June 18, 2014 -- Screening for hepatocellular carcinoma
(HCC) in patients with chronic liver disease can detect early-stage cancer, but
it's unclear whether systematic screening would yield a survival advantage over
clinical diagnosis, according to an analysis published on Tuesday in the Annals of Internal Medicine.
The review included 22 studies in the
literature and assessed the utility of methods such as ultrasound and serial
alpha-fetoprotein screening. The team of researchers, led by Dr. Devan
Kansagara of Portland Veterans Affairs Medical Center, found that "the
body of evidence on which current recommendations for screening are based has
substantial shortcomings."
The research project was commissioned by the
U.S. Veterans Health Administration.
Controversial recommendations
A number of professional societies recommend
using imaging methods and tumor markers for HCC screening, primarily in
patients at higher risk due to chronic hepatitis B or cirrhosis; however, these
recommendations remain controversial due to concerns over the quality and
paucity of existing evidence to support screening, and the potential of
overdiagnosis and patient harms, according to the researchers.
To better understand the incremental
benefits and harms of routine HCC screening compared with clinical diagnosis,
the study team conducted a systematic review of the literature. They searched
Medline, PsycInfo, the Cochrane Central Register of Controlled Trials, the
Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from the
inception of the databases to June 2013. They later updated the Medline,
PsycInfo, and ClinicalTrials.gov searches in April 2014 (Ann Intern Med, June 17, 2014).
Kansagara and colleagues included all
English-language controlled clinical trials and observational studies that
assessed the effects of screening on HCC-specific and all-cause mortality in
adults. Studies also had to include a comparison group of patients who did not
have routine screening. Observational studies that did not consider important
confounding factors were excluded. Using a tool developed by the Cochrane
Collaboration, two reviewers independently assessed each included trial's
quality, and disagreements were resolved through discussion.
Two reviewers also graded the strength of
evidence for outcomes by using published criteria that considered a body of
evidence as well as the internal validity of individual studies, according to
the researchers. In addition, existing tools were adapted to evaluate the
quality of observational studies.
Low-strength evidence
Of the 286 potentially relevant studies
gathered from the literature search, 22 studies met the group's inclusion
criteria. Of these 22, two trials and 18 observational studies provided only
very-low-strength evidence regarding the effect of HCC screening on mortality.
The researchers concluded that the two
trials -- both conducted in China -- had substantial methodological flaws that
threatened their internal validity, and their findings have limited
applicability beyond the hepatitis B patient population. They also noted,
though, that the observational studies, most of which included patients with
cirrhosis and hepatitis B, hepatitis C, or alcoholic liver disease, showed that
screening detects patients with earlier-stage disease and who more frequently
receive curative therapy.
"However, it is impossible to say
whether the longer survival in patients with screen-detected disease was a true
effect of screening or reflects lead- and length-time biases inherent to all
observational studies, as well as selection biases that were common in many of
the studies," they wrote.
Two additional trials compared ultrasound screening
intervals: One was a Taiwanese study that compared four-month and 12-month
screening intervals in patients with serologic evidence of hepatitis B or C.
Despite more patients in the four-month screening interval group having
early-stage disease, survival rates were similar among both screening
intervals. Furthermore, the "study had an unclear risk of bias because of
poor reporting of outcome assessment and statistical analyses," they
wrote.
The other trial, which had a low risk of
bias, compared three-month and six-month ultrasound screening intervals, and
found similar all-cause mortality rates among both groups.
Observational studies
The 18 observational studies compared
survival in patients with screening-detected HCC and those diagnosed with HCC incidentally
as part of another workup or because of symptoms. The researchers noted that
patients in these studies who had undergone screening had earlier-stage HCC
than those who hadn't received screening. They also determined that more
screened patients received potentially curative treatment, and survival was
generally higher among screened patients.
However, several methodological
considerations temper confidence for drawing conclusions from these studies,
according to the researchers.
"Most of the studies were single-center
retrospective cohort studies in which all patients with diagnosed HCC were
first identified and screening status was subsequently determined," they
wrote. "Few studies reported data on loss to follow-up, and many did not report
using a comprehensive method to assess mortality outcomes equally in screening
and nonscreening groups."
In addition, selection bias was a concern
for 15 of the studies, and none of the studies reported any direct harms of
screening or examined the psychological effects of screening, the authors
noted.
Kansagara and colleagues concluded that
there is very-low-strength evidence from which to draw conclusions about the
effects of HCC screening on mortality in high-risk patients with chronic liver
disease.
"Screening can identify more patients
with earlier-stage disease who are candidates for potentially curative
treatments, but there is limited evidence from which to draw firm conclusions
about the balance of health outcome benefits and harms of using routine screening
to identify HCC," the researchers wrote.
They noted, though, that their findings
neither support nor refute current policy recommendations for HCC screening.
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