Locoregional Treatments for HCC Applications in Transplant Candidates Matthew Casey, MD March 31, 2016 Locoregional Treatments for HCC Applications in Transplant Candidates *No disclosures *Off-label uses of agents discussed Why discuss LRT at a transplant conference? Goals of LRT Patients in need of a liver transplant tend to be patients who develop HCC Patients with HCC infrequently good candidates for surgical resection Best chance for cure of unresectable HCC is liver transplant But, wait for an organ can be long and patients run the risk of HCC progressing beyond Milan criteria, hence dropping out LRT can bridge a patient to organ availability Preserve liver transplant candidates with HCC within Milan criteria Milan criteria - no extra-hepatic tumor, single tumor <5cm or </= 3 tumors <3cm Extend survival of patients with HCC even if disease has progressed beyond Milan criteria Downstage HCC to get within Milan Locoregional Therapies for HCC Patients receiving LRT Locoregional Therapies (LRT) consist of percutaneous and trans-arterial treatments LRT may be curative and/or palliative May be used to maintain transplant eligibility in patients with HCC BCLS staging system of HCC Bruit, J Sherman, M Management of Hepatocellular Carcinoma. Hepatology 2005; 42:1208-1236 1
Thermal Ablation Radio frequency (RF) Cryoablation Microwave Electroporation Percutaneous Ethanol Injection (PEI) Generally reserved for 3 or fewer tumors Typically tumors are <3cm in size Tumors must be safely accessible percutaneously Ablation feasibility and success influenced by adjacent structures (e.g. heat sink from large vessels or potential for damage to unintended target) Percutaneous ethanol injection (PEI) Effective in small tumors Less concern about adjacent organs or heat sink Usually requires multiple treatments Largely supplanted by thermal techniques in the US Radiofrequency (RF) ablation Complete ablation of small to medium sized tumors in a single session in 80% and >90% in 2 sessions* 5 year survival 40-58% compared to overall 5 year survival for HCC in Europe and US of <10%* Limited by heat sink effect of adjacent vessels, inability to achieve lethal temperature in large tumors Risks include hemorrhage, bile duct injury, abscess, adjacent organ or intestinal damage, tumor tract seeding *McWilliams, et al JVIR 2010; 21:s204-s213 Microwave (MW) ablation Similar to RF in that heat is used to induce coagulation necrosis Shorter treatment time Less heat sink effect Overall results and complications similar to RF* *McWilliams, et al JVIR 2010; 21:s204-s213 2
Cryoablation Uses cyclical application of low temperatures Requires less anesthetic Less frequently deployed in liver because it usually requires more, and larger, probes than RF or MW So far, cryoablation has been less effective and more prone to complications* New/experimental MR guided High intensity focused ultrasound (HiFU) Irreversible electroporation (IE) *McWilliams, et al JVIR 2010; 21:s204-s213 Bland embolization Conventional chemoembolization (TACE) Drug-eluting bead chemoembolization (DEB- TACE) Principles of trans-arterial treatment of HCC most tumors in the liver are supplied by primarily by branches of the proper hepatic artery while normal liver is primarily supplied by branches of the portal vein agents delivered to the liver via branches of the proper hepatic artery are relatively concentrated in tumors with relative sparing of the normal hepatic parenchyma Bland embolization Introduction of small particles into branches of the proper hepatic artery (lobar or superselective) with intent to induce ischemic necrosis of tumors 3
Trans-arterial chemo-embolization (TACE) Introduction of chemotherapy drug(s) via branches of the proper hepatic artery (lobar or superselective) for treatment of liver tumors Embolic particles are injected after the chemotherapeutic drugs *There is no FDA approved drug regimen for TACE despite relatively long experience with this procedure and most drugs used for TACE have recently been removed from the market. This disruption in supply has removed conventional TACE as an option for treatment locally. Chemo-embolization with Drug Eluting Beads (DEB-TACE) Chemotherapy drug loaded into specially designed embolic particles. Drug slowly eluted from particles after injection. Relatively new. Protocols are evolving. Most commonly used TACE drug (doxorubicin) can be used in DEB-TACE Advantages over TACE include less systemic effects of chemotherapeutic agent (less nausea and malaise) and greater intra-tumoral concentration of chemotherapeutic agent Not yet proven to offer survival benefit over TACE but presumed to be at least equivalent Untreated HCC survival Survival data for TACE 32% survival at 6 months* Median survival 1.6 months (8.3 months for Okuda stage 1) Survival benefits of TACE well demonstrated in case control and retrospective studies compared to untreated patients Survival rates after TACE of 64%, 38%, 27% and 27% at 1, 2, 3, and 4 years respectively* Compared to 18%, 6%, and 5% at 1, 2, and 3 years for untreated, case-control patients *Okuda, et al. Cancer 1985; 56:918-928 *Bronowicki, et al. Cancer 1994; 74:16-24 Survival data for TACE DEB-TACE survival Few attempts at true RCT of TACE. Many flawed attempts failed to show benefit of TACE* Median survival of 54.2 months for BCLC-A and 47.7 months for BCLC-B* *Ramsey, et al. JVIR 2002; 13:s211-s221 *Burrel, et al. Hepatology 2012: 56:1330-5 4
(aka selective internal radiation therapy) Introduction of radiation emitting embolic particles into branches of the proper hepatic artery (lobar or superselective) Yttrium-90 (a beta emitter) can be loaded onto embolic particles. Emitted radiation travels up to 11 mm and delivers radiation for approximately 2 weeks (half life is 64 hours) DEB TACE v. Y-90 embolization for HCC is hotly debated within IR. Two companies produce Y-90 loaded particles and insurance coverage is variable (total treatment costs >$100k) First Y-90 case in South Dakota 69 year old previously healthy patient with vague abdominal pain found to have large tumor in liver. Biopsy proven to be HCC (not the typical path to diagnosis but patient was not cirrhotic). 7/30/2010 After first round of chemo-embolization 10/8/2010 After 3 rounds of chemo-embolization 12/31/2011 Still not transplant candidate Post bilobar radio-embolization 4/18/2014 5
Patient alive 3/31/2016 at age 74, nearly 6 years after diagnosis TACE achieved objective response, Y-90 made patient transplant candidate, transplant provided cure Post transplant 12/2/2014 Y-90 survival data Median survival after SIRT for HCC* 24.4 months for BCLC-A 16.9 months for BCLC-B 10.0 months for BCLC-C *Sangro, et al. Hepatology 2011; 54: 868-878 SIRT v. TACE From abstract to be presented by Northwestern group at SIR 2016 this week* 43 patients (BCLC A/B, Child-Pugh A/B) randomized to ctace v. glass Y-90 SIRT resulted in significantly longer TTP (not reached v. 6.4 months) Trend towards survival benefit SIRT resulted in lower dropout from transplant listing (13/18 v. 6/15) *Gordon, et al. JVIR 2016; 27: s61-s62 LRT increases the likelihood of transplant, specifically for patients with long wait times* LRT is successful in keeping patients on the wait list* In a retrospective study, median survival within Milan criteria was 644 days for patients receiving LRT and 162 days for patients receiving supportive care (survival follow-up truncated at death, exceeding Milan, transplant or study end) *Sheth, et al. JVIR 2015; 26:1761-1768 Dhaneskaran, et al JVIR 2010; 21:1197-1204 6
In patients not receiving transplant, median survival is 502 days with LRT, 151 days without Dhaneskaran, et al JVIR 2010; 21:1197-1204 7