Overall 5-year survival of HCC is about 10%With curative treatment, 5-year survival can exceed 50% 3
“OLT is the best available curative OLT treatment for HCC in cirrhotic livers”Potentially “Resection with wide margins is the curativetreatments Resection treatment of choice for HCC in patients without cirrhosis” for HCC 4 “Local ablation is safe and effective Ablation therapy for patients who cannot undergo resection” Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
Limited supply of organs Restrictive criteria OLT • • 1 tumor up to 5 cm; up to 3 tumors, each up to 3 cm No vascular invasion or extrahepatic spread 10-20% of HCC patients qualify Must be non-cirrhotic orPotentially minimally cirrhotic curative Need adequate volume oftreatments Resection future liver remnant <5% of HCC patients in for HCC Western world qualify 7 Size of ablation zone limits use to smaller tumors Ablation May be unsafe in hilar or exophytic tumors Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.
Overall 5-year survival of HCC is about 10%With curative treatment, 5-year survival can exceed 50% How do we achieve cure? 8
How do we make more patients eligible for curative therapy? 9
Transarterial therapiesRationale HCC takes its blood supply almost exclusively from the hepatic artery Surrounding normal liver has dual blood supply (with portal vein) Cytotoxic agent administered into hepatic artery can kill tumor while sparing normal liver
Transarterial chemoembolization Conventional TACE• Chemotherapy (doxorubicin or cisplatin) emulsified with ethiodized oil is admistered into tumor-bearing artery • Ethiodol acts as carrier agent to concentrate chemo into tumor • After chemo delivered, block supplying artery with gelfoam or particles• Proven to improve survival in HCC • Patient selection: ECOG 0-2, Child A or B, no extrahepatic spread • 40-50% response rate, mostly partial • Repeated treatments necessary 3-year survival:• Post-embolization syndrome 26-29% with TACE 3-17% with supportive care • Pain, nausea, low-grade fever, fatigue • 1-3 day hospitalization
Transarterial chemoembolization Drug-eluting beads• Similar to conventional TACE, but beads rather than oil carry the chemotherapy • Simultaneous chemotherapy and embolization • Slower elution = fewer systemic side effects• RCT of DEB-TACE vs. TACE • Tendency toward better response rate with DEB-TACE • Significant reduction in liver toxicity and side effects with DEB-TACE• Post-embolization syndrome still can be severe
Transarterial radioembolization Y90• Transarterial administration of radioactive microspheres (Yttrium-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• Nontarget embolization of bowel or lung can cause radiation damage • Prior to Y90 treatment, mesenteric mapping must be performed, with coil embolization of mesenteric branches arising from the liver circulation • Test dose of Tc-MAA used to measure shunt fraction to lungs• Similar indications and effectiveness to TACE • ECOG 0-2, Child A or B, preserved liver function • ~40% response rate, median survival 8-17 months• Less embolic than TACE • Less post-embolization syndrome • Outpatient therapy
Downstaging to transplantEligibility criteria Treatment with embolization or ablation 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
Downstaging to transplant Data and analysis Patients with tumors exceeding Milan do well with transplant after downstaging • In 8 studies totaling 720 patients Success of downstaging 24-69% If downstaging is successful, post-transplant 5-year survival 55-94% • Outcomes are comparable to non-downstaged patients within Milan Successful downstaging selects less aggressive tumors • Able to be downstaged • Remains downstaged over a waiting period of 3-6 months or more • 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.
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 Outside Milan criteria for OLT doxorubicin on LC beadsReferred for locoregional therapy and possible down-staging MRI 12/1/2009: 2 tumors, each 4 cm
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
TACE #3 11/18/2010 75 mg doxorubicin on LC beads to R phrenic and R hepatic arteries MRI 10/25/2010:Intrahepatic recurrence
MRI 12/20/2010: Minimal residual tumorSuccessful OLT 1/22/2011 (1 year after first intervention) Now almost 2 years s/p OLT, doing well without recurrence
August 2009 – present Mean age: 61 20 patients with HCC beyond 17 Child A, 3 Child B Milan referred for downstaging 10 ECOG 0, 10 ECOG 1 or 2 Mean # of tumors: 1.7 Mean size of largest tumor: 5.4 cm 49 total procedures 36 DEB-TACE, 9 RFA, 3 MWA, 1 cTACE 5 patients downstaged 5 patients downstaged 3 patients downstaged 5 patients could not be and transplanted and awaiting OLT then tumor recurrence downstaged 4 1 4 1 2 1 4 1 Alive, disease Alive, Alive, Alive, small Alive, off list Deceased Alive, off list OLT in free possible disease free residual China recurrence Complications (10%): Mean 399 days from 1st intervention to OLT Mean 359 days from 1st intervention 3 PES requiring re- admission. 2 liver insufficiency requiring admission.
OLT for HCCDownstaging: consensus statement “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.
Resection Limitations• Resection with wide margins is the treatment of choice for HCC in patients without cirrhosis • Also acceptable for mildly cirrhotic patients without portal hypertension • Any size HCC can be resected • Highly selected patients with multifocal HCC or vascular invasion may be resected, though recurrence rates are high• Liver resection is often limited due to inadequate volume of the future liver remnant • Normal patients need 20% of their liver volume to survive • Post-chemotherapy patients need 30% • Patients with fibrosis or early cirrhosis need 40%
Portal vein embolization PVE• Particles and coils are used to block off the portal vein branches supplying the lobe to be resected • Redirection of nutrient-rich portal vein blood enlarges the future liver remnant • May enable resection in patients who otherwise would not be candidates• Results at 4 weeks post-PVE • 53-90% hypertrophy of the FLR in non-cirrhotics • 28-42% hypertrophy of the FLR in cirrhotics• Considerations • Same-day procedure • Well-tolerated • Occasional transient liver insufficiency in cirrhotics • Tumor growth or spread may occur while waiting for hypertrophy to occur 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.
Pre-treatment: Left lobe volume 250 cc Sequential technique TACE and PVE• PVE alone may not provide sufficient hypertrophy of FLR, especially in patients with chronic liver disease • Compensatory increase in hepatic artery flow may blunt PVE response• Performing TACE prior to PVE may increase FLR hypertrophy as well as provide better tumor control• 71 patients with sequential TACE and PVE compared to 64 patients with PVE alone • 26% more hypertrophy with TACE and PVE • But, addition of TACE requires additional delay before surgery• May be useful in patients who need considerable increase in FLR volume Post TACE and PVE: Left lobe volume 751 cc Yoo H, et al. Sequential transcatheter arterial chemoembolization and portal vein embolization versus portal vein embolization only before major hepatectomy for patients with hepatocellular carcinoma. Ann Surg Oncol 2011:18;1251-1257.
Sequential technique PVE and HVE Pre-treatment: Left lobe volume 406 cc• PVE alone may not provide sufficient hypertrophy of FLR, especially in patients with chronic liver disease • Compensatory increase in hepatic artery flow may blunt PVE response• Performing HVE after PVE blocks liver outflow, reducing Post-PVE: Left lobe volume hepatic arterial inflow 591 cc• 16 patients had HVE after insufficient response to PVE • Further 10-15% hypertrophy of FLR was achieved • Well-tolerated Post PVE + HVE:• May be useful in patients who need additional increase in Left lobe volume 670 cc FLR volume after PVE Hwang S, et al. Sequential preoperative ipsilateral hepatic vein embolization after portal vein embolization to induce further liver regeneration in patients with hepatobiliary malignancy. Ann Surg 2009;249:608-616.
PH 49 y/o female NASH Incidental discovery of large liver mass during hematuria work-up Taken to OR and deemed unresectable due to cirrhosis and need for extended R hepatectomy Referred for locoregional therapy Pre-TACE: 11 cm HCC7/7/2010
PH 49 y/o female NASH Incidental discovery of large liver mass during hematuria work-up Taken to OR and deemed unresectable due to cirrhosis and need for extended R hepatectomy Referred for locoregional therapy Post-TACE #17/7/2010 9/27/2010
PH 49 y/o female NASH Incidental discovery of large liver mass during hematuria work-up Taken to OR and deemed unresectable due to cirrhosis and need for extended R hepatectomy Referred for locoregional therapy Post-TACE #27/7/2010 9/27/2010 12/20/2010
PH 49 y/o female NASH Incidental discovery of large liver mass during hematuria work-up Taken to OR and deemed unresectable due to cirrhosis and need for extended R hepatectomy Referred for locoregional therapy Post-TACE #3: 6 cm mass, mostly devascularized7/7/2010 9/27/2010 12/20/2010 3/2/2011
3/2/2011 6/17/2011 PH 49 y/o female NASH 5/3/2011 Incidental discovery of large liver mass during hematuria work-up Taken to OR and deemed unresectable due to cirrhosis and need for extended R hepatectomy PV embolization to hypertrophy left lateral segment Referred for locoregional therapy7/7/2010 9/27/2010 12/20/2010 3/2/2011
PH 49 y/o female NASH 1/9/2012Incidental discovery of large liver mass during hematuria work-upTaken to OR and deemed unresectable due to cirrhosis and need for extended R hepatectomy Referred for locoregional therapy To OR for extended R hepatectomy and intra-op RFA 7/22/2011 Now >1 year post-op without recurrence
August 2009 – present Mean age: 66 9 patients with potentially 9 Child A resectable HCC but inadequate 7 ECOG 0, 2 ECOG 1 or 2 3 solitary tumors, 6 multifocal future liver remnant 3 PV invasion Mean size of largest tumor: 8.4 cm 24 total procedures 9 DEB-TACE, 3 RFA, 1 MWA, 9 PVE, 1 HVE, 1 EtOH 4 patients downstaged 2 patients downstaged 1 patient downstaged but 2 patients could not be and resected and awaiting resection could not be resected downstaged 3 1 2 1 1 1 Alive, disease Alive, Alive, Alive, small Alive, lung Hospice free intrahepatic disease free residual mets care recurrence Complications (8%): 2 PES requiring re- admission
Thermal ablation RFA and MWA• Radiofrequency ablation • RF current induces thermal coagulation necrosis • Complete ablation rates >80% for small to medium HCC • Local recurrence uncommon (1-12%)• Microwave ablation • Field of electromagnetic energy causes thermal coagulation • Larger ablation zones, less heat sink than RFA• Thermal ablation techniques can provide local cure for small to medium HCC • TACE or Y90 can be used to shrink larger tumors, followed by definitive treatment with ablation • This can achieve local cure in patients who do not qualify for other curative therapies
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
MRI 1 month later – mass mostly100 mg doxorubicin on devascularized, some LC beads residual at superior margin
Percutaneous Follow-up MRI –microwave ablation complete necrosis, no recurrence at 4 mos
August 2009 – present Mean age: 67 68 patients with unresectable, 56 Child A, 12 Child B non-transplantable HCC 24 ECOG 0, 42 ECOG 1 or 2, 2 ECOG 3 35 with solitary tumor, 16 with 2-4 tumors, 17 multifocal Mean size of largest tumor: 4.9 cm 148 total procedures 94 DEB-TACE, 39 RFA, 7 MWA, 5 cTACE, 1 Y90, 1 EtOH 17 patients alive, 22 patients alive, with 6 patients alive, with 23 patients deceased tumor-free recurrent/residual tumor extrahepatic mets Mean 290 days from 1st intervention Mean 293 days from 1st intervention Mean 504 days from 1st intervention Mean 383 days from 1st intervention Complications (8%): 2 deaths (1 resp failure and 1 variceal bleed), 1 biloma requiring drainage, 1 hemothorax, 1 urinary retention requiring Foley, 1 resp failure requiring extended stay, 6 PES requiring extended stay or re-admission.
Hepatocellular carcinoma My approach• Establish the goal of treatment • In cirrhotics, try to bridge or downstage to transplant • In non-cirrhotics, try to downstage to resection • In patients who will not be surgical candidates, try to fully eliminate the disease with minimally invasive techniques • If disease elimination is not possible, strike a balance between extension of life and quality of life• Select the most appropriate treatment • Favor ablation: Small lesions (<3-4 cm), few lesions (<4) • Try to achieve “R0” ablation; ablate the lesion plus a 0.5-1.0 cm margin; microwave useful for achieving large ablation sizes • Hydrodissection, GPS technologies allow treatment of lesions in most locations • Favor TACE: Large lesions, multiple lesions, exophytic or hilar lesions, can’t tolerate anesthesia • Use DEB-TACE, small particles, superselective treatment and achieve complete stasis whenever possible • Favor Y-90: Widespread multifocal disease, main portal vein invasion, poor response to TACE• Close follow-up and communication with the patient and oncologist • Monitor effectiveness and tolerance of treatment and arrange re-treatment if needed • Consider alternative therapies
Things I’ve learned HCC patients are often my favorite patientsAblation, when feasible, can produce complete and durable tumor control; this is harder to achieve with TACE aloneWidely multifocal HCC, infiltrative HCC, and HCC with portal vein invasion are difficult to control by any means Both ablation and TACE are effective at bridging to OLT Close follow-up and a flexible, individually tailored treatment regimen can improve survival in HCC Best results are achieved with a team effort!
August 2009 – present Mean age: 59 34 patients with HCC within Milan 18 Child A, 16 Child B referred for bridge to OLT 25 ECOG 0, 9 ECOG 1 or 2 Mean # of tumors: 1.1 Mean size of largest tumor: 3.3 cm 57 total procedures 22 DEB-TACE, 27 RFA, 4 MWA, 1 cTACE, 3 EtOH 16 patients bridged and 12 patients bridged and 6 patients bridged but transplanted awaiting OLT later removed from list 13 1 2 12 2 3 1Alive, disease Alive, Deceased Alive, Died on list Tumor Clinical Complications (7%): free possible (graft disease free (liver failure, recurrence decompens recurrence failure) variceal or spread 1 death from liver ation bleed) failure. 1 bleed Mean 275 days from 1st intervention to list removal requiring Mean 311 days from 1st intervention to OLT Mean 262 days from 1st intervention embolization. 1 PTX requiring drainage. 1 PES requiring admission.
Downstaging to transplant Personal experience 20 patients referred for attempt at downstaging prior to OLT • 11 solitary, mean tumor size 6.1 cm • 9 multifocal, mean size of largest tumor 4.5 cm • 17 Child A, 3 Child B • 10 ECOG 0, 10 ECOG 1 Total 49 procedures performed (mean 2.5 procedures/patient) • 36 DEB-TACE • 9 RFA • 3 MWA • 1 cTACE No procedural complications, 5 post-procedure complications (~10%) • Pain requiring ER visit • Fever, fatigue, hyponatremia – 3 day hospital stay • Pain – 3 day hospital stay • Urinary retention and confusion – 4 day hospital stay • Hyponatremia and liver insufficiency – 10 day hospital stay 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.