From the AGA Journals

Locoregional therapy lowers wait-list dropout in HCC

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Worrisome data or food for thought?

In 1996, Mazzaferro and colleagues reported the results of a cohort of 48 patients with cirrhosis who had small, unresectable hepatocellular carcinoma (HCC). The actuarial survival rate was 75% at 4 years, and 83% of these patients had no recurrence, so, orthotopic liver transplantation became one of the standard options with curative intent for the treatment HCC. Because of HCC biology, some of these tumors grow or, worst-case scenario, are outside the Milan criteria. Locoregional therapies (LRT) were applied to arrest or downsize the tumor(s) to be within the liver transplantation criteria.

Dr. Ruben Hernaez

Kwong and colleagues, using the data of the Organ Procurement and Transplantation Network database, showed an exponential increase of LRT over 15 years: from 32.5% in 2003 to 92.4% in 2018. The Barcelona Clinic Liver Cancer staging system classifies chemoembolization, the most common LRT modality used in this cohort, as a palliative treatment rather than curative. Not surprisingly, the authors found that radioembolization was independently associated with a 15% reduction in the wait-list dropout rate, compared with chemoembolization. Further, listing in longer wait-time regions and more recent years was independently associated with a higher likelihood of wait-list dropout.

These data may be worrisome for patients listed for HCC. The median Model for End-Stage Liver Disease at Transplant Minus 3 National Policy, introduced in May 2019, decreases the transplantation rates in patients with HCC. Consequently, longer wait-list time leads to increase utilization of LRT to keep these patients within criteria. Radioembolization could become the preferred LRT therapy to stop tumor growth than chemoembolization and, probably, will be more cost effective. Future work should address explant outcomes and outcome on downstaging with external radiation therapy and adjuvant use of immunotherapy.

Ruben Hernaez, MD, MPH, PhD, is an assistant professor at the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston. He has no relevant conflicts to disclose.



The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.

According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.

Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.

The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.

Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.

The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”

In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.

Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.

A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.

The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.

The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).

In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.

The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.

The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.

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