TREATMENT FOR HCC AND CHOLANGIOCARCINOMA. Shawn Pelletier, MD

TREATMENT FOR HCC AND CHOLANGIOCARCINOMA Shawn Pelletier, MD

Treatment for HCC Treatment strategies Curative first line therapy Thermal ablation vs Resection vs Transplant Other first line therapies TACE vs TARE (Y90) vs ablation Downstaging

Early HCC 4.7 cm 2.3 cm/1.2 cm

Barcelona Clinic Liver Cancer Staging Classification (BCLC) Stage 0 PST 0, Child-Pugh A Stage A-C Okuda 1-2, PST 0-2, Child-Pugh A-B Stage D Okuda 3, PST >2, Child-Pugh C Very early stage (0) Single <2 cm Carcinoma in situ Early stage (A) Single or 3 nodules <3 cm, PST 0 Intermediate stage (B) Multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1 2 Terminal stage (D) Single Portal pressure/bilirubin Increased 3 nodules <3 cm Associated diseases Portal invasion, N1, M1 Normal No Yes Resection Liver transplantation (CLT/LDLT) Curative treatments 50%-75% at 5 years PEI/RFA Chemoembolism Nexavar Randomized controlled trials 40%-50% at 3 years vs 10% at 3 years Supportive Care > 6 months CLT/LDLT=cadaveric liver transplantation/living donor liver transplantation; PST=Performance Status Test. Llovet JM et al. Lancet. 2003;362:1907-1917.

National Volumes of Inpatient Surgical Procedures Ltxp AAPC 20.9% Ablation AAPC 17.3% Wedge resection AAPC10.8% Hepatectomy AAPC 5.6% *Average Annual Percent Change Nathan et al. Cancer 2012 Apr 1;118(7):1838-44

RFA Other modalities Ablation Microwave, laser, HiFU, Cryo, irreversible electroporation, PEI Preponderance of the literature on RFA RFA major complications 6% Pain, seeding, abscess, intestinal perforation, pleural effusion, and bleeding (Kong World J Gastroenterol 2009, Livraghi Radiology 2003, Lin Gastroenterology 2004) RFA mortality 0.3% (Kong World J Gastroenterol 2009, Giorgio AJR 2005, Zhao Eur J Radiol 2012)

Efficacy of RFA >80% CR for tumors <3cm ~50% CR for tumors 3-5cm 5 yr survival rates of 40-70% Llovet J Hepatol 2008 Orlando Am J Gastroenterol 2009 Bouza BMC Gastroenterol 2009

RFA for Very Early Stage HCC Author N 1-yr 3-yr 5-yr Lencioni Child A 144 100 76 51 Child B 43 89 46 31 Tateishi Child A 221 96 83 63 Child B 98 90 65 31 Choi Child A 359 NA 78 64 Child B 160 NA 49 38 Lencioni R, et al. Radiology 2005;234:961 Tateishi R, et al. Cancer 2005;103:1201 Choi D, et al. Eur Radiol 2007;17:684

Probability (%) Survival of HCC after Resection 100 80 No portal hypertension, normal bilirubin 60 40 portal hypertension, normal bilirubin 20 0 Log Rank p=0.00001 portal hypertension, bilirubin > 1 0 12 24 36 48 60 72 84 96 Llovet et al, Hepatology 1999;30:1434 Months

Resection of Large HCC

Lap vs. Open

Resection vs RFA Resection In hospital mortality 2.6% Complications 14.5% RFA In hospital mortality 0.3% Complications 4.5% Mortality risk factors Older age Extended lobectomy Low hospital volume Renal comorbidity Mortality risk factors Older age Cardiac comorbidity Sato, Journal Gastroenterology 2012; national survey of 54,145 patients

RCT RFA vs Resection: Overall Survival RFA = 81 (residual tumor n=8) Resection = 83 (residual tumor n=1) All were Child Class A or B HCC <2 tumors < 4 cm diameter p=0.34 Feng J Hepatol 2012

RCT RFA vs Resection: Disease Free Survival p=0.12 Feng J Hepatol 2012

Multifocal HCC Overall Survival of Pts with 2 HCC 77.0% 47.5% p=0.02 Feng J Hepatol 2012

Liver Transplantation for Early Stage HCC 48 patients with unresectable HCC but < 5 cm Milan Criteria: Single lesion < 5 cm < 3 lesions < 3 cm Actuarial survival at 4 yrs 75% 8% recurred Mazzafero V, et al NEJM 1996; 334:693

Survival from Listing (%) Intention to Treat: Survival for Liver Transplantation 100 80 4-yr surv 66% P<0.0001 60 40 Within Milan Exceed Milan 20 Patients at risk 0 20 40 60 80 100 Time (months) 2790 2092 1618 1311 1199 346 169 140 55 55 Pelletier S, et al. Liver Transpl. 2009 Aug;15(8):859-68.

Post Transplant Survival of LRT vs. No LRT * p=0.03 Freeman RB, et al. Am J Transplant 2008; 8(4 Pt 2):958-76.

Limitations of Liver Transplantation Shortage of liver grafts Stringent patient selection criteria, HCC <2cm constitutes a low MELD score / least priority to receive a graft before the disease progresses Stage II HCC and Child Class A cirrhosis Very low survival benefit 6 mos waiting for exception or LDLT 10% mortality

Survival Benefit of Ltxp: HCC in Child s A Cirrhosis 3-yr 5-yr Post-Ltxp Lifetime (mos) 31.6 49.4 Post-Resection Lifetime (mos) 30.9 46.6 Post-RFA Lifetime (mos) 30.1 43.7 Benefit of Ltxp over resection (mos) Benefit of RFA over resection (mos) 0.7 2.8 1.5 5.7 Berry Am J Transplant 2012

Surgical Treatment of HCC in North America: Can Hepatic Resection Still Be Justified? Chapman et al. J Am Coll Surg, 2015

Surgical Treatment of HCC in North America: Can Hepatic Resection Still Be Justified? Chapman et al. J Am Coll Surg, 2015

Downstaging of HCC

Downstaging: TACE vs Y90 Lewandoski et al. AJT 2009

Ann Surg 2018

Cholangiocarcinoma Univ. of Michigan experience 2003-2008 N=136 Singal et al. Alim Pharmacol Ther 2010

Hilar Cholangiocarcinoma (CCA) 1-2 per 100,000 in the U.S. >50% of patients greater age 65 Majority extrahepatic CCA at the hilum Risk factors: PSC, choledochal cysts, hepatolithiasis, Clonorchis, Opisthorchis, other chemicals/toxins? PSC: 8 20 % incidence Greenlee et al, CA Cancer J Clin, 2001 Broome et al, Gut, 1996 Nashan et al, Hepatology, 1996

Hilar Cholangiocarcinoma (CCA)

Bismuth Classification

Resection of Hilar CCA Hepatic Lobectomy and caudate resection, portal lymphadenectomy, bile duct resection Vascular resection 11-35% R0 achievable in 76-80% Mortality 9-10% Complications ~40%

Resection Outcomes LN-, R0 patient survival 85% at 5 years (median not reached) Rocha et al, J Hepatobiliary Pancreat Surg, 2009

Patient Survival % Cholangiocarcinoma Cincinnati Transplant Tumor Registry 207 patients, 1968-1997 100 80 60 40 20 0 0 1 2 3 4 5 Year Transplantation 2000; 69:1633

Neoadjuvant Chemoradiotherapy Univ. Pitt. 9 pts 65% 5 yr survival Univ. of Neb.* 11 pts 45% 3 yr survival *1987-2003 Mayo Clinic 65 pts 76% 5 yr survival Patients with LN negative disease (assessed by laparotomy) tumors less than 3 cm

Exclusion Criteria Intrahepatic cholangiocarcinoma Uncontrolled infection Prior radiation or chemotherapy Prior biliary resection or attempted resection Intrahepatic metastases Evidence of extrahepatic disease History of other malignancy within 5 years Transperitoneal biopsy (including EUS) Radial diameter > 3cm

Bx of the Primary Tumor Should NOT Be Done Heimbach et al. HPB 2011

Murad et al. Gastroent 2012

Risk of Dropping Out Prior to OLT Murad et al. Gastroent 2012

Survival after Operation 100 92% % 80 60 40 82% 82% 82% 48% 20 Transplantation (n=38) Resection (n=26) 21% 0 0 1 2 3 4 5 Time (years) Ann Surg 2005; 242:451

University of Virginia Protocol 2 wks 2 wks 3 wks 4-6 wks < 3 mo.

Conclusions No definitive answer for best treatment of early HCC Multidisciplinary approach may be best Surgical resection may be 1 st option for compensated cirrhotics without PHTN / synthetic dysfunction Ablation effective for small tumors or centrally located Transplant associated with best disease free survival but has several limitations