HCC Incidence in Korea :Up or Down, What Is Real? 임영석울산의대서울아산병원소화기내과, 간센터
Metrics of Disease Burden 발병률 / 유병률 (Incidence/Prevalence) 원인 - 특이적사망률 (Cause-Specific Mortality) Cause-specific mortality is one of the most fundamental metrics of population health. Age-specific, sex-specific, and cause-specific mortality and their trends for each country is critical for informed priority setting (prioritizing policy and research for new health technologies). Trends in causes of death provide an important geographical summary of whether society is or is not making progress in reducing the burden of premature (and especially avoidable) mortality and where renewed efforts are needed. Lozano R, et al. Lancet 2012;380:2095. GBD 2013 Mortality and Causes of Death Collaborators. Lancet 2015;385:117.
HCC Incidence & Mortality : Which Estimates? How big is the HCC burden and how much resources will need to address a HCC in this country? How big is the influence of aging society on HCC burden in comparison to other countries? Crude rates! Age-adjusted (standardized) rates!
Crude Rates
Calculating Age-adjusted Rates The Question We Would Like to Answer: "What would the comparable death rate be in each state if both populations had identical age distributions?" Florida Alaska Age group Population (STANDARD) % of Total Death Rate per 100,000 Population % of Total Death Rate per 100,000 <5 850,000 7% 284 7% 274 5-19 2,280,000 18% 57 18% 65 20-44 4,410,000 36% 198 36% 188 45-64 2,600,000 21% 815 21% 629 >64 2,200,000 18% 4,425 18% 4,350 Total 12,340,000 100% 1,069 100% 399
Calculating Age-adjusted Rates
Crude Rates vs. Age-Adjusted Rates Crude rates are helpful in determining the cancer burden and specific needs for services for a given population Age-adjusted rates ensures that differences in incidence or deaths from one year to another, or between one geographic area and another, are not due to differences in the age distribution of the populations being compared.
(Events/100,000 people) 간암 - 조발생률 vs. 연령표준화발생률 - 35 30 28.9 32.0 25 28.2 20 15 10 조발생률 연령표준화발생률 * 20.8 5 0 * 우리나라 2000 년주민등록연앙인구를표준인구로사용 Korea Central Cancer Registry (http://ncc.re.kr)
(Events/100,000 people) 간암 - 조발생률 vs. 조사망률 - 35 30 28.2 32.0 25 20 15 20.5 조발생률 * 22.6 10 조사망률 5 0 * 우리나라 2000 년주민등록연앙인구를표준인구로사용 우리나라 2005 년주민등록연앙인구를표준인구로사용 Korea Central Cancer Registry (http://ncc.re.kr) Korea National Statistical Office (http://meta.narastat.kr)
간암조사망률은 30 년간증가추세! (Deaths/100,000 people) 35 30 25 20 15 10 5 0 간암간질환 Year Korea National Statistical Office, http://meta.narastat.kr
우리나라간암의원인 HBV+HCV, 1% NBNC, 14% HCV, 12% HBV, 73% De Martel C, et al. Hepatology 2015;62:1190-1200.
Sometimes there are COHORT EFFECTS that need to be considered as specific groups may vary in exposures or treatments as they move together through time. Age-Specific Death Rates per 100,000 From Tuberculosis (All Forms), Males, Massachusetts, 1880-1930 Year Age (yr) 1880 1890 1900 1910 1920 1930 0-4 760 578 309 309 108 41 5-9 43 49 31 21 24 11 10-19 126 115 90 63 49 21 20-29 444 361 288 207 149 81 30-39 378 368 296 253 164 115 40-49 364 336 253 253 175 118 50-59 366 325 267 252 171 127 60-69 475 346 304 246 172 95 70+ 672 396 343 163 127 95 Data from Frost WH: The age selection of mortality from tuberculosis in successive decades. J Hyg 30:91-96, 1939.
간암환자들의 5 년생존률 - 30% 에불과! - 완치를의미하지않음!
간암환자들의 10 년생존률 : 17% 에불과!
암유병률
연령대별사망원인 -2013 년 (Deaths/100,000 people) 순위 전체사망률 30 대 40 대 50 대 60 대 1 악성신생물 150.9 자살 27.9 악성신생물 48.6 악성신생물 144.6 악성신생물 344.4 2 심장질환 52.4 악성신생물 14.7 자살 32.4 자살 36.4 심장질환 67.1 3 뇌혈관질환 48.2 운수사고 5.9 간질환 13.2 심장질환 29.3 뇌혈관질환 59.8 4 자살 27.3 심장질환 4.2 심장질환 12.2 간질환 26.7 자살 37.5 5 폐렴 23.7 뇌혈관질환 3 뇌혈관질환 10.1 뇌혈관질환 22.1 당뇨병 32.8 6 당뇨병 20.7 간질환 2.7 운수사고 8 운수사고 13.3 간질환 27.5 7 만성하기도질환 14.1 추락 1 당뇨병 3.5 당뇨병 11.6 운수사고 20.7 8 간질환 13.1 당뇨병 0.7 추락 2.6 추락 6.2 폐렴 15.6 9 운수사고 11.2 가해 ( 타살 ) 0.7 정신장애 1.8 폐렴 4.8 만성하기도 11.6 10 고혈압성질환 10 폐렴 0.6 폐렴 1.3 정신장애 3.7 추락 9.8 2015 년, 통계청사망원인통계 http://kosis.kr/metadata/
Cause of Cancer Deaths in 2013 (Deaths/100,000 people) 100 80 60 40 Lung Liver Stomach Colorectal 20 0 Total 30-39 40-49 50-59 60-69 Age Group Korea National Statistical Office, http://meta.narastat.kr
Cause of Deaths in 2013 (Deaths/100,000 people) 120 100 80 60 40 20 Lung ca Liver ca, dis Stomach ca Colon ca 0 Total 30-39 40-49 50-59 60-69 Age Group Korea National Statistical Office, http://meta.narastat.kr
Cause of Deaths in Men in 2013 (Deaths/100,000 people) 180 160 140 120 100 80 60 40 20 0 Total 30-39 40-49 50-59 60-69 Age Group Lung Liver ca, dis Stomach Colorectal Korea National Statistical Office, http://meta.narastat.kr
Lee KS, et al. Cancer Res Treat 2015;47:387-398.
(million US$) Values in rounded parentheses are presented as share of mortality cost. Lee KS, et al. Cancer Res Treat 2015;47:387-398.
간세포암종누적발생률 (%) 혈청 HBV DNA 역가와간세포암의발병상관관계 16 14 Multivariate-adjusted Relative Risk 환자수 = 3,653 (*HBeAg negative N=3,088) Baseline HBV DNA 10 6 (copies/ml) RR* 6.6 12 10 5 <10 6 6.1 10 8 6 p<0.001 4 10 4 <10 5 2.3 2 300 <10 4 1.1 0 <300 1.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 추적년수 *Multiple Cox Proportional Hazard Regression Analyses Chen CJ, et al. JAMA. 2006;295:65-73. 22
간암누적발생률 (%) 만성 B 형간염환자들에서항바이러스제 (Lamivudine) 장기사용으로간암발생감소 : 무작위대조군비교연구결과 P =.047 10 Placebo 0 Lamivudine 0 6 12 18 24 30 36 간암발병까지의시간 ( 월 ) Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.
Risk of HCC with ETV vs. LAM in Patients with Cirrhosis Selection bias: LAM-treated patients who had no rescue therapy were used in the comparison. Low power: Only about 10 HCC cases in each group. Hosaka T, et al. Hepatology. 2013:58;98-107.
Estimated Cumulative Incidence Of Death or Transplantation (%) Estimated Cumulative Incidence Of Hepatocellular Carcinoma (%) LAM vs. ETV in Tx-Naïve CHB Death/Transplantation HCC 100 80 60 40 20 20 15 10 5 0 Lamivudine 0 1 2 3 4 5 6 PS Matching Analysis HR 0.49, 95% CI 0.37-0.64, P<0.001 Entecavir 100 80 60 40 20 20 15 10 PS Matching Analysis HR 1.01, 95% CI 0.80-1.27, P=0.95 5 0 Entecavir Lamivudine 0 1 2 3 4 5 6 0 0 1 2 3 4 5 6 Years After Starting Treatment Lim YS, et al. Gastroenterology 2014;147:152 161. 0 1 2 3 4 5 6 Years After Starting Treatment Number at Risk Number at Risk LAM 1792 1778 1740 1660 1601 1531 1389 LAM 1792 1777 1699 1585 1496 1409 1262 ETV 1792 1777 1436 966 563 224 21 ETV 1792 1777 1384 911 511 200 19 0
Estimated Cumulative Incidence of Death or Transplantation (%) Estimated Cumulative Incidence Of HCC (%) B 형간염대상성상태 (compensated state) 에서주요사망원인은간암! Death/Transplantation HCC 100 80 Decompensated Cirrhosis Compensated Cirrhosis No Cirrhosis 100 80 60 60 40 P<0.001 40 P<0.001 20 20 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Lim YS, et al. Gastroenterology 2014;147:152 161.
HBV-Associated Hepatocarcinogenesis
NUC : Modes of Action Zoulim F, Durantel D. Cold Spring Harb Perspect Med 2015;5:a021501.
Two Ways of HBV-Associated Hepato-carcinogenesis Chronic HBV Infection Chronic inflammation Fibrosis Liver cell regeneration Cirrhosis Insertional mutagenesis Genomic alterations Chromosomal instability Cellular gene transactivation (HBx protein) Oxydative stress HCC Chemin I and Zoulim F. Cancer Letters 286 (2009) 52 59. Xu C, et al. Cancer Lett 2014;345:216-22. Zoulim F, Durantel D. Cold Spring Harb Perspect Med 2015;5:a021501.
Role of NUC in HBV-Associated Hepato-carcinogenesis Chronic HBV Infection NUC Chronic inflammation Fibrosis Liver cell regeneration Cirrhosis Insertional mutagenesis Genomic alterations Chromosomal instability Cellular gene transactivation (HBx protein) Oxydative stress HCC Chemin I and Zoulim F. Cancer Letters 286 (2009) 52 59. Xu C, et al. Cancer Lett 2014;345:216-22. Zoulim F, Durantel D. Cold Spring Harb Perspect Med 2015;5:a021501.
Cumulative Probability at 5-Years in HBV Cirrhotic Patients ETV cohort Untreated cohort Hepatic event HCC Liver-related mortality All-cause mortality 25.5% (22.7% to 28.3%) 45.8% (39.7% to 51.9%) HR 0.51; 95%CI 0.34 to 0.78 13.8% (11.3% to 16.3%) 26.4% (20.7% to 32.1%) HR 0.55; 95%CI 0.31 to 0.99 5.0% (3.6% to 6.4%) 23.3% (18.0% to 28.6%) HR 0.26; 95%CI, 0.13 to 0.55 8.3% (6.6% to 10.0%) 28.2% (22.7% to 33.7%) HR 0.34; 95%CI, 0.18 to 0.62 Wong GLH, et al. Hepatology. 2013;358:1537-1547.
Hypothesis : HCC incidence in HBV LC Patients The annual incidence of HCC is reduced by antiviral treatments. The mortality is further reduced by antiviral treatments. The prolonged life span of patients may increase the cumulative incidence of HCC. Ex. Annual HCC Incidence Life Span Cumulative HCC Incidence Control 5% 5 year 25% AVT 2.5% 20 year 50%
70 65 Changes in Mean Age at Death 64.8 60 55 50 60 56.3 63.9 HCC (P<0.001) Cirrhosis (P<0.001) 45 1995 2000 2005 2010 2015 Year An J, Lim YS, et al. APDW 2015, Paper ID; 1673. Korea National Statistical Office (http://meta.narastat.kr)
No. Patients with HBV on LT Waitlist in US Kim WR. Hepatology 2009;49:S28-S34.
Su TH, Kao JH, et al. AASLD 2014; LB-30.
Increasing Incidence of HCC in Korea During recent 15 years when the effective antiviral treatments for hepatitis B and C have been introduced, mortality rate by liver diseases has significantly decreased, while incidence of HCC and mortality by HCC have significantly increased. There results suggest that HCC is becoming the main cause of death in patients with CHB.