VIENNA, Austria—Another attempt to improve outcomes for patients with inoperable liver cancer undergoing transcatheter arterial chemoembolization (TACE) again failed to show any better outcome than use of TACE by itself, researchers reported here at the International Liver Congress, sponsored by the European Society for the Study of the Liver.
This time researchers from South Korea used the oral tyrosine kinase inhibitor orantinib (also known at TSU-68) in the hopes of extending survival in these patients, but the targeted agent that inhibits vascular growth did not seem to make any impact in the Phase III randomized, placebo-controlled trial.
In an interim analysis, patients treated with TACE plus orantinib achieved a median overall survival of 31.1 months compared with 32.3 months among the patients treated with TACE alone, said Joong-Won Park, MD, Chief Scientist of the Liver and Pancreatobiliary Cancer Branch of the National Cancer Center in Goyang, South Korea.
“TSU-68 combined with TACE did not improve overall survival in this interim analysis,” he said in his plenary report.
Of the 444 patients assigned to receive the vascular endothelial growth factor receptor blocker orantinib, 168 patients died during the three-year study compared with 163 of 444 patients assigned to receive placebo plus TACE. Statistically, that translated to a hazard ratio of 1.0, meaning that there was no difference, he said.
The researchers scrutinized the data by subgroups of patients and by region—Japan, Korea, and Taiwan—but there were few hints that the combination made any difference in outcome.
With the negative findings in the interim look at the study, the researchers and the study sponsor, Taiho Pharmaceutical Co., Ltd., terminated the trial.
The use of TSU-68 to change the survival pattern in patients with unresectable liver cancer treated with TACE isn't the first time that an additional treatment has been attempted in these patients, noted Markus Peck-Radosavljevic, MD, Associate Professor of Medicine and Vice-chairman of the Department of Gastroenterology and Hepatology at Medical University of Vienna.
“This is another study that shows that the combination of agents really does not have any benefit,” he explained in an interview. Peck, who is also EASL's Secretary-General, said that while there were some subgroups with a hint of benefit, he didn't give those findings much weight: “I don't think it gives you a major signal,” he said.
He said he has no faults with how the study was conducted. “There have been several combination trials that have failed—using TACE with a drug. It just confirms my general feeling that in this setting it is better to use these treatments sequentially than concomitantly. We now use sorafenib when TACE fails.”
Possible Avenue to Be Explored
In his presentation of the trial, called ORIENTAL, Park suggested that one of the hints that might be explored further was that the time to failure of TACE appeared to be extended among the patients receiving TSU-68.
The median time to TACE failure was 23.9 months in the group receiving the targeted agent compared with 19.8 months among the patients receiving placebo, which he called a trend toward benefit. However, that ‘trend’ was driven by patients in Japan, and was not seen in patients in Korea or in Taiwan.
He also reported results favored a couple of other subgroups: the median time to TACE failure in the orantinib arm was significantly prolonged in patients with low VEGF-C at baseline. That subgroup on orantinib achieved a median of 25.5 months to TACE failure compared with18.4 months for patients on placebo. Patients treated with orantinib and who entered the trial in Barcelona Clinic of Liver Cancer stage-B cancer achieved a median of 22.1 months time to TACE failure compared with 14.9 months for patients receiving placebo plus TACE, a difference that had borderline significance.
The combination was well tolerated with most adverse events in the TSU-68 groups being ascites, facial edema, and peripheral edema reported in about 30 percent of the patients on the active agent. However, fewer than five percent of patients had Grade 3-5 adverse events for these or any other conditions. Park said these drug-associated adverse effects did not appear to cause discontinuation. One patient's death was considered drug-related.
Hepatocellular carcinoma is a common cancer worldwide and TACE is an effective treatment when it is inoperable, Park said. But the procedure does not usually achieve complete control of the disease, especially when the tumor is large, and it potentially causes tumor hypoxia, which can induce angiogenesis. Hence, the research team thought that by adding an anti-angiogenesis agent, TSU-68, the effectiveness of TACE could be improved.
Patients were treated with TACE and received 200 mg of orantinib daily or were given placebo after the TACE procedure. Patients continued on the treatment until TACE failure or unacceptable toxicity. The primary endpoint was overall survival, while a key secondary endpoint was the time to TACE failure.
Repeated TACE procedures were permitted in the trial, but use of the treatment was halted if an intra-hepatic lesion could not be controlled by TACE; if the patient's arterial pathways deteriorated; if the cancer severely invaded the vascular system; if there was metastatic spread outside the liver and if the Child-Pugh status reached a level of C for 28 days.
The patients in the study were about 67 years old; 82 percent were men; and 90 percent were in ECOG Performance Status 0, with the rest in ECOG Performance Status of 1. About 40 percent of the patients had liver cancer that arose from infection with Hepatitis B virus; another 40 percent had been infected with Hepatitis C.
About 40 percent of the patients had not previously received TACE before being enrollment in the study. About half the patients (432) were from Japan; 340 were from Korea, and 116 were from Taiwan.
‘Noble Idea’ Goes Awry with Changes for Poster Process at EASL Liver Congress
Sometimes people would be wise not to try to fix things that ain't broke.
At the 50th anniversary meeting of the European Association for the Study of the Liver here, organizers decided that the poster sessions, one of the long-time social as well as scientific features of the meeting, should go the way of electronics.
“Horrendous,” David Bernstein, MD, Chief of the Division of Hepatology at North Shore University Hospital in Manhasset, NY, told OT. “It was just horrendous. I am trying to be polite in my assessment.”
The block of 80 flat screen monitors held all the data of hundreds of presenters, but figuring out how and when the presentations would appear required a phalanx of IT personnel—and even they seemed confused.
Before even getting to the poster “oblong” you needed to access at least three websites:
- One provided the poster abstracts, as well as the oral presentations;
- A second website had to be consulted to determine when the poster presenters were scheduled to be there, and at what monitor they would be at;
- A third website would give you a look at the poster on your own computer or smartphone, but that meant you didn't throw out a suspiciously labeled gift card tucked into the conference bags that contained the necessary computer codes. Even with that card, though, it took a special tutorial from friends and neighbors to guide you through the half dozen or more hoops to make the card-access work.
And if a presenter did figure out when and where the presentation was (the attendants at the tents for poster discussions were of no help), then came the problem of someone monopolizing the screen, which contained a dozen or so presentations. And each presenter was given just 15 minutes to review his or her data and answer questions from interested parties.
“You couldn't get on the system,” Bernstein said. “You couldn't look at posters. They had 80 screens for 7,000 people. I hope they get feedback and don't repeat this. It takes away a big part of this meeting. You lose the scientific interaction. It's like they cut the heart out of the meeting.”
He said he prefers the paper poster session “where you can see what people are doing and talk to them about their ideas. It gives you a chance to interact with people.”
Another attendee, Norman Sussman, MD, Associate Professor of Surgery at Baylor College of Medicine, said: “When you think of the amount of paper put up by thousands of people with posters, I think the electronic poster was a noble idea. But you are going to need more space, and the idea of timing out after 15 minutes wasn't good.”
The attendance at the session was also troubling, he said. “If you look at how sparsely this was attended, it is disturbing,” he said, taking in the area with remarkably few people. “Posters can be a very important part of the meeting. It gives you a change to meet one-on-one.”