Hepatocellular Carcinoma

Transcription

1 Hepatocellular Carcinoma Derek Jonker, MD FRCPC Medical Oncologist, The Ottawa Hospital October 4, 2015 Conflict of Interest Disclosure Remuneration: none Research support: none beyond direct costs running trials. Indirect salary support: none 1

2 Case Study 52 year old 2001 Hematemesis; esophageal varices Banding U/S liver fatty liver, cirrhosis Hep B/C serology negative Dec 2012 U/S 5.9cm mass liver Jan 2013 MRI liver 6cm liver mass HCC Invasion of tumour into portal vein AFP 15,000 Case Study No contrast Arterial Venous/Delayed 2

3 Case Study March 2013 Biopsy liver hepatocellular ca Started sorafenib 400mg po bid Case Study AFP Sorafenib x24 months déc. 01, 12 janv. 01, 13 févr. 01, 13 mars 01, 13 avr. 01, 13 mai 01, 13 juin 01, 13 juil. 01, 13 août 01, 13 sept. 01, 13 oct. 01, 13 nov. 01, 13 déc. 01, 13 janv. 01, 14 févr. 01, 14 mars 01, 14 avr. 01, 14 mai 01, 14 juin 01, 14 juil. 01, 14 août 01, 14 sept. 01, 14 oct. 01, 14 nov. 01, 14 déc. 01, 14 janv. 01, 15 févr. 01, 15 mars 01, 15 avr. 01, 15 mai 01, 15 juin 01, 15 juil. 01, 15 août 01, 15 sept. 01, 15 Baseline 18 months later 3

4 Case Study Sorafenib 400mg po bid Diarrhea, high blood pressure. Dose reduction Unusually good response (PR), drop AFP Long control Jan 2015 two angry skin lesions on leg Bx keratoacanthoma Rising AFP Feb 2015 stop Rx Case Questions: What surveillance should cirrhotic patients have for HCC? How useful is AFP as a tumour marker? What is required to diagnose HCC? What scan to order? What is LiRADS? What are the treatment options for HCC? 4

5 Worldwide variation in HCC Worldwide 750,000 new cases annually 5th most common cancer, 3rd leading cancer death Hot spots: sub Saharan Africa, East Asia 9.2% of all cancers Case fatality ratio 96% in developing countries El Serag, et al. Gastroenterology 132(7): , 2007 Aflatoxin is produced by the Aspergillus fungus Grows on food such as corn, peanuts, pistachios in warm damp conditions Binds to DNA and can cause p53 mutation Synergistic with viral hepatitis, 60x risk if HBV infection 5

6 Hepatitis B Virus Responsible for 55% of HCC worldwide 400 million people infected Transmission 90% vertical transmission (maternal/newborn) in endemic areas In Canada is mostly sexual or parenteral Responsible for 85% of HCC in ethnic Chinese Men 3:1 HCC in Canada Lifetime probability of developing liver cancer is 0.8% for men, 0.3% for women Predominantly age >60 yrs 5-year overall survival 20% (only lung, esophagus and pancreas are worse) 6

7 Fastest increasing Incidence 2.4% per year for 10 years El Serag, et al. Gastroenterology 132(7): , 2007 Canadian Cancer Statistics Toronto, ON: Canadian Cancer Society;

8 HCC: Etiology Cirrhosis EtOH HCV 65% of HCC in Canada HBV Remaining 35%? NASH Rare: Hereditary hemochromatosis A-1 anti-trypsin Autoimmune hepatitis Porphyria Hepatitis C 170 million infected worldwide Vertical transmission In Canada immigrants, iv drug users, transfusion before ,000 infected in BC chronic infection leads to cirrhosis in 25% Interval infection to HCC 20+ years Curable 8

9 Harvoni : Ledipasvir + Sofosbuvir Randomized trials 12 week treatment, once daily 99% sustained virologic response Covered in most provinces E.g. EAP in Ontario $1000 per pill $84K Afdhal et al, NEJM 370(20): , 2014 Holkira Pak : Paritaprevir, ombiasvir, dasabuvir, ritonavir 3 pills per day % cure in genotype 1 Add ribavirin if genotype 1a or or 1b $56,000 for a 12 week course 9

10 Let me play the fool; With mirth and laughter let old wrinkles come, And let my liver rather heat with wine, than my heart cool with mortifying groans. Gratiano, Merchant of Venice Alcohol: Too much? Cirrhosis: Heavy for prolonged periods g per day OR X ½ bottle 5% x 341ml x3 = 51g HCC only if cirrhosis, no independent carcinogenic effect Synergistic effect if concomitant viral hepatits 13.5% x 750ml = 101g 10

11 Obesity Aside from immigration, the factor most responsible for the rise in HCC in Canada is obesity. Rise in obesity in NA has closely matched the rise in the incidence of HCC. Elevated BMI has a pronounced effect on relative risk of HCC in men. BMI>30 doubles your risk and BMI>35 quadruples the risk. This effect is not seen nearly as much in women Calle et al, NEJM 2003 Metabolic Syndrome in Canada, Statistics Canada [ 11

12 Obesity Metabolic Syndrome Non Alcoholic Fatty Liver Disease (NAFLD) Non Alcoholic Steatohepatitis (NASH) NASH cirrhosis Accumulation of fatty acids and glucose in the liver increases TNF a, NFK b, EGF, leptin NASH associated HCC now as frequent as HCV HCC NASH associated HCC New HCC: Evaluation for etiology History: iv drugs? Transfusion before 1992? EtOH? Prior hepatitis? Diabetic or metabolic syndrome Lab: anti-hcv Ab (prior infection) HBsAg (ongoing infection), HBsAb (prior infection/immunity) 12

13 Rare causes: work up Autoimmune hepatitis Female > male Associated autoimmune disorders: Celiac, IBD, Graves, Hashimoto s, GN, SLE sclerosing cholangitis, type I DM, RhA, Sjogren s Anti smooth muscle Ab, anti nuclear Ab Hereditary hemochromatosis Fasting transferrin saturation Evaluate further if >45% for males, >35% in women Ferritin only specific if >1000ng/mL Mutations: C282Y and H63D Other: MRI to measure iron, liver biopsy Alpha 1 antitrypsin deficiency Lung disease (emphysema) by age 50 Often unrecognized; 1/3000 of European descent; rare in Asians Genetic test SERPINA1 mutations Screening in cirrhotics? U/S every 6 months Further evaluation of any lesion > 1cm with either triphasic CT or dynamic contrast enhanced MRI AASLD guidelines, Canadian Consensus Guideline Meta-analysis [Aliment Pharmacol Ther Jul;30(1):37-47] Detect HCC at any stage Pooled sensitivity 94%, specificity 94% Detect HCC at early stage: sensitivity 63% higher sensitivity with U/S every 6 months (70%) than annual (50%); P =

14 AFP? Combining with U/S for screening does not improve detection Sensitivity 60% at level of 20ng/mL But, 20% of cirrhotics have level >20ng/mL 90% false positives Sensitivity 22% at level of 200ng/mL Useful as surrogate for response to treatment if >200 at baseline. AFP response better predictor of survival than ORR, ECOG PS, T-stage, or Childs-Pugh Riaz et al, JCO 2009 Diagnosis: Biopsy vs DI? Biopsy 2% risk of tumour seeding 10% false negative rate Non-invasive diagnostic standard: Li-RADs Liver Imaging Reporting and Data System 5 categories Li-RADS5-100% specific Forner et al Hepatology 2008» Sensitivity only 33% for lesions <2cm LiRAD4 only 80%(?) HCC follow or biopsy 14

15 Diagnosis of HCC Li-RADs By 4-phase CT or Dynamic contrast enhanced MRI Must record arterial and venous phases Threshold growth def: >100% (>6mos), >50% (<6mos), or new Capsule: noted in portal venous or delayed images What is Li-RADS5 Must have arterial enhancement Three additional factors: Growth Venous washout Capsule Li-RAD5 if 2cm+ and one of above 1-2cm and two of above 15

16 A B C 16

17 Child Pugh Classification 1 point 2 points 3 points INR < >2.3 Albumin (g/l) > <28 Bilirubin ( mol/l) < >50 Ascites (clinical) Absent Slight or diuretic controlled Score range 5 to 15 Childs A = 5 6 (ie maximum one risk) B = 7 9 C = (end stage liver disease) Moderate Encephalopathy None Mild Moderate HCC Management Solitary <2cm, Childs A 1-3 nodules <3cm (Milan Criteria) Larger or >3 nodules Childs-Pugh C PS >2 Fit Age <70 Comorbidities Age >70 Liver limited, Childs A/B Childs-Pugh A N+ or M+ Portal v inv TACE TACE Resect (or RFA) Transplant RFA TACE Sorafenib Palliation Adapted from the Barcelona-clinic liver cancer staging system 17

18 Milan criteria Score to predict risk of recurrence of HCC following liver transplant Criteria: single tumors 5 cm in diameter or no more than three tumors 3 cm in diameter 83% RFS at 26months 75% OS at 4 years Mazzaferro, NEJM 1996 Priority for Transplant: The MELD score Model for End Stage Liver Disease (MELD) system Score from 6 (less ill) to 40 (gravely ill) determines how urgently patient needs liver transplant within next 3 months MELD calculation: MELD = 3.78 ln[ min(1,bili/17.2)] ln[min(1,inr)] ln[min(1,cr/ 88.4)] MELD and mortality MELD score 3 month mortality Time on wait list? 40 71% Some transplant prioritization schemes also include 3 points for each 3 months % a patient is on the wait list % While you wait % TACE <10 1.9% More TACE 18

19 RFA (Radiofrequency Ablation) Heat 57 o C coagulative necrosis Percutaneous with local (conscious sedation), outpatient Criteria: Unresectable <3cm No extra-hepatic disease No vascular inv No adjacent loops bowel Childs A-B Post ablation zone is larger than initial lesion radiologist needs to know about ablation to interpret scan Post-ablation Nausea + pain post-op, resolve in 4 hrs flu-like symptoms x5d (fever, malaise) Bleeding 1%, seeding <1%, abscess 1%, diaphragmatic burn, Local control 80% Chemotherapy Typically low response rates Doxorubicin 0-15% Doxo/5FU/Methyl-CCNU 19% Doxo/bleo 16% Etoposide 13-18% Cisplatin 1% Absence of benefit in randomized trials 19

20 TACE: Arterial Chemoembolization HCC single blood supply hepatic artery Rest of liver protected Dual supply Chemotherapy agent Cisplatin (Not available) Doxorubicin 60-75mg/m2 Embolizing agent Lipiodol, gelfoam 55 vs 25% 2yOS HR % Childs A, 30% Childs B Average 3 sessions of TACE Llovet et al, Lancet 2 20

21 TACE: Toxicities Pain, fever, fatigue acute liver failure, 7.5% (range 0-49%) encephalopathy, 1.8% (0-16%) ascites, 8.3% (0-52%) acute renal failure, 1.8% (0-13%) upper gastrointestinal bleeding; 3% (0-22%) hepatic or splenic abscess, 1.3% (0-2.5%) treatment-related mortality 2.4% (0-9.5%) mainly due to acute liver failure. TACE: Doxo vs Drug Eluting-Beads? DC-BEADs bead loaded with doxorubicin Bead trapped in capillary, slowly releases doxo Lower systemic release of chemo Several small RCTs Less transaminitis, less abd pain No difference survival Cost driving choice of TACE Doxorubicin 100mg $420 DCBEADS $3000 Sacco et al, J Vasc Interven Radiol 2011 Golferi et al, BJC

22 TACE vs TEA? (Transarterial Ethanol Ablation) Lipiodol-ethanol mixture Ethanol causes arteriole endothelial damage Induces embolization Small comparative trials No difference in survival No concerns for anthracycline systemic toxicity (eg cardiac history) Very reasonable alternative Probably cheapest Sorafenib Sorafenib (Nexavar, Bayer HealthCare) Inhibits RAF, VEGRF, PDGR SHARP Trial Advanced HCC, Child-Pugh A, 92% ECOG 0-1 Sorafenib 400mg bid Placebo 22

23 SHARP Trial 97% Childs-Pugh A ORR 2 vs 1% mos 10.7 vs 7.9 months HR 0.69, p< yOS 44vs 33% Llovet et al, NEJM 20 Toxicity: Sorafenib toxicity Anorexia (14 vs 3%) Weight loss (9 vs 1%) Diarrhea (39 vs 11% Alopecia (14 vs 2%) Dry skin (8 vs 4%) Hand Foot reaction (21 vs 3%) Voice change (6 vs 1%) Hypertension (5 vs 2%) Abdominal pain (8 vs 3%) Rare: keratoacanthoma, SqCellCa Management Symptomatic (e.g. imodium), dose reduce (eg BID 200 QD) 23

24 Sorafenib for Childs-Pugh B? No RTC evidence N=297 consecutive patients, A+B Much worse outcome for CP-B Toxicity no different mos 10 vs 3.8 months (A vs B) Not fundable PCODR Sorafenib as an adjuvant? STORM trial evaluated post resection/ablation Sorafenib vs Placebo to maximum 4 years Results: No difference in RFS, OS More toxicity with sorafenib Bruix et al, ASCO

25 Special considerations Thrombocytopenia Some improvement with splenectomy or splenic embolization. Value? Variceal bleeding Non cardio-selective beta-blocker (eg propranolol) banding Ascites control Diuretics Pleurx catheter What s New? PD-1 cmet 25

26 Nivolumab and Immune Checkpoint Inhibition Nivolumab is a fully human IgG4 anti PD 1 monoclonal Ab that blocks interaction between PD 1 and PD L1/PD L2, restoring T cell immune activity directed against the tumour cell. Topailian et al, NEJM 2012 PD-1 / PD-L1 in HCC Upregulation of PD-1 and PD-L1 poor prognostic factors Phase I/II study HCC Inclusion: HCV, HBV and non-infected Child-Pugh A+B (no ascites or encephalopathy) Failed (68%) or refused sorafenib RD2DL: Nivolumab 10mg/kg q2 weeks ORR 19% (14% PR, CR 5%) 75% of these ongoing El-Koueiry, ASCO

27 Nivolumab in HCC El-Koueiry, ASCO 2015 El-Koueiry, ASCO 27

28 <br />MET as a Prognostic Factor Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting 28

29 Phase III Cabozantinib vs Placebo NCT Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting High-cMET expressor subgroup 7.2 vs 3.8 months mos HR 0.38, p=0.01 Trivantinib Placebo 29

30 Phase III Tivantinib vs Placebo NCT Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting HCC Management Solitary <2cm, Childs A 1-3 nodules <3cm (Milan Criteria) Larger or >3 nodules Childs-Pugh C PS >2 Fit Age <70 Comorbidities Age >70 Liver limited, Childs A/B Childs-Pugh A N+ or M+ Portal vein inv TACE TACE Resect (or RFA) Transplant RFA TACE Sorafenib Palliation Nivolumab, Tivantinib, Cabozantinib Adapted from the Barcelona-clinic liver cancer staging system 30

31 Questions 31