weeks after mesenteric mapping, patient returns for Y90 administration2. Repeat celiac/hepatic angiography • Ensure continued occlusion of embolized vessels3. Position microcatheter in lobar artery supplying the most tumor and infuse Y904. If bilobar disease, patient will return in 1month for Y90 treatment of opposite lobe
  35. 35.  108 patients with unresectable  291 patients with unresectable intermediate intermediate or advanced HCC or advanced HCC • No extrahepatic disease • PVT and limited extrahepatic disease allowed • 17% BCLC A; 28% B; 52% C; 3% D 159 sessions of TheraSphere Y-90 • 40% response rate (almost all partial)  526 sessions of TheraSphere Y-90 • Time to progression 10 months • 42% response rate • Overall median survival 16 months • Time to progression 8 months • Transient fatigue syndrome and • Survival: 17 months Child A; 8 months Child B abldominal pain • Fatigue, pain, nausea, elevated LFTs (all 20-50%)
  36. 36.  8-center study of 325 patients with unresectable intermediate or advanced HCC • 82% Child A, 18% Child B • 24% solitary, 76% multifocal • 9% extrahepatic metastases • 14% branch PV occlusion, 10% main Overall median survival 12.8 months Predictors of poor survival: • ECOG status • >5 nodules • INR >1.2 • Extrahepatic disease
  37. 37.  Y90 expected to be better tolerated than TACE in patients with PV invasion • Y-90 is less embolic; therefore less risk of hepatic infarction • Median overall survival 7-10 months  4 months in main PV invasion • Mostly grade 1 and 2 toxicities  Abdominal pain (38%)  Nausea (28%)  Fatigue (22%)  Ascites (13%)  Encephalopathy (13%) Y90 is safe and shows tumor response in patients with branch or lobar PV invasion.
  38. 38. Resection vs. TACEResection vs. ablation Ablation vs. TACE TACE vs. Y90
  39. 39.  185 patients with resectable early-  419 patients with resectable HCC stage HCC and Child A cirrhosis • 46 had TACE • 73 had superselective TACE • 311 had resection • 112 had resection • 62 refused treatment (supportive care) 5-year survival  5-year survival • TACE: 52% (ns) • TACE: 34% (ns) • Resection: 57% (ns) • Resection: 43% (ns) • Supportive care: 7% (p = 0.0001)
  40. 40.  3225 patients with HCC  87 patients with resectable HCC retrospectively grouped by clinical • 20 had TACE prognosis and tumor burden • 67 had resection Compensated patients with 3 or fewer  5-year survival tumors, any size • TACE: 18% • Surgery: 45-55% 5-year survival • Resection: 55% (p<0.05) • TACE: 17-20% 5-year survival
  41. 41.  115 RFA vs. 115 surgery  180 patients with solitary HCC <5 cm • HCC within Milan criteria • Half had HCC <3 cm, half had HCC 3-5 cm Survival at 5 years:  Survival at 4 years: • RFA 55% • RFA 68% • Surgery 76% (p<0.05) • Surgery 64%  DFS at 4 years: DFS at 5 years: • RFA 46% • RFA 29% • Surgery 52% • Surgery 51% (p<0.05)  RFA had fewer adverse events (55% vs 4%) RFA had fewer adverse events (32 vs. 5)
  42. 42.  5317 American patients with HCC 7185 patients with HCC (3 tumors up to 3 • Median tumor size 6 cm cm) and Child A/B liver function • 52% solitary; 28% multiple; 20% extrahepatic • 30-day mortality was 8% resection; 3% OLT; 3% 3022 RFA patients ablation; 31% no or incomplete local therapy • 55% tumor recurrence in 2 years • 5-year survival 67% OLT; 35% resection; 20% ablation; • 1.6% death rate at median 10 months 3% no or incomplete local therapy 2857 resection patients  Prognostic factors • 35% tumor recurrence in 2 years • Disease extent • 1.9% death rate at median 10 months • Tumor grade • Tumor size Relative risk or recurrence was 0.62 in • Vascular invasion resection group; no difference in survival • Age  Selection bias is likely
  43. 43.  91 patients with unresectable HCC (up to 3 nodules, each up to 5 cm)  258 patients with hypervascular HCC (1 nodule 40 TACE patients <5 cm or up to 3 nodules <3 cm) • Mean 6 sessions • 58% survival at 2 years • Mean tumor size 1.7 cm in both groups • TACE group had more multifocal tumors, more 51 RFA patients peripheral tumors, more previously treated tumors • Mean 1 session • 72% survival at 2 years (ns)  133 TACE patients Morbidity higher for RFA (28% vs. 10%) • Local recurrence 51% at 2 years No treatment-related mortality  105 RFA patients Similar time to progression • Local recurrence 40% at 2 years (p<0.05)
  44. 44.  790 patients with unresectable intermediate-stage HCC +/- PVT 245 comparable patients with unresectable intermediate-stage  99 had TheraSphere Y-90 vs. 691 had HCC and no PVT repetitive cTACE • Overall median survival 11.5 vs. 8.5 months 123 underwent TheraSphere Y-90 (p<0.05) vs. 122 had TACE • But, TACE group had more severe liver disease • 72% vs. 69% response rate (ns) • No difference in survival after controlling for • Time to progression 13 vs. 8 months underlying disease (p=.046) • Y-90 (outpatient, 1 or 2 treatments) is compelling • Overall median survival 20 vs. 17 months as a palliative treatment option compared to (ns) TACE (inpatient stay, multiple treatments) • Less abdominal pain and LFT increase with Y90
  45. 45.  73 comparable patients with unresectable HCC, ~35% with vascular invasion • Segmental PV occlusion could have TACE or Y90 • Extensive PV occlusion favored Y90 38 underwent TheraSphere Y-90 vs. 35 had TACE • 7 Y90 patients and 2 TACE patients crossed over • Median survival 8.0 vs. 10.3 months (ns) • Mean total hospitalization (initial + re-hospitalization) days 0.5 vs. 3.5 (p<0.001) • Complication rate higher for TACE, mostly due to more severe PES
  46. 46. TACE + ablationTACE + sorafenib
  47. 47.  37 patients with solitary HCC 3.1-5.0 cm  89 patients with 93 HCC <3 cm • TACE-RFA same day vs. RFA alone • TACE then RFA 1 week later vs. RFA • Slightly larger ablation size with TACE-RFA alone (5.0 vs. 4.1 cm) • Local tumor progression 18% vs. 14% at 4 • Local tumor progression 6% vs. 39% at 3 years (ns) years (p=.012) • Overall survival 73% vs. 74% at 4 years • Overall survival 93% vs. 80% (ns) (ns) • Rate of major complications ~1% for both • Rate of major complications ~2% in both groups groups
  48. 48. What have we learned?
  49. 49.  Interventional radiology plays a key role (maybe the key role!) in liver cancer treatment • Percutaneous ablation • Early HCC • TACE • • Preserved liver function: Resection or ablation Compromised liver function: Transplantation • Bridge to transplant with ablation or TACE • Y-90 • Intermediate HCC: • Preserved liver function: TACE, Y90 and/or ablation • Portal vein embolization • Downstage to transplant if possible • Compromised liver function: Supportive care • Consider extended criteria OLT or LDLT • Downstaging to transplant • Advanced HCC: • Bridging to transplant • • Preserved liver function: Sorafenib or Y90 Compromised liver function: Supportive care • Percutaneous biopsy • Transjugular pressure measurements • Salvaging operative mishaps
  50. 50. TS 65 y/o female Hepatitis B cirrhosis Routine screening US and CT demonstrated two adjacent 4-cm HCCs Not a surgical candidate TACE 1/26/2010: 75 mg doxorubicin on LC beads Outside Milan criteria for OLTReferred for locoregional therapy and possible down-staging
  51. 51. MRI 2/25/2010: No residual tumor.Patient downstaged, exception points awarded for OLT TACE #2 6/8/2010 22.5 mg doxorubicin on LC beads to R hepatic Awaiting OLT artery CT 4/24/2010: Intrahepatic recurrence
  52. 52. TACE #3 11/18/2010 75 mg doxorubicin on LC beads to R phrenic and R hepatic arteries MRI 10/25/2010:Intrahepatic recurrence
  53. 53. MRI 12/20/2010: Minimal residual tumorSuccessful OLT 1/22/2011 (1 year after first intervention) Now almost 1 year s/p OLT, doing well without recurrence
  54. 54. YO 58 y/o male Hepatitis B and C and HIV Abdominal pain prompted CT 7 cm biopsy-proven HCCNot a surgical or transplant candidate Referred for locoregional therapy
  55. 55. MRI 1 month later –100 mg doxorubicin on mass mostly LC beads devascularized
  56. 56. Follow-up MRI – Percutaneous complete necrosis, nomicrowave ablation recurrence at 4 mos
  57. 57. TG 39 y/o female Fibrolamellar HCC diagnosed in 2001Left lobe resection of 9 x 11 cm mass in 2001 Recurrence 2007 with partial right lobe resection CT 4/9/2010: At leastPresents with multifocal recurrence 2/2010 10 hypervascular liver masses Not a surgical or transplant candidate Presented at tumor board and referred for locoregional therapy
  58. 58. TACE 5/3/2010 100 mg doxorubicin on LC beads 2 weeks later, returns with fevers, RUQ pain
  59. 59. CT 5/19/2010: near- complete tumor necrosis Prolonged CT 8/6/2010: Biloma Percutaneous biloma catheter resolved, but drainage drainage intrahepatic recurrence and new lung nodule. To study drug
  60. 60. August 2009 –present 100 patients with HCC referred for locoregional treatment 3 contraindicated for treatment (bilirubin too high, extrehepatic disease, hepatofugal flow) 3 insurance denials 13 did not receive 2 decided against treatment 1 awaiting treatment locoregional treatment 1 direct to OLT 87 patients treated 1 referred for surgery 1 referred for Y-90 152 total procedures, mean 10 mo 1 died prior to treatment follow-up 19 patients treated 66 patients treated 2 patients had initially with RFA initially with TACE combo TACE/RFA 2 free of disease12 2 2 3 8 15 7 10 18 8Alive, disease Alive, brid Alive, with Dead Alive, dise Down- Alive, und Alive, brid Progressive Awaiting-free ged to recurrence ase-free staged er ged to OLT disease follow up OLT treatment 1 TACE 1 ALL 1 trial drug 1 asp PNA 1 OLT 2 13 4 6 8 rejection Surgery RFA Extrahepatic Intrahepatic Dead progression progression 1 awaiting 7 1 Nexavar 3 Y-90 7 liver cancer surgery alive, diseas 3 Unknown 3 Nexavar 1 unknown 1 e-free cause alive, diseas 1 alive, OLT e-free 2 dead 3 alive with recurrence
  61. 61. Liver transplantation Indications and outcomes MELD Downstaging BridgingSurgical resectionPercutaneous ablationTransarterial chemoembolizationYttrium-90 radioembolizationSystemic chemotherapy
  62. 62.  Treatment with TACE or RFA can downstage tumors into Milan criteria UCSF criteria for downstaging • One lesion 5-8 cm • 2-3 lesions up to 5 cm, total tumor diameter up to 8 cm • 4-5 lesions up to 3 cm, total tumor diameter up to 8 cm 3 months after tumor is downstaged, exception points for OLT are granted • “Ablate and wait” crudely assesses tumor biology Yao FY, Kerlan RK, Jr, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis Hepatology 2008
  63. 63.  Patients with tumors exceeding Milan do well with transplant after downstaging • Success of downstaging 24-90% • If downstaging is successful, post-transplant 5-year survival 55-94% Successful downstaging selects less aggressive tumors • Able to be downstaged • Remains downstaged over a waiting period of 3-6 months • Infiltrative tumors and high AFP predict downstage failure Eligibility for downstaging is unclear • Only tumors slightly beyond Milan? • Any tumor without major vessel invasion or extrahepatic disease? Barakat O, et al. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to- treat analysis. Liver Transplantation 2010;16:289-299.
  64. 64.  Systematic review of downstaging for HCC beyond Milan criteria 8 studies, 720 patients Successful downstaging 24-69% 3-year survival 79-100% 5-year survival Barakat O, et al. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to- treat analysis. Liver Transplantation 2010;16:289-299.
  65. 65.  “Downstaging with a subsequent interval of observation to assess biologic aggressiveness should be considered for patients beyond Milan criteria. Downstaged patients should be considered for MELD exception points.” Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  66. 66.  Natural history of patients with HCC within Milan criteria, at 1 year • 70% will have tumor growth • 20% will develop vascular invasion • 9% will develop metastases Risk of drop-out is up to: • 11% at 6 months • 57% at 12 months • 75% at 18 months Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  67. 67.  87 patients listed for OLT  52 patients listed for OLT • 43 non-TACE and 22 TACE • Bridged with RFA patients were comparable • Complete tumor necrosis in 85% • TACE group had drop-off rate of • Drop-off rate of 6% at 1 year 3% • Post-OLT survival of 76% at 3 • Non-TACE group had drop-off years, no HCC recurrence rate of 15%
  68. 68.  “Bridgingtherapy with TACE and RFA have low morbidity, favorable HCC response, and probably reduce drop-out for patients with wait times >6 months” Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  69. 69.  “OLT is the preferred treatment for patients with cirrhosis and HCC meeting Milan criteria” “OLTshould be considered on a highly selective basis for patients beyond Milan but within UCSF criteria” Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  70. 70. Liver transplantationSurgical resection Indications and outcomes Portal vein embolizationPercutaneous ablationTransarterial chemoembolizationYttrium-90 radioembolizationSystemic chemotherapy
  71. 71.  Standard treatment for resectable HCC in patients without cirrhosis Only~5% of HCC patients in the Western world qualify Perioperative mortality rates • Cirrhotic liver: 7-25% • Non-cirrhotic liver: <3% Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  72. 72.  Advantages • No restrictions on tumor size or number (within a lobe) • Macrovascular invasion acceptable • No obligatory waiting time • Allows complete pathologic evaluation Disadvantages • Only feasible in non-cirrhotic or mildly cirrhotic livers without portal hypertension • Precancerous cirrhotic liver remains • Perioperative mortality about 5% • Significant post-operative morbidity Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
  73. 73.  Overall 5-year survival for hepatic resection in HCC is 25-50% • If solitary tumor and non-cirrhotic liver, 5-year survival is 41-74% • If HCC is multifocal or has vascular invasion, 5-year survival is <25% Liver function and portal hypertension are important predictors of post-operative liver failure and 5-year survival • Normal serum bilirubin and no portal HTN: 70% • Normal serum bilirubin and portal HTN: 50% • Elevated serum bilirubin and portal HTN: 30% Post-resection recurrence rates are high • 70% at 5 years • >80% intrahepatic; usually due to dissemination from primary tumor • Associated with high AFP, larger/more numerous tumors, and vascular invasion Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111(4):1018–22..
  74. 74.  Liver resection is often limited due to inadequate volume of the future liver remnant • Normal patients can survive if 20% of liver volume remains • Post-chemotherapy patients need 30% of liver • Patients with fibrosis/early cirrhosis need 40% of liver Portal vein embolization can pre-operatively enlarge the future liver remnant • Redirection of nutrient-rich portal vein blood enlarges the FLR • May enable resection in patients who would otherwise not be candidates De Baere T, et al. Preoperative portal vein embolization: indications and technical considerations. Tech Vasc Interv Radiol 2007;10:67-78. Memorial Sloan-Kettering Cancer Center. “Portal vein embolization.” Patient brochure, 2005.
  75. 75.  Technical considerations • Access ipsilateral (into tumor bearing lobe) • 5F sheath and pigtail portogram; consider pressures • Kumpe catheter and microcatheter for segment IV (if needed) • Simmons-2 or Sos-2 catheter for right portal branches • 100-700 micron Embospheres followed by coils; or NBCA • Final portogram • Embolize access tract with coils or gelfoam  Results at 4 weeks post-PVE • 53-90% hypertrophy of FLR in normal liver • 28-42% hypertrophy of FLR in cirrhotic liver  Complications • Well-tolerated • Occasional transient liver insufficiency in cirrhotics • Poor technique can occlude entire PV • If tumor is present in FLR, its growth may be more rapidMadoff D, et al. Portal vein embolization with polyvinyl alcohol particles and coils in preparation for major liver resection forhepatobiliary malignancy: safety and effectiveness- study in 26 patients. Radiology 2003;227:251-260.De Baere T, et al. Preoperative portal vein embolization: indications and technical considerations. Tech Vasc Interv Radiol2007;10:67-78.
  76. 76.  “Resection with wide margins is the treatment of choice for HCC in patients without cirrhosis” “Resection is acceptable for cirrhotic patients (Childs A without portal hypertension) with single HCC, regardless of size.” “Highly selected patients with multifocal HCC or major vascular invasion may be resected, but recurrence rates are high.” Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

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