Hepatocellular Carcinoma. Markus Heim Basel

Transcription

1 Hepatocellular Carcinoma Markus Heim Basel

2 Outline 1. Epidemiology 2. Surveillance 3. (Diagnosis) 4. Staging 5. Treatment

3 Epidemiology of HCC Worldwide, liver cancer is the sixth most common cancer ( new cases), the third cause of cancer-related death ( ), and accounts for 7% of all cancers 90% of liver cancers are HCCs 80%-90% of HCCs arise in cirrhotic livers, > 95% of HCC develop on the background of chronic liver disease Incidence of HCC increases with age, reaching a peak at 70 years (in Chinese and black African populations, mean age is younger) Male to female ratio = 2.4

4 Global HCC incidence (per per year) Switzerland Total: 5.2 Men: 8.7 Women: 2.0

5 Global HCC mortality (per per year) Switzerland Total: 4.0 Men: 6.7 Women: 1.7

6 Projection of HCC Incidence 2030 Valery et al. Hepatology, 2018;67:

7 HCC risk factors Others 10% HCV Alcohol 44% 32% HBV 13% Western Europe EASL clinical practice guidelines HCC, J Hepatol 2018

8 Non-alcoholic fatty liver disease (NAFLD) and HCC Incidence of NAFLD is increasing Incidence of NASH-cirrhosis is increasing Incidence of NAFLD associated HCC is increasing 2/3 occurs in NASH-cirrhosis 1/3 in non-cirrhotic NAFLD

9 HCC surveillance with 6 monthly US (+AFP) PAGE-B (Platelet, Age, Gender, hepatitis-b) Age Gender Platelet count years points points 10E9/l points Male Female < Low Risk 9 almost 0 % HCC at 5 y Intermediate % HCC at 5 y EASL clinical practice guidelines HCC. J Hepatol, 2018 High Risk % HCC at 5 years

10 HCC risk in CHB treated with entecavir or tenofovir European, 10-center, cohort study, adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for 1 year Overall No cirrhosis Cirrhosis 1.22% 0.73% 0.49% 0.47% 3.22% 1.57% Papatheodoridis, Hepatology. 2017;66:1444

11 Surveillance recommendation of AASLD all cirrhotics HBV infection: all blacks asian male > 40y asian female > 50 family history of HCC Diagnosis, Staging and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology, 2018

12 Natural history of HCC The natural history of hepatocellular carcinoma is variable. In many patients the tumor has a long-lasting subclinical incubation period and often grows as a solitary mass to a size at which it can be detected by ultrasound (1-2 cm diameter). In other patients the onset of the tumor is multinodal with great variations in the growth rates. The median time of doubling volume for a small HCC may range from 1 to 20 months Prognostication of patients with hepatocellular carcinoma takes into account the size and number of tumor nodules vascular invasion and metastasis the degree of liver impairment

13 Diagnosis Diagnosis should be made by an experienced center In cirrhotic patients, diagnosis can be made using stringent criteria on multiphase imaging (CT/MRI LI-RADS ). Diagnosis can also be established by liver biopsy. In non-cirrhotic patients, diagnosis requires a biopsy.

14 Tang et al, Radiology. 2018:2018;286:29

15 Staging Number and size of tumor nodules Macro-vascular invasion Metastasis Liver function (Child-Pugh) ECOG Performance Status (Eastern Cooperative Oncology Group)

16 Forner, Reig, Bruix. Lancet 2018

17 Treatment allocations Early stage Intermediate stage Advanced stage Terminal stage curative treatments treatments with impact on survival best supportive care Resection Liver transplantation Ablation (RF, MW) TACE Transarterial Chemoembolisation TARE Transarterial Radioembolisation (Y90) Sorafenib Lenvantinib Regorafenib Cabozantinib TARE

18 Treatmen of early stage HCC Resection is the treatment of choice for localized HCC occurring in the absence of cirrhosis, or resectable HCC occurring in the setting of cirrhosis with intact liver function and absence of clinically significant portal hypertension. (AASLD 2018) Thermal ablation with radiofrequency is the standard of care for patients with BCLC 0 and A tumours not suitable for surgery (evidence high; recommendation strong). (EASL 2018) In patients with very early stage HCC (BCLC-0) radiofrequency ablation in favourable locations can be adopted as first-line therapy even in surgical patients (evidence moderate; recommendation strong). (EASL 2018)

19 Early Stage HCC: resection versus ablation Retrospective study including patients from a nationwide Japanese survey with 3 tumors and liver damage A or B treated with surgical resection (5361), percutaneous ethanol injection (2059) or radiofrequency ablation (5548) between 2000 and 2005 Surgical resection RFA Age (years) PEI Albumin Overall survival Time to recurrence Liver function Tumor number (%) Bilirubin Platelet count single two three Tumor size (median, mm) Hasegawa et al. J Hepatol 2013;58:

20 Microwave versus RFA Randomized controlled, single-blinded phase 2 trial at 4 centers in France and Switzerland patients with HCC, 3 lesions of 4 cm, not eligible for surgery primary outcome: proportion of lesions with local tumour progression at 2 years follow-up Hypothesis (H1): microwave is superior to RFA Microwave ablation 71 patients RFA 73 patients Treatment complications comparable Overall survival not different Violi et al. Lancet Gastroenterol Hepatol 2018 (published online 1.March)

21 Liver transplantation for HCC Transplantation is the treatment of choice for patients with early stage HCC occurring in the setting of clinically significant portal hypertension and/or decompensated cirrhosis, though access is limited by the extreme organ shortage. (AASLD 2018) LT is recommended as the first-line option for HCC within Milan criteria but unsuitable for resection (evidence high; recommendation strong). (EASL 2018)

22 Selective internal radiotherapy (SIRT) Biocompatible polymer resin microspheres of a median diameter of 32.5 microns (range between 20 and 60 microns) loaded with yttrium-90 beta radiation penetrating an average of 2.5 mm in tissue Yttrium-90 has a half-life of 64.1 hours (94% delivered to tissue over 11 days)

23 C.A., 75y, male SIRT

24 SIRT versus TACE Randomized phase 2 study; Chicago; ; BCLC A (80%) and B (20%); 24 patients treated with Y90, 21 with TACE. Salem et al. Gastroenterology, 2016;151:

25 380 patients included, randomized to SIRT vs sorafenib Sample size calculated to detect a 4 month difference (10.7 m in sorafenib vs 15 m in SIRT) in median survival with 80% power, 5% type error. BCLC stage: A = 4/5%, B = 28/27%, C = 68/67% Portal venous invasion 63%/58% 63% had 1 SIRT treatment 72% had hemi-liver, 18% sector, 10 segmental SIRT Median overall survival in the per-protocol population was the same in both groups (9.9 months) Lancet Oncol. 2017;18:

26 Serious adverse events occurred in 77% of SIRT and 82% of sorafenib treated patients 139 of the 216 patients in the sorafenib group discontinued sorafenib for drug-related toxicity (108 permanently) Grade 3 events SIRT Sorafenib fatigue 9% 19% liver dysfunction 11% 13% increased liver values 9% 7% haematological abnormalities 10% 14% diarrhoea 1% 14 abdominal pain 3% 6% increased creatinine 2% 6% hadn-foot skin reaction <1% 6% Lancet Oncol. 2017;18:

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28 360 patients included, randomized to SIRT vs sorafenib 130 treated with SIRT, 162 with sorafenib Sample size calculated to detect a 4.5 month difference (9.35 m in sorafenib vs 14 m in SIRT) in median survival with 90% power, 5% type error. BCLC stage: B = 51/55%, C = 48/45% Portal venous invasion 30%/30% Median overall survival in the per-protocol population was 8.8 months in SIRT vs 10 months in Sorafenib group (p = 0.38). Significantly fewer 3 AEs in SIRT (28%) versus sorafenib (51%).

29 DAA treatment of HCV cirrhosis and HCC Current DAA efficacy and safety allows to treat cirrhosis (large numbers of older patients, advanced disease treated with DAA s) DAAs reduce mortality caused by worsening of liver function (Increasing the proportion of HCCs diagnosed?) Any increased incidence of HCC would nullify the survival benefit

30 Note of caution from Barcelona Increased incidence of De novo (i.e. indident) HCC Recurrent HCC More aggressive and faster progression of HCC in patients treated with DAA s 58 patients with prior HCC, treated with DAA, median FU 5.7 m, 28% tumor recurrence Scientific hypothesis: DAA cure leads to resolution of inflammation, and the lack of inflammation (T cells) weakens the J Hepatol Oct;65(4): tumor immuno surveillance

31 Benefit of SVR: ~75% decrease of de novo HCC-risk patients Kanwal et al, Gastroenterology. 2017;153:996 Li et al, Hepatology. 2017

32 No increased HCC recurrence risk after DAA treatment 267 patients with CHC and cured HCC, 189 received DAA, 78 no treatment 178 patients with CHC and cured HCC, 89 received DAA, 89 matched controls without DAA treatment ANRS, J Hepatol. 2016;65:734 Ikeda et al, Dig Dis Sci. 2017;62:2932

33 HCC and DAA treatment Compelling evidence that DAA treatment reduces risk of decompensation and de novo HCC in patients with CHC and cirrhosis Circumstantial evidence (Barcelona) that DAA treatment increases risk of HCC recurrence, but this could not be confirmed in larger cohorts Patients with CHC and advanced fibrosis/cirrhosis should be treated and cured with DAAs, irrespective of previous history of HCC

34 Summary 1. Epidemiology 2. Surveillance HCC incidence will probably increase cave NAFLD! US (6monthly) in cirrhotics (and F3). In patients with HBV controversial 3. (Diagnosis) Expert center: imaging and/or biopsy 4. Staging BCLC (Barcelona Clinic Liver Cancer) 5. Treatment Constantly evolving concepts and treatment modalities Tumor boards in expert centers Treat HCV cirrhotics, but continue screening