NCCN: Screen for Liver Cancer in Patients at Risk

Nick Mulcahy

April 23, 2018

ORLANDO, Florida — In the last 20 years in the United States, the incidence of hepatocellular carcinoma (HCC) has tripled from about 2 to 7 per 100,000 adults. In addition to the rising incidence, the cancer is also one of the most deadly, with a 5-year survival rate of only 18%.

These comments were made here by Anne Covey, MD, a radiologist from the Memorial Sloan Kettering Cancer Center, New York City, at the National Comprehensive Cancer Network (NCCN) 23rd Annual Conference in March.

Covey said physicians should be on the lookout for patients with diseases that precede a HCC diagnosis and should suggest screening if appropriate.

Two groups of patients should be screened for HCC: those with cirrhosis and all hepatitis B carriers, according to the NCCN guidelines.

Covey explained that cirrhosis is a pathologic diagnosis and is caused by other conditions. Most common causes are hepatitis B or C, alcohol abuse, genetic hemochromatosis, nonalcoholic liver diseases, advanced primary biliary cholangitis, and α1-antitrypsin deficiency.

Anyone with these diseases or conditions is at risk for HCC — but only if their disease first proceeds to cirrhosis.

Hepatitis B is the exception. An estimated 30% to 50% of patients with HCC and hepatitis B do not have cirrhosis. Hence, the recommendation is that all patients with hepatitis B be screened, including those who do not have cirrhosis.

Especially concerning are hepatitis B carriers with additional risk factors for HCC, such as family history, Asian males (age > 40 years), Asian females  (age ≥ 50 years), and black people from Africa or North America, said Covey.

A problem that throws a wrench into this guidance is that most patients with risk factors for HCC have not undergone biopsy to establish the presence or absence of cirrhosis, Covey added.

Per the NCCN guidelines, recommended screening consists of ultrasonography with or without α-fetoprotein (AFP). The serum test is optional because it substantially increases cost with only a slight increase in sensitivity, said Covey.

If ultrasonography-detected nodules are negative, testing should be repeated in 6 months. If the nodules are small (<10 mm), repeat in 3 to 6 months.

For patients who have a positive AFP test result or have large nodules (≥10 mm) or have capsular retraction or vascular invasion, proceed to additional work-up. That includes further "multiphase" imaging with computed tomography (CT) or MRI, a complex process that allows for a definitive diagnosis.

Covey explained that HCC is one of the few cancers that can be diagnosed "by imaging alone."

The NCCN guidance is "in line" with recommendations from the American Association for the Study of Liver Disease, she added.

She also said that available nomograms help clinicians with risk analysis for HCC screening; for example, the factors that increase risk for HCC among patients with chronic hepatitis B  include male sex, increased viral load, and age. These factors are incorporated in the nomograms. The problem, she said, is that the nomograms are from Asian studies and "may not apply in the US."

Meeting attendee Edward Wos, DO, an oncologist from Bismarck, South Dakota, wondered whether the availability of liver transplant in certain countries affects the efficacy of screening.

"Does transplant play a role in survival to make screening more valuable vs not valuable?" he asked.

Covey answered in a roundabout way. She said that patients who have decompensated liver failure should not be screened — unless they are in a transplant program — because they may benefit significantly from transplant. "There is no doubt that liver transplant offers the best overall survival for patients with HCC," she said. But there are other curative options for HCC patients with small tumors, including resection and ablation, she said.

But, in general, it is "unlikely" that patients with early-stage HCC will get a liver transplant in the United States or anywhere else, she summarized.

Five Principles of Cancer Screening

HCC meets the criteria for the five principles of screening for a disease, said Covey: (1) substantial morbidity/mortality and common in a population; (2) an identifiable population at risk; (3) a low-risk, low-cost effective method to detect disease; (4) the ability to be treated once detected and then have an improved outcome; and (5) the ability to be followed up after treatment with surveillance.

Examining these key principles, Covey said that it was well known that HCC was a "bad actor" but perhaps lesser known was that its 5-year survival rate was the same as that of lung cancer. Smoking also ups the risk for HCC by 1.5 times, she added.

Among cancers currently screened for, HCC most closely aligns with lung cancer because "we know the patients who are at relatively high risk," Covey said. Approximately 80% of patients with HCC have a known risk factor for HCC, she added.

In terms of incidence, HCC is on par with cervical cancer (also 7 per 100,000).

As a screening tool, ultrasonography fits the bill of being low cost and low risk, said Covey. It has pros, including being inexpensive and nontoxic, and cons, including being "operator dependent." In cirrhotic livers, the specificity of ultrasonography is 58% to 89% and the sensitivity is 80% to 90%. However, she acknowledged that CT and MRI are probably now more commonly used than ultrasonography when screening for HCC. Both increase cost but without a significant increase in detection rates. Both higher-tech tools also "tend to detect nonsignificant lesions," she said.

A Chinese randomized study of more than 18,000 patients with chronic hepatitis B infection offers evidence that screening can improve outcomes, which is another hallmark of effective and worthwhile screening.

In the study, patients (age 35 to 59 years) were randomly assigned to "strict" screening (ultrasonography plus AFP every 6 months — just like the NCCN guidance) or to "usual" screening (whenever a doctor ordered it). In the strict screening group, 60% were found to have "subclinical" HCC (ie, very early or early stage) vs 0% in the usual screening group. This indicates that "when we do screening we are finding disease is potentially amenable to curative treatment," said Covey.

The study also reported improved survival at 1, 3, and 5 years for the screened group.

A Dutch study also found that at-risk patients in a screening program had smaller tumors upon detection than did those not in the program; the screening program participants also had significantly improved overall survival (P < .001).

Covey has disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 23rd Annual Conference. Presented March 24, 2018

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