Local therapy with sorafenib does not improve liver cancer survival

Combining sorafenib (Nexavar) with internal radiation therapy or transarterial chemoembolization did not improve overall survival for people with liver cancer, but it did appear to help certain groups of patients, according to research presented at the 2018 International Liver Congress this month in Paris.

Over years or decades, chronic hepatitis B or C virus infection, heavy alcohol consumption, fat accumulation in the liver and other causes of liver injury can lead to the development of liver cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer.

Liver cancer is often detected late, when it is difficult to treat. Depending on its stage, HCC may be treated with surgery to remove part of the liver (known as resection), liver transplantation, local therapies to destroy tumours within the liver or systemic drugs. But many people experience continued disease progression or recurrence, and survival is typically measured in months.

Sorafenib is the standard first-line systemic treatment for people with advanced HCC and for those with early tumours who are either unsuited for or experience disease progression despite local therapies, according to new EASL HCC guidelines presented at the conference. Sorafenib is a kinase inhibitor that interferes with signalling proteins that promote the growth of cancer cells and blood vessels that supply them.

Jens Ricke of Ludwig-Maximilians University in Munich, Germany, reported findings from the Phase II SORAMIC trial, evaluating sorafenib plus selective internal radiation therapy, or SIRT. The study was conducted in eleven European countries and Turkey.

This analysis looked at 424 participants with locally advanced HCC in the palliative cohort of the study. They were not considered suitable for potentially curative therapy and were instead assigned to receive palliative care, which aims to improve symptoms but is not expected to produce sustained remission or a cure.

This cohort included mostly men with a median age of 66 years. Eighty per cent had cirrhosis. About 40% had liver disease related to alcohol, about a quarter had hepatitis C and about 10% had hepatitis B. Most were Child-Pugh Class A, meaning they had well-preserved liver function, and BCLC Stage B or C. The median number of tumours was three and a quarter had cancer metastasis outside the liver. They could have received prior liver resection surgery or local therapies, but not external beam radiation therapy. They were considered ineligible for transarterial chemoembolization (TACE), though some had received it previously.

These participants were randomised to receive either twice-daily sorafenib plus SIRT or sorafenib alone. SIRT was administered using microspheres containing radioactive yttrium-90 injected into arteries supplying the tumour. Actual treatment varied considerably in the intention-to-treat population; a quarter of the people assigned to sorafenib plus SIRT in fact received sorafenib alone, SIRT alone or no treatment.

Overall survival did not differ significantly in the SIRT plus sorafenib and sorafenib only groups (median 12.1 vs 11.5 months, respectively). People who actually received SIRT plus sorafenib in the per-protocol or as-treated population lived slightly longer (14.1 months), but the difference still was not statistically significant.

Looking at various patient subgroups in the per-protocol population, however, those under age 65, those without liver cirrhosis and those without alcoholic liver disease appeared to do better with SIRT plus sorafenib, Ricke reported.

Among the people without cirrhosis, median overall survival was 22.2 months with the combination vs 9.9 months with sorafenib alone. Among those without alcoholic liver disease, overall survival was 15.3 vs 11.1 months, respectively. Among those under age 65, it was 18.6 vs 11.3 months. Although the numbers were small, all these differences reached statistical significance.

Treatment was generally safe but side-effects were common. Diarrhoea was the most frequent adverse event in both groups, reported by nearly half of people. Nearly 40% in both groups reported hand and foot syndrome, or redness, swelling and pain on the palms and soles, a known side-effect of sorafenib. Fatigue was more common in the SIRT plus sorafenib group (35% vs 22%). Serious adverse events were rare in both groups and reported quality of life was similar.

Going forward, Ricke said it will be important to better define patient populations that might benefit from SIRT plus sorafenib, such as those with good liver function. Most people with liver cancer are older and have cirrhosis, but many people have liver disease related to causes other than alcohol use.

"Although we were disappointed to find no overall survival benefit of adding SIRT to sorafenib across the entire study population, we did observe a survival benefit in younger patients, those with a non-alcoholic aetiology of the cirrhosis, and those with no cirrhosis at all," Ricke said in an EASL press release. "We believe our results have generated some very interesting new hypotheses in terms of the types of HCC patients that might benefit from combination therapy of SIRT and sorafenib, and we hope to explore these further in the future."

In a related study, Joong-Won Park of the National Cancer Centre in South Korea and colleagues compared sorafenib plus conventional transarterial chemoembolization versus sorafenib alone for people with advanced HCC.

TACE destroys tumours by injecting chemotherapy drugs and ethiodized poppyseed oil (Lipiodol) to block the blood vessels that supply them. It is the most widely used first-line local therapy for unresectable or inoperable liver cancer.

The Phase III STAH trial enrolled 339 participants from 13 hospitals in South Korea. More than 80% were men and the mean age was about 61 years. Three-quarters had hepatitis B and 68% had cirrhosis.

Here too, overall survival was similar for people randomly assigned to receive sorafenib plus TACE and those assigned to sorafenib alone (median 12.8 vs 10.8 months, respectively). However, combination therapy led to significantly longer survival when looking at people who received two or more TACE sessions (18.6 months).

Other measures including median time to progression (5.3 vs 3.5 months, respectively), progression-free survival (5.2 vs 3.6 months) and tumour response rate (61% vs 47%) significantly favoured combination therapy.

Serious adverse events were significantly more frequent in the sorafenib plus TACE group compared with the sorafenib only group (33% vs 20%, respectively). Severe side-effects including elevated liver enzymes, elevated bilirubin and ascites were much more in the combination group. About 50% in both groups had hand and foot reactions.

Based on these findings, the researchers concluded, "In the patients who were able to undergo conventional TACE more than once, [sorafenib plus TACE] increased survival."