Screening At-Risk Patients for Liver Cancer: Uncertain

Roxanne Nelson

June 19, 2014

Chronic hepatic disease has been recognized as a risk factor for hepatocellular carcinoma (HCC), but does that mean that all patients should be screened?

It remains uncertain whether systematic screening leads to a survival advantage over clinical diagnosis, conclude the authors of a new meta-analysis, published online June 17 in the Annals of Internal Medicine.

"Many guidelines recommend screening for cancer, mostly for patients with chronic hepatitis B infection and also cirrhosis," commented lead author, Devan Kansagara, MD, MCR, Portland Veterans Affairs Medical Center, Oregon. "Our task was to clarify the evidence base for screening, and we didn't find any clinically actionable answer. But it is valuable to know what the evidence says."

Both the incidence and related mortality of HCC have increased worldwide during the past 40 years, with localized tumors accounting for most of this increase, the authors note. Thus, the rationale for screening is that imaging tests, such as ultrasonography, might be able to detect early-stage disease, which allows for a greater range of treatment options.

Several professional societies have issued recommendations for HCC screening using imaging studies and tumor markers, primarily in patients who face a higher risk for disease due to chronic hepatitis B or cirrhosis.

As previously reported by Medscape Medical News, a meta-analysis published earlier this year found screening to be beneficial for patients with cirrhosis.

According to the study, patients who undergo surveillance with liver ultrasound with or without serum α-fetoprotein have cancers detected at an earlier stage, are more apt to receive curative instead of palliative treatment, and live longer than their peers who do not have regular surveillance.

However, the recommendations for HCC screening remain controversial, note the authors, "in part because of concerns over the quality and paucity of existing evidence," as well as concerns about the risk for overdiagnosis. In addition, patient harms have been highlighted with other types of cancer screening programs.

This analysis helps clarify the strength of evidence about screening, and these results can be useful in discussions with patients, Dr. Kansagara told Medscape Medical News. "This can help patients make informed decisions, and they should be aware of the strength of evidence."

Basically, there is a lack of strong evidence one way or the other, he noted. "You want to minimize the possible associated harms and maximize the benefits," he said. "So clinicians should make sure that the patient is at high risk, and would be a good candidate for treatment or a transplant."

Flaws and Poor Methods

In this review, Dr. Kansagara and colleagues searched the literature for English-language clinical trials and observational studies that compared screening vs no screening, studies of harms, and trials comparing different screening intervals.

A total of 22 studies met their inclusion criteria, and overall, they found the strength of evidence on the effects of screening to be very low. Although screening can identify patients with early-stage HCC and some of these patients do well with curative therapy, the authors found there is very-low-strength evidence from which "to draw conclusions about the balance of benefits and harms of screening for HCC."

When looking at the effects of screening on mortality, 2 clinical trials and 18 observational studies provided very-low-strength evidence from which to draw conclusions about the mortality effects of HCC screening, as compared with no screening.

Both of the trials were conducted in China in areas with high HCC prevalence, and most participants had hepatitis B with or without cirrhosis. One of the trials (n = 9757) offered serum α-fetoprotein testing and ultrasonography every 6 months, and participants in the control group (n = 9443) were not made aware of the study or actively followed. HCC mortality was less frequent in the screened group (83.2 vs 131.5 per 100,000 person-years; rate ratio, 0.63).

In the second trial, patient-level randomization stratified by township was used to assign patients with hepatitis B to screening (n = 3712), which consisted of serial α-fetoprotein tests followed by ultrasonography for high α-fetoprotein values, or usual care (n = 1869). Only 28.8% of the screening participants completed all scheduled testing, but all completed at least 1 screening test. The results showed less stage III HCC in the screening group (19.8% vs 41.0%; P value not reported), but disease-related mortality was similar in both groups (1138 vs 1114 per 100,000 person-years; P = 0.86), as was all-cause mortality (1843 vs 1788 per 100,000 person-years; P = not significant).

The authors note that both of these papers had "substantial methodological flaws that threatened their internal validity," and thus the findings would have limited applicability beyond patients with hepatitis B.

As a group, the observational studies showed that screening identified patients with earlier-stage disease, who more frequently receive curative therapy. Most of the trials included patients with cirrhosis and hepatitis B, hepatitis C, or alcoholic liver disease. But the authors pointed out that it was impossible to determine 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. There were also selection biases in many of the studies.

"We looked at observational trials to see if there were any clues there," Dr. Kansagara said. "Many showed that patients who had been part of a surveillance program had earlier-stage disease and could qualify for treatment that might possibly be curative."

However, he added that it is hard to know whether that is a true effect of screening or just the result of length- and lead-time bias.

Harms Unclear

When looking at possible harms related to screening, none of the included studies reported direct harms of screening, and none examined the psychological effects of screening. A meta-analysis of 8 studies found a 2.7% risk for needle-track seeding from liver biopsy for suspected HCC, while a recent systematic review of the diagnostic accuracy of imaging for HCC screening and diagnosis found that few of the studies reported harms data.

Clinically Important Benefits

"The Achilles' heel of evidence-based medicine is that the state of evidence for many common clinical interventions is not sufficient to either confirm or refute their benefits," write the authors of an accompanying editorial. In the current review, the evidence of the mortality benefit of screening remains insufficient to make a strong recommendation for or against screening.

It remains unclear whether any future randomized trials will be forthcoming, note editorialists David Atkins, MD, MPH; David Ross, MD, PhD, MBI; and Michael Kelley, MD, all from the Department of Veterans Affairs in Washington, DC, and Durham, North Carolina (Dr. Kelley). Thus, it prompts the question: "What is the appropriate practice and policy response while we wait for better evidence?"

They write, "Some would argue that we should halt all screening in the absence of stronger evidence" and that this approach would not only be cost-conscious but adhere to the Hippocratic principle of "First, do no harm."

But while they agree that current screening should not be expanded and new screening programs should not be initiated, they note that "the range of uncertainty includes a clinically important benefit of screening."

Screening has a much greater potential to produce benefits that exceed harms in the highest-risk patients, and it is appropriate to allow clinicians caring for these patients to continue to offer screening, they say. Offers of screening, however, should be targeted only to those who are good candidates for treatment and "should include a shared decision-making approach that explicitly acknowledges the limitations of the evidence."

But most important, screening should be paired with "efforts to collect better data, including baseline characteristics and long-term outcomes in screened and unscreened patients, which may help reduce our uncertainty," the editorialists write. "Given the high mortality from HCC and the high costs of delivering a truly effective program of early detection and treatment, better evidence is imperative."

The U.S. Department of Veterans Affairs, Veterans Health Administration, supported the study. The authors and editorialist have disclosed no relevant financial relationships.

Ann Intern Med. Published online June 17, 2014. Abstract Editorial

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