Long-term clinical outcomes of hepatocellular carcinoma : surveillance program for early detection in high risk patients

Abstract

[한글]간세포암은 예후가 불량하기 때문에 정기적인 초음파 검사 및 혈청 alpha-fetoprotein (AFP) 등의 종양표지자를 이용한 감시검사 (surveillance test)를 통해 조기에 진단하는 것이 중요하다. 본 연구에서는 간세포암의 조기 진단을 위해 고위험군을 대상으로 한 감시검사의 장기적 임상결과를 알아보고자 하였다. 또한, 검사 간격 (surveillance interval)에 따라 생존률 등의 결과에서 차이가 발생하는지를 조사하였고, 감시검사의 시기 (surveillance period)에 따른 임상 결과를 비교하였다.1990년부터 2005년까지 최소 1년 이상, 2회 이상의 정기적 초음파 검사AFP를 시행받은 환자는 모두 10,370명이었다 (연령: 32-87세). 이들 중 감시검사로 간세포암을 진단받은 환자는 400명이었고, 검사 간격에 따라 1군(간격 ≤6개월, 219명)과 2군 (간격 >6개월, 181명)으로 나누었다. 검사 시기에 따라서는 I군 (1990-1995년, 123명), II군 (1996-2000년, 157명), III군 (2001-2005년, 120명)의 세 군으로 나누고 각 군간의 임상결과를 비교하였다.평균 추적관찰 기간은 30±24개월 (범위: 1-141개월)이었다. 전체 400명 환자들의 평균 연령은 57세 (범위: 33-85세)였고, 남성의 비율이 72%였다. 간세포암의 원인으로는 B형 간염 289명 (72.3%), C형 간염 76명 (19.0%), 기타 32명 (8.0%)였다. 2군과 비교하여 1군에서 단일 결절로 발견된 간세포암의 비율이 높았고 (90.4% vs. 72.9%, P<0.001), 침윤형 간세포암의 비율은 2군에서 유의하게 높았다 (4.1% vs. 11.6%, P<0.001). 3cm 이하의 단일 결절로발견된 간세포암의 비율은 1군에서 의미있게 높았다 (62.1% vs. 51.5%,P=0.003). 5년 생존률은 1군과 2군에서 각각 25%, 16%로 유의한 차이를 보였다 (P=0.006). 검사 시기에 따른 비교에서, III군의 환자들이 I군 또는 II군에 비해 낮은 병기로 진단되어, TNM 병기 1 또는 2에 속하는 비율이 각각 65.1%, 67.6%, 85.8%였다 (P<0.05). 종양의 평균 크기도 I, II군에 비해 III군에서 유의하게 작았다 (4.2cm vs. 3.2cm vs. 2.9cm, P<0.005). 감시검사의 간격이 6개월 이하인 환자 비율 역시 I, II군에 비해 III군에서 의미있게 높았다 (46.3% vs. 39.5% vs. 80.8%, P<0.001). 5년 생존률은 각각 17%, 19%, 65%로 I, II군에 비해 III군에서 높았다 (P<0.001). 이상의 결과로, 감시검사 간격을6개월 이하로 엄격히 지킨 고위험군 환자들에서 간세포암이 보다 조기에발견되고 생존률이 유의하게 높은 것을 알 수 있었다. 또한, 최근 5년간 감시검사를 통해 간세포암을 진단받은 환자들의 병기가 과거보다 낮아지고생존률도 향상되었다는 것을 알 수 있었다.

[영문]Although most liver clinics conduct some forms of surveillance for the early detection of hepatocellular carcinoma (HCC) in high risk patients, it is still debated whether such surveillance may increase the patient survival. The aim of this study was to elucidate whether strict adherence to surveillance interval affected the clinical outcomes of patients diagnosed with HCC. Another aim was to compare the outcomes of patients diagnosed with HCC during different periods of surveillance.Between May 1990 and December 2005, a total 10,307 high risk patients (32-87 years of age) were followed-up with at least two times of regular ultrasound examination and serum alpha-fetoprotein measurements for at least one year in our institution. Among those, 400 patients diagnosed with HCC were divided into two groups according to surveillance interval; Group 1 (interval ≤6months, n=219) and Group 2 (interval >6months, n=181). These patients were also divided into three groups according to surveillance period; Group I (1990-1995, n=123), Group II (1996-2000, n=157), and Group III (2001-2005, n=120).The mean follow-up duration was 30±24 months (range; 1-141). The mean age of all patients was 57 years (range; 33-85) and there was a male predominance (72%). The etiology of HCC was hepatitis B virus in 289 (72.3%) patients, hepatitis C virus in 76 (19.0%), and non B-non C in 32 (8.0%). Single nodular HCC was more prevalent in Group 1 than in Group 2 (90.4% vs. 72.9%, P<0.001). On the contrary, diffuse type HCC was more common in Group 2 (4.1%, vs. 11.6%, P<0.001).The frequency of solitary HCC ≤3cm was significantly higher in Group 1 compared with Group 2 (62.1% vs. 51.5%, P=0.003). Five-year survival in Group 1 was significantly better than that of Group 2 (25% vs 16%, P=0.006, log-rank test). In comparison according to surveillance period, the patients in Group III were diagnosed with HCC at an earlier stage compared to Group I or II; the frequency of patients in TNM stage I/II was 65.1%, 67.6%, and 85.8%, respectively (P<0.05). In addition, the frequency of single nodular HCC was 82.1%, 73.2%, and 95.0%, respectively (P<0.05). The mean tumor size was also significantly lower in Group III compared to Group I or II (4.2cm vs. 3.2cm vs. 2.9cm, P<0.005). The proportion of patients in whom surveillance interval was ≤6 months was significantly higher in Group III compared with Group I or II (46.3% vs. 39.5% vs. 80.8%, P<0.001). The comparison of 5-year survival among three groups showed a significant difference between Group I (or II) and Group III (17%, 19%, and 65%, P <0.0001).Our data suggest that strict adherence to surveillance interval (≤6 months) resulted in the detection of HCC at an earlier stage and improved survival. Furthermore, the patients developing a HCC during the last 5 years survived longer than previously, probably as a consequence of more intensive surveillance program in this period.