Amit Singal and colleagues conducted a systematic review of the evidence that surveillance for hepatocellular carcinoma in patients with cirrhosis improves early detection, receipt of curative treatment, and overall survival.
Please see later in the article for the Editors' Summary
Surveillance for hepatocellular carcinoma (HCC) has level I evidence among patients with hepatitis B but only level II evidence in patients with cirrhosis. This lack of randomized data has spurred questions regarding the utility of HCC surveillance in this patient population; however, lack of randomized data does not equate to a lack of data supporting the efficacy of surveillance. The aim of our study was to determine the effect of HCC surveillance on early stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis.
Methods and Findings
We performed a systematic literature review using Medline from January 1990 through January 2014 and a search of national meeting abstracts from 2009–2012. Two investigators identified studies that reported rates of early stage tumor detection, curative treatment receipt, or survival, stratified by HCC surveillance status, among patients with cirrhosis. Both investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for a random effects model.
We identified 47 studies with 15,158 patients, of whom 6,284 (41.4%) had HCC detected by surveillance. HCC surveillance was associated with improved early stage detection (odds ratio [OR] 2.08, 95% CI 1.80–2.37) and curative treatment rates (OR 2.24, 95% CI 1.99–2.52). HCC surveillance was associated with significantly prolonged survival (OR 1.90, 95% CI 1.67–2.17), which remained significant in the subset of studies adjusting for lead-time bias. Limitations of current data included many studies having insufficient duration of follow-up to assess survival and the majority not adjusting for liver function or lead-time bias.
HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis.
Please see later in the article for the Editors' Summary
Hepatocellular cancer (HCC) is the commonest form of primary liver cancer—a type of cancer that starts when a cell in the liver acquires genetic changes that allow it to grow uncontrollably. Primary liver cancer is the third leading cause of cancer-related death worldwide, killing more than 600,000 people every year. The symptoms of HCC are vague and rarely appear until the cancer has spread throughout the liver. They include unexplained weight loss, feeling sick, tiredness, and jaundice (yellowing of the skin and eyes). If liver cancer is diagnosed in its early stages, it can be treated by surgically removing part of the liver, by liver transplantation, or by a procedure called radiofrequency ablation in which an electric current is used to destroy the cancer cells. However, most people are diagnosed with HCC when the cancer is advanced and cannot be treated. These individuals are given palliative treatment to relieve pain and discomfort. Although most patients who are diagnosed with HCC at an early stage survive more than 5 years, patients with more advanced HCC have an average survival less than one year. The exact cause of HCC is unknown, but it is thought to be related to cirrhosis (scarring) of the liver. This condition is the end result of long-term (chronic) liver damage caused by, for example, alcohol abuse or infection with hepatitis B virus (HBV).
Why Was This Study Done?
Because HCC tends to be untreatable when it is diagnosed at a late stage, if the tumor can be found early by regularly measuring blood levels of alpha fetoprotein (a liver cancer biomarker) and using ultrasound, outcomes for patients at high risk of developing HCC might be improved. Indeed, American and European guidelines recommend HCC surveillance with ultrasound every 6 months in patients with HBV infection and/or cirrhosis. However, although randomized controlled trial results support HCC surveillance among patients infected with HBV, no randomized trials have investigated its use among patients with cirrhosis. Here, the researchers use predefined criteria to identify all the published cohort and case-control studies (two types of non-randomized studies) that have examined the impact of HCC surveillance on outcomes in patients with cirrhosis. They then pool the data from these studies using a statistical approach called meta-analysis to estimate whether HCC surveillance is associated with improvements in early tumor detection, curative treatment receipt, and survival rates among patients with cirrhosis.
What Did the Researchers Do and Find?
The researchers identified 47 studies that examined the association of HCC surveillance with outcomes in 15,158 patients with cirrhosis who developed HCC. In 41.4% of these patients, HCC was detected by surveillance. Among patients who had undergone HCC surveillance, the pooled rate of early detection was 70.9%, whereas among patients who had not undergone surveillance but who were diagnosed incidentally or who presented with symptoms, the pooled rate of early detection was 29.9%. The researchers calculated that the pooled odds (chances) of early detection among patients undergoing surveillance compared to early detection among patients not undergoing surveillance was 2.08 (an odds ratio [OR] of 2.08). The pooled rate of curative treatment receipt among patients undergoing surveillance was 51.3% compared to only 23.8% among patients not undergoing surveillance (OR 2.24). Finally, among those patients for whom the relevant data were available, 50.8% of patients who had undergone HCC surveillance but only 28.2% of those who had not undergone surveillance survived for at least 3 years after diagnosis (OR 1.90).
What Do These Findings Mean?
These findings show that HCC surveillance is associated with significant improvements (improvements that are unlikely to have happened by chance) in early tumor detection, receipt of curative treatment, and overall survival among patients with cirrhosis. Importantly, the association with improved overall survival remained significant after adjusting for the possibility that patients who underwent surveillance died at the same time as they would have done without surveillance but appeared to survive longer because they were diagnosed earlier (this is called adjustment for lead-time bias). These results must be interpreted cautiously, however, because many of the studies included in the meta-analysis had insufficient follow-up to assess survival adequately, not all the studies adjusted for lead-time bias, and none of the studies assessed potential downstream harms of HCC surveillance such as complications of liver biopsies. Nevertheless, overall, these findings provide sufficient evidence to support guidelines that recommend regular HCC surveillance for patients with cirrhosis.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001624.
The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer and about screening for primary liver cancer (in English and Spanish)
The American Cancer Society also provides information about liver cancer (available in several languages)
The UK National Health Service Choices website provides information about primary liver cancer and about cirrhosis (including patient stories)
Cancer Research UK (a not-for-profit organization) also provides detailed information about primary liver cancer
MedlinePlus provides links to further resources about liver cancer and cirrhosis (in English and Spanish)
Information is available at the American Liver Foundation
American Association for the Study of Liver Diseases provides practice guidelines