Hepatocellular Carcinoma (HCC): What Treatment Modality for Which Tumor?

Transcription

1 K. Rajender Reddy, MD, CG Hepatocellular Carcinoma (HCC): What Treatment Modality for Which Tumor? K. Rajender Reddy, MD, CG Ruimy Family President s Distinguished Professor of Medicine Director of Hepatology Director, Viral Hepatitis Center Medical Director, Liver Transplantation University of Pennsylvania HCC Is Not One Disease Cancer with underlying liver disease(s) Clinically and physiologically diverse cancer Physiological staging Anatomical staging Molecularly diverse cancer Gene sequencing Cellular biomarkers Distinct molecular subtypes have begun to be identified. Molecular drivers are still expanding Angiogenesis is a validated target in HCC Finn RS. Clin Cancer Res. 2010;16: Page 1 of 16

2 K. Rajender Reddy, MD, CG Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach Hepatobiliary Surgery Hepatology Oncology Pathology Radiology Liver Transplant Program Current Treatment Options for HCC Surgical Non-surgical Hepatic Resection Liver Transplantation Transarterial Chemoembolization (TACE) Intra-arterial Radioembolization With Yttrium-90 Ablation Therapy Chemotherapy Gene Therapy Page 2 of 16

3 K. Rajender Reddy, MD, CG Barcelona Clinic Liver Cancer Staging (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) Single >5 cm or multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1 2 Terminal stage (D) Single 3 nodules <3 cm Portal pressure / bilirubin Increased Associated diseases Portal invasion, N1, M1 Normal No Yes Resection Liver transplantation (CLT/LDLT) PEI/R Chemoembolism Targeted Rx Symptomatic treatment Curative treatments 50%-7 at 5 yrs Randomized controlled trials 40%-50% at 3 yrs vs 10% at 3 yrs Survival < 3 mo Llovet JM, et al. Lancet. 2003;362:1907 Hepatic Resection Patients deemed resectable and unresectable at diagnosis 70% Unresectable 30% Resectable 5-10 % resectable in the US Adapted from Colombo M, Sangiovanni A. Antiviral Res. 2003;60: Page 3 of 16

4 K. Rajender Reddy, MD, CG Survival After Surgical Resection for HCC Llovet JM et al. Hepatology. 1999;30: Resection versus Transplantation: Issues and Controversies RESECTION VORABLE CTORS readily available compensated cirrhosis without significant portal hypertension NEGATIVE CTORS high rate of recurrence of HCC good survival up to 3 years TRANSPLANTATION VORABLE CTORS Curative in early stage advanced cirrhosis NEGATIVE CTORS shortage of donor livers drop-out while awaiting transplantation higher post-operative mortality; significant morbidity from recurrent hepatitis C-thing of the past fortunately Page 4 of 16

5 K. Rajender Reddy, MD, CG Liver Transplant for HCC in Cirrhosis Milan Criteria Single, not >5 cm Up to 3, none >3 cm + Absence of macroscopic vascular invasion Absence of extrahepatic spread Mazzaferro V, et al. N Eng J Med 1996;334: Liver Transplantation For HCC in Patients with Cirrhosis: 4-Year Survival % % 4-yr survival rate (%) % Unselected 1991 Milan Criteria Other Dx Mazzaferro V, et al. N Eng J Med 1996;334: Page 5 of 16

6 K. Rajender Reddy, MD, CG Death or removal ( too sick) by HCC and non-hcc Goldberg D et al Liver Transpl 2012;18: Indications for liver transplant in the US 100% 90% 80% 70% 60% 50% 40% Non-HCC exceptions HCC exceptions No MELD exception points 30% 20% 10% 0% Year of transplant Page 6 of 16

7 K. Rajender Reddy, MD, CG Current MELD exception for HCC HCC within Milan 6 mo hold CT chest: neg MR/CT abd MELD 28 3 mo MR/CT abd: in Milan MELD 29 3 mo MR/CT abd: in Milan MELD 31 3 mo MR/CT abd: in Milan MELD 32 What is a reasonable wait time; The so-called sweet spot Page 7 of 16

8 K. Rajender Reddy, MD, CG PREDICTORS OF HCC RECURRENCE: UNIVARIATE ANALYSIS (WAIT TIME): The Sweet Spot Wait Time* (HCC Diagnosis to LT) Univariate HR (9 CI) p- value <3 months 1.1 ( ) 0.73 <6 months 1.4 ( ) 0.13 >12 months 0.9 ( ) 0.68 >18 months 1.8 ( ) 0.06 <6 or >18 months 1.5 ( ) 0.05 * As compared to all others Factors associated with HCC Recurrence After LT Large tumor burden Macrovascular invasion Tumor rupture Satellite lesions Lymph node involvement Histologic differentiation Elevated Alfa-fetoprotein >400 ng/ml Page 8 of 16

9 K. Rajender Reddy, MD, CG How can we do better? Extended Milan criteria Role of bridging therapy Role of downstaging Adjuvant molecular targeted therapy Expanding the number of available livers ex. LDLT, split LT, higher donor risk index liver Proposal of Expansion of Milan Criteria Study Expended criteria Outcome Yao et al. (1) San Francisco, USA N=70 Mazzaferro et al. (2) Multicenter (Europe + USA) N=1556 UCSF criteria Single HCC 6.5 cm or up to 3 nodules with largest 4.5 cm and cumulative diameter 8.0 cm Up-to-seven limits a sum of the combination of sizeand-number covariates 7; 5 nodules 2 cm (5+2=7), 4 nodules 3 cm (4+3=7), 3 nodules 4 cm (3+4=7), 2 nodules 5 cm or single HCC 6 cm (1+6=7) without vascular invasion 1-yr survival yr survival 72.4% Recurrence 11.4% 5-yr survival within Milan 73. Within up-to Outside up-to yr survival Within Milan 69.6% Within up-to % Outside up-to % 5-yr recurrence Within Milan 12.8% Within up-to % Outside up-to (1) Yao FY, et al. Hepatology 2001;33: ; (2) Mazzaferro V, et al. Lancet Oncol 2009;10:35-43 Page 9 of 16

10 K. Rajender Reddy, MD, CG Current Treatment Options for HCC Surgical Non-surgical Hepatic Resection Liver Transplantation Transarterial Chemoembolization (TACE) Intra-arterial Radioembolization With Yttrium-90 Ablation Therapy Chemotherapy Gene Therapy Treatment: Chemoembolization Normal liver gets 7 of blood supply from portal vein and 2 of blood supply from hepatic artery. Tumor receives most of its blood supply from the hepatic artery. Injection into the hepatic artery spares most of the normal liver. Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor. Tumor Liver Portal vein Catheter placement for chemoembolization Hepatic artery Ramsey DE, Geschwind J-F. Appl Radiol. 2004;33. Available at Page 10 of 16

11 K. Rajender Reddy, MD, CG Chemoembolization: Randomized Trials (Nearly Identical Techniques) Lo et al 1 : N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal) Technique Survival, % Year 1 Year 2 Year 3 TACE Supportive care Llovet et al 2 : N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal) Technique Survival, % Year 1 Year 2 TACE Supportive care Lo CM et al. Hepatology. 2002;35: Llovet JM et al. Lancet. 2002;359: Technique TACE vs Surgical Resection Case-Control Prospective Study N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors <3 cm Survival, % Year 1 Year 2 Year 3 Year 5 TACE Surgical resection Surgery superior to TACE for tumors <2 cm and/or CLIP stage 0 BUT for tumors >3 cm and/or CLIP stage 1 2, 5-year survival identical for both groups Median OS (P=0.1529) Resection: 65.1 months TACE: 50.4 months CLIP = Cancer of the Liver Italian Program. Lee HS et al. J Clin Oncol. 2002;20: Page 11 of 16

12 K. Rajender Reddy, MD, CG Intra-arterial Radioembolization With Yttrium-90 Rationale and History Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors Yttrium-90 microspheres Average diameter = µm 100% pure beta emitter ( MeV) Physical half-life = 64.2 hours Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm) Murthy R et al. Biomed Imaging Interv J. 2006;2:e43. Percutaneous and other External Ablative Therapies for Hepatocellular Carcinoma Percutaneous ethanol injection Radiofrequency Microwave Cryoablation SBRT IMRT Cyber-knife Y90 Chemical ablation Thermal ablation External/internal radiation therapy SBRT = stereotactic body radiotherapy; IMRT = intensity-modulated radiation therapy. Lau WY et al. Ann Surg. 2003;237: Lencioni R et al. J Hepatobiliary Pancreat Sci. 2010;17: Page 12 of 16

13 K. Rajender Reddy, MD, CG Angiogenic Signaling in Cancer Tumor cell Pericyte/ Stellate cell PDGF VEGF VEGF Endothelial cell Proliferation and migration Survival probability Sorafenib Phase III SHARP Trial: OS ITT Population Sorafenib Median: 46.3 weeks (10.7 months) (9 CI, ) Placebo Median: 34.4 weeks (7.9 months) (9 CI, ) 0.25 Hazard ratio in sorafenib group = 0.69 (9 CI, ) P = * Time (weeks) Patients at risk sorafenib placebo Llovet JM et al. N Engl J Med. 2008;359: *O Brien-Fleming threshold for statistical significance = P= Page 13 of 16

14 K. Rajender Reddy, MD, CG Progression-free probability Sorafenib Phase III SHARP Trial Time to Tumor Progression (Independent Review) Sorafenib Median: 24.0 weeks (5.5 months) (9 CI, ) Placebo Median: 12.3 weeks (2.8 months) (9 CI, ) 0.25 Hazard ratio = 0.58 (9 CI, ) P< Time (weeks) Patients at risk sorafenib placebo Llovet JM et al. N Engl J Med. 2008;359: Toxicity Hand-Foot Skin Reaction More than 90% of patients experience skin reactions on multi-targeted TKI therapy Hand-foot reaction reported as high as 60% Yang CH, et al. Br J of Dermatology. 2008:158(3): Page 14 of 16

15 K. Rajender Reddy, MD, CG Hepatic differentiation 34% MAPK1/3 GRB2 JAK1 JAK1 CRAF SMARCE1 SMARCE1 MAPK10 MAPK10 EP300 EP300 WNT10B WNT10B WNT10A WNT10A PIK3C2B PIK3C2B AXIN2 AXIN2 GSK3B TSC1 TSC1 CUL3 CUL3 NFE2L1 NFE2L1 NFE2L3 NFE2L3 DNA CTNNB1 37% CTNNB1 37% TP53 24% TP53 24% MTOR MTOR NFE2L2 6% NFE2L2 6% KEAP1 4% KEAP1 4% AXIN1 1 AXIN1 1 AKT2 AKT2 TSC2 TSC2 RPS6KA3 7% RPS6KA3 7% MACF1 MACF1 PI3K 1 STAT1 < STAT1 < FZR1 FZR1 JAK3 JAK3 IGF1R IGF1R FLTs 6% FLTs 6% ACVR2A ACVR2A IL genes FGF4 FGF4 INHB genes CCND1 CCND1 ATM 6% ATM 6% CCNE1 CCNE1 CDK4/6 < CDK4/6 < CDK2 PRKDC PRKDC ATR ATR PCAF CREBBP CREBBP TCF7L2 TCF7L2 TCF genes LEFs RB1 4% RB1 4% MDM2 MDM2 HUWE1 HUWE1 DAPK1 DAPK1 PTEN PTEN RHEB USP34 USP34 CDKN1A CDKN1A Oxidative stress 1 Wnt-ßCatenin 54% IL6-JAK-STAT 9% PI3K-AKT-mTOR 5 MLL4 MLL4 MLL3 MLL3 MLL2 6% MLL2 6% MLL5 MLL5 MLL complex Chromatin remodeling complexes 28% Epigenetic regulators 3 P53 cell cycle 49% TGFß MAPK 4 CDKN2B CDKN2B MET MET Telomere maintenance 60% SMARCB1 SMARCB1 ARID1B ARID1B ARID1A 1 ARID1A 1 ARID2 7% ARID2 7% PBRM1 PBRM1 SMARCA4 SMARCA4 SMARCD SMARCD SMARCC2 SMARCC2 ACTL6A/B ACTL6A/B pbaf BAF SMARCC1 SMARCC1 IRF2 IRF2 APC APC PIK3R2 PIK3R2 TERT 60% TERT 60% BRAF < BRAF < GDF15 < GDF15 < IL6 FGA FGA CFH CFH HNF1A HNF1A A2M A2M CFHRs CFHRs F8 F8 GDF1 < GDF1 < JAK2 Cytoplasm Nucleus ALB 1 ALB 1 FGF19 FGF19 SRCAP SRCAP SETD2 SETD2 CHD7 CHD7 SMC3 SMC3 PHF20L1 PHF20L1 NCOR2 NCOR2 SMCHD1 SMCHD1 SLX4 SLX4 PIK3CA PIK3CA ZNRF3 ZNRF3 INSR INSR VEG VEG Protumorigenic macrophages NTRK3 NTRK3 FGFRs FGFRs MYC MYC FOS JUN ERBB2 < ERBB2 < EGFR EGFR KDR < KDR < TEK TEK STAT3 APOB 9% APOB 9% IL6ST IL6ST WNT7B WNT7B IL6R IL6R SMARCA2 SMARCA2 CDKN2A 9% CDKN2A 9% KIT KIT PDGFRs PDGFRs BCR ABL1 ABL1 HGF HGF FGF3 4% FGF3 4% EPHA4 EPHA4 SOS1 SOS1 MAPKK1 MAP3K10 MAP3K10 MLL1 Extra cellular space Inactivation Inactivation Activation Activation Unknown Unknown No alteration Can we identify new therapeutic targets using sequencing? HRAS, NRAS, HRAS, NRAS, KRAS Schulze K et al. Nat Genet. 2015;47: Cirrhosis is a factor! Page 15 of 16

16 K. Rajender Reddy, MD, CG Staging Treatment Algorithm HCC PST 0, Child-Pugh A PST 0 2, Child-Pugh A-B PST >2, Child-Pugh C Very early stage 0 Single <2 cm 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 No Yes Resection OLT R/MW Down stage TACE/TABE /TARE Combination w/sorafenib Down stage TARE (PVT) Sorafenib/ Clinical trial/ Combination Symptomatic/ Palliative Adapted from Llovet JM et al. J Natl Cancer Inst. 2008;100: Page 16 of 16