Ultrasonography surveillance improves prognosis of patients with hepatocellular carcinoma
- Authors:
- Published online on: June 25, 2019 https://doi.org/10.3892/mco.2019.1888
- Pages: 325-330
Abstract
Introduction
Hepatocellular carcinoma (HCC), one of the most commonly occurring malignant tumors worldwide (1,2), often develops in patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) infection (3,4), who are defined as high-risk for HCC and are recommended to undergo protocol screening for tumor development with a surveillance program. Detection of HCC at an early stage is important to improve patient prognosis, as tumor burden is an important prognostic factor along with hepatic reserve function (5–7). The progression of surgical resection (8) and/or radiofrequency ablation (RFA) (9,10) as curative treatments have improved patient prognosis when diagnosed at an earlier stage. In addition, the development of tyrosine kinase inhibitors (11–14) has contributed to a better HCC prognosis in patients who are allocated an unresectable status. Ultrasonography (US) is a popular and economical examination method that does not involve X-ray exposure, which is deemed to be suitable for HCC surveillance. Early stage HCC diagnosis is important for treatment (15), meaning that a suitable surveillance program should be evaluated.
Although the surveillance program for HCC, which primarily utilizes US, has been performed in patients with a high risk of HCC in Japan, few reports of surveillance efficacy for the improvement of prognosis have been performed. Only a limited number of studies have examined the effectiveness of HCC surveillance performed at regional hub hospitals in Japan (16). Herein, the outcomes of HCC patients with and without surveillance using with US were analyzed to elucidate its usefulness and impact for improving prognosis.
Materials and methods
Patients and definition of surveillance for HCC
The records of 872 patients with naïve HCC who were examined from October 2006 to December 2014 were analyzed, following the exclusion of 170 cases without information regarding HCC surveillance. The enrolled patients were divided into those who did (S-group, n=398) and did not (non-S group, n=474) undergo surveillance. In addition, the S-group was divided into two sub-groups: i) Those who underwent surveillance at Ehime Prefectural Central Hospital (EPCH), an expert medical institution (SE-group, n=189); and ii) those who received surveillance at general clinics (SG-group, n=209; Fig. 1). Patients whose surveillance of HCC was performed only with AFP examination or whose HCC was pointed out incidentally were classified as the non-S group. The outcomes and clinical characteristics of the S- and non-S groups were compared in a retrospective manner, while those of the SE- and SG-groups were also compared as a sub-analysis.
Surveillance program
EPCH is a qualified regional hub hospital, where surveillance for HCC is performed for a fixed interval (3 or 6 months) with US and α-fetoprotein (AFP) in accordance with liver disease grade [chronic hepatitis (CH; n=200) or liver cirrhosis (LC; n=198)], following practical guidelines for HCC used in Japan since 2005 (17,18).
Diagnosis of HCC
When HCC is suspected based on US findings, contrast enhanced US (CEUS), dynamic CT, or gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (EOB-MRI) (19) was typically performed as an additional examination. HCC was diagnosed in patients based on increasing AFP expression, as well as dynamic CT (20), magnetic resonance imaging (MRI), and/or CEUS with perflubutane (Sonazoid®; Daiichi Sankyo Co., Ltd., Tokyo, Japan) (21,22) findings. Tumor, Node, Metastasis (TNM) stage was determined according to the Liver Cancer Study Group of Japan, 6th edition (23).
The study protocol was conducted in compliance with the Helsinki Declaration and was approved by the Institutional Ethics Committee of EPCH (approval no. 26-11). Values are expressed as the mean ± standard deviation. Statistical analyses were performed using Student's t test, Welch's test, Fischer's exact test, Mann-Whitney's U test, and the Kaplan-Meier method with a log-rank test using EZR version 1.29 (24), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). P<0.05 was considered to indicate a statistically significant difference.
Results
Although age was not significantly different between the S- (n=398) and non-S (n=474) groups (S, 70.2±9.2 vs. non-S, 70.4±10.7 years; P=0.689), the frequency of male gender (S, 66.1% vs. non-S, 76.8%; P<0.001), surgical resection (S, 21.1% vs. non-S, 31.4%; P<0.001), NBNC-HCC (S, 14.5% vs. non-S, 36.7%; P<0.001), lower grade of Child-Pugh classification (B and C; S, 23.1% vs. non-S, 36.4%; P<0.001), and TNM stage IV (S, 1.3% vs. non-S, 29.1%; P<0.001) was greater, while tumor size (S, 2.3±1.2 vs. non-S, 5.4±3.7 cm; P<0.001) and tumor number (S, 1.6±1.1 vs. non-S, 2.5±2.0; P<0.001) were significantly larger in the non-S group. Furthermore, those non-S patients had higher levels of tumor markers, including AFP (S, 201.8±1228.6 ng/ml vs. non-S, 15,123.4±77,037.9 ng/ml; P<0.001), fucosylated-AFP (AFP-L3; S, 9.2±17.0% vs. non-S, 19.9±25.8%; P<0.001), des-γ-carboxy prothrombin (DCP; S, 757.2±4918.0 mAU/ml vs. non-S, 17,472.5±46,451.4 mAU/ml; P<0.001; Table I). In addition, the overall survival rate (OSR) after 1 (S, 91.6% vs. non-S, 71.8%), 3 (S, 75.3% vs. non-S, 47.8%) and 5 years (S, 55.2% vs. non-S, 34.7%) was significantly higher in the S group, compared with the non-S group, as was median survival time (MST; S, 68.2 vs. non-S, 34.1 months; P<0.001; Fig. 2).
Sub-analyses were also performed for comparison of patient characteristics and prognosis. The S-group was divided into those who underwent surveillance at EPCH, an expert medical institution (SE-group, n=189), and at a general clinic (SG-group, n=209). It was determined that average age was older (SG-group, 71.4±8.8 vs. SE-group, 68.8±9.5 years), tumor size was larger (SG-group, 2.5±1.3 vs. SE-group, 2.0±1.0 cm), and frequency of TNM stage II and III (SG-group, 71.8 vs. SE-group, 52.9%) was greater in the SG-group (all P<0.001; Table II). Although there were significant differences in tumor size and frequency of TNM stage II and III, tumor number was not significantly different (SE-group, 1.5±1.1 vs. SG-group, 1.7±1.2; P=0.164). As a result, the 1-, 3- and 5-year OSR (SG-group, 92.4, 76.0 and 55.8% vs. SE-group, 90.8, 74.5 and 54.6%, respectively) and MST (SG-group, 67.1 vs. SE-group, 72.1 months) were not significantly different between the SG- and SE-groups (P=0.931; Fig. 3).
Discussion
Surveillance for HCC in high-risk patients, such as those with viral hepatitis or LC has been expected to improved patient prognosis due to earlier tumor detection. There are a number of reasons why a surveillance program improves prognosis, including advancements in imaging modalities such as CEUS (21,22,25) and EOB-MRI (19), allowing the rapid detection and diagnosis of smaller HCC. In addition, the development of therapeutic modalities and assistance methods with low invasiveness, such as RFA (10,26), virtual US (VUS) (27), and artificial effusion in RFA (28) have bettered small HCC treatment. Surveillance for smaller HCC detection in high-risk patients is important to increase the likelihood of successful curative treatment, thus obtaining a better prognosis.
Singal et al (29), reported that the combination of US and AFP maximizes the sensitivity for HCC detection at an early stage, compared to surveillance with US or AFP alone (combination, US alone, AFP alone sensitivity: 90, 44 and 66%, respectively; specificity: 83, 92 and 91%, respectively) (29). In a randomized control trial (RCT), it was demonstrated that biannual screening for HCC with US and AFP in HBV patients reduced mortality by 37%, as compared to the control group that did not undergo screening (30). In addition, surveillance with US and AFP in patients with LC significantly improved survival as compared to patients with incidentally detected HCC (15). On the other hand, in another report, biannual AFP screening in HBV patients did not result in an overall reduction in mortality (31). Thus, it is thought that surveillance with both US and AFP is most effective. Costentin et al (32) reported that compliance with HCC surveillance guidelines (fewer than 7 months between image evaluations) lead to early diagnosis, allocation of curative treatment, and a longer adjusted OS of patients with compensated HCV- or HBV-associated cirrhosis and a diagnosis of HCC (32). In the present study, average tumor size of the SG-group was larger than that of the SE-group (P<0.001). This result may have depended on an easier access system to CEUS, CT or MRI in the SE-group. However, the frequency of curative treatments (resection, RFA and PEIT) did not show a significant difference between the groups, and prognosis was similar. Surveillance with US and AFP improves the prognosis of patients with chronic liver disease. The clinical usefulness of AFP-L3 and DCP other than AFP as tumor markers for HCC surveillance should be examined in additional future studies. Lead-time bias should be taken into consideration for this type of investigation. Toyoda et al (33) reported that the surveillance group exhibited a significantly better survival than the non-surveillance group after adjusting for lead-time bias (MST: Surveillance vs. non-surveillance group, 7.18 vs. 5.65 years; P<0.0001). Further study is required to confirm the influence of lead-time bias to survival.
In the present cohort, the frequency of NBNC-HCC was greater in the non-S group, compared with the S-group. Along with an increasing aging population in Japan, the frequency of patients without HCV or HBV (NBNC-HCC) has increased (34–36), thus establishment of a method for identifying affected patients without viral hepatitis or alcohol abuse is becoming increasingly important. Recently, non-alcoholic steatohepatitis (NASH) has been recognized to increase the risk for development of HCC; therefore, patients with NASH must be enrolled in a HCC screening program (37). Nevertheless, many patients with diabetes mellitus (DM), who often also have NASH, are receiving regular medical check-ups at local clinics. To control DM, it may be possible to focus high-risk patients, who require HCC surveillance with US, from those with DM. It has been proposed that age and fibrosis-4 index (38,39) are factors that indicate individuals at high risk for HCC among DM patients without alcohol abuse (alcohol intake: >60 g/day) (37). Additional investigations to form a surveillance strategy for detection of HCC at an earlier stage in patients without viral hepatitis or alcohol abuse are required.
US is easily introduced due to its lower cost relative to other radiological modalities, such as enhanced CT and EOB-MRI (40). Furthermore, examinations may be repeatedly performed, although some issues remain. The accuracy of US findings for HCC surveillance is strongly dependent on the quality of the equipment and expertise of the performing operator (41), thus special training is warranted for ultrasonographers. Although tumor diameter and TNM stage in the SG-group of the present study were greater compared with the SE-group, tumor number and OSR were not significantly different between those groups. It was speculated that the reason why repeated surveillance screening for HCC using the combination of US and AFP was effective, was because of the increased chance for detection of smaller sized and fewer tumors, resulting in the possibility to be treated with a curative method.
The present study has certain limitations. First, the present study was retrospective. Second, the quality of US examination of each institution could not be exactly compared. Additional analyses with a prospective study or RCT, if possible, are required. However, physicians and their patients should be notified of the importance of surveillance for HCC with a combination of US and AFP for high-risk patients with viral hepatitis and/or alcohol abuse. In addition, management of high-risk patients without viral hepatitis or alcohol abuse is necessary. It was concluded that repeated surveillance with US and AFP leads to diagnosis of HCC at an earlier stage, and improved prognosis of affected patients compared with patients who did not undergo surveillance.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets of this study are not publicly available, but are available from the corresponding author on reasonable request.
Authors' contributions
AH and HY conceived the present study, analyzed the data and wrote the manuscript. YH, BM, AM and MH conceived, reviewed and edited the manuscript of the current study. TM, HI, HU, MO, TA, TO, RI, YS, KMo, HM, ET, MK, TN and KMi acquired the data.
Ethics approval and consent to participate
The study protocol was conducted in compliance with the Helsinki Declaration and was approved by the Institutional Ethics Committee of EPCH (approval no. 26-11).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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