RADIOEMBOLIZATION FOR HCC

BARCELONA, Spain — Treating locally advanced hepatocellular carcinoma (HCC) with radioembolization results in better tumor responses and quality of life than the current standard of care, sorafenib (Nexavar, Bayer), although survival is similar, conclude French researchers.

The results come from a phase 3 study of radioembolization with selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres, known as the SARAH trial, which compared this therapy with the multikinase inhibitor sorafenib.

Presenting the data here at the 19th World Congress on Gastrointestinal Cancer (WCGC), the French team noted that the overall or progression-free survival was similar in both groups of patients.

However, the group treated with SIRT, which included patients for whom transarterial chemoembolization (TACE) had failed, showed significant improvements in tumor responses and quality of life over the course of follow-up, with significantly fewer adverse events.

Although acknowledging that SIRT did not improve overall survival, presenter Mohamed Bouattour, MD, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon, Paris, France, said: "We can see that SIRT offers a higher tumor response, a better tolerance, with less treatment-related effects and better quality of life over the time than sorafenib."

"Of course, future analyses will evaluate prognostic factors, cost-effectiveness, and dose-released efficacy in the SIRT group," he added

Study Details

Dr Bouattour began his presentation by pointing out that the choice of treatment for HCC depends on the size and extension of the tumor and the severity of liver disease. Sorafenib is the current reference treatment for advanced HCC, and TACE is the standard of care for intermediate disease.

The current SARAH study was conducted in patients with either locally advanced or inoperable HCC after treatment with TACE had failed. The participants were randomly assigned to receive either SIRT or sorafenib.

After assessing 496 patients for eligibility, 467 were included in the trial. There were 237 SIRT patients and 222 sorafenib patients in the intention-to-treat population, 226 and 216 patients, respectively, in the safety population, and 174 and 206 patients, respectively, in the per protocol population.

There were no significant differences in baseline characteristics between the SIRT and sorafenib populations: the mean age was 65 years, the majority of patients (90%) were male, and more than 60% of patients had an ECOG performance status of 0.

The median treatment dose in the sorafenib arm was 800 mg. The median cumulative period of intake was 2.8 months. The permanent discontinuance rate was 61.1%.

The researchers found that the median overall survival in the intention-to-treat population was 8.0 months with SIRT vs 9.9 months in the sorafenib arm, with no significant difference between the two groups (P = .18). There was no difference in overall survival in the per protocol group, at 9.9 months in both groups.

Dr Bouattour also reported that overall survival was unaffected when patients were stratified by age, sex, disease severity, tumor characteristics, and laboratory examination results.

He said there was no significant difference in progression-free survival between the SIRT and sorafenib arms in both the intention-to-treat and per protocol populations.

However, there was significantly less radiologic progression with SIRT vs sorafenib when the liver as the first site (P = .014), although no significant differences were seen for progression outside the liver.

SIRT was also associated with a significantly objective response, defined as complete responses plus partial responses, compared with sorafenib, at 19.0% vs 15.2% (P = .042).

The team found that, compared with sorafenib, SIRT was associated with significantly fewer adverse events of any grade (P < .001) and adverse events of grade ≥3 (P < .001), as well as in the proportion of patients with ≥1 adverse events of any grade (P < .001) and adverse events of grade ≥3 (P < .001).

The median number of adverse events per patient of any grade was also significantly lower with SIRT vs sorafenib (P < .001).

Specifically, SIRT was associated with significantly lower rates of adverse events of any grade in terms of fatigue, weight loss, hand and foot skin reactions, anorexia, diarrhea, nausea/vomiting, abdominal pain, and hypertension.

Grade ≥3 event rates were significantly lower with SIRT vs sorafenib for fatigue, weight loss, hand and foot skin reactions, diarrhea, abdominal pain, and hypertension.

Quality of life, as measured using the EORTC QLQ-C30 questionnaire Global Health Status subscore, was significantly better in the SIRT group (group-time interaction P = .45), although only a total of 65 questionnaires were completed at the 12-month assessment compared with 355 at baseline.

Which Is the Better Approach?

Discussing the findings, Michel Ducreux, MD, PhD, of Institut Gustave Roussy, Villejuif, France, said that the question remains: "Is it better to do radioembolization, or is it better to do sorafenib?"

Praising the design and execution of the SARAH study, he said that the results can be put into perspective by considering another recently reported study, the phase 2 SIRveNIB trial, which was presented at the most recent annual meeting of the American Society of Clinical Oncology, held in June 2017.

Although SIRveNIB included fewer patients than the current study, it reached the same conclusion, which was that there was no significant difference in overall survival between radioembolization and sorafenib therapy in locally advanced HCC.

The earlier trial did show some improvements in progression-free survival, but only in treated patients, and the difference was not statistically significant. Radioembolization was, again, better tolerated than sorafenib, with significantly fewer adverse events of any grade and adverse events of grade ≥3.

Dr Ducreux continued: "If we put together these two trials, this is a little bit disappointing, because we can say that radioembolization did not show any advantage in terms of overall survival when compared to sorafenib, and we can say that sorafenib remains the standard of care.

"But we are quite consistent in the fact that this treatment has a very good tolerance and that it is able to induce a better response and better liver disease control, and maybe this is something that we could use for new hypotheses and to build up trials in specific subgroups of populations."

Consequently, Dr Ducreux argued, radioembolization is not finished as a treatment in this population and "could be there in between TACE and sorafenib, and that we can create a specific subpopulation for this treatment."

"Why should I have this tool in my box?" he asked, referring to SIRT. "Because it's completely different from sorafenib," he commented, although questions remain as to the use of radioembolization.

"The first one is clearly cost-effectiveness. If radioembolization is less expensive than sorafinib, that is something that could be useful to continue to work on this type of treatment. At this time, we do not know exactly," he said.

Referring to the different lengths of time in treatment between SIRT and sorafinib, Dr Ducreux added: "The choice of the patients could be interesting too, if we consider that the level of activity is exactly the same.

"So, I would ask my patient: Do you prefer a kick in the back to treat your disease, or do prefer continuous pressure with drugs that are a completely different way to work your disease?"

With respect to sequencing, he said, "We may imagine that this is a neutral, so we can do radioembolization and then maybe if it does not work, we could propose to patients that they then take sorafinib.

"But, in fact, when we look at the literature, we can see that there are only a few patients who are able to receive sorafinib after failure of radioembolization.... So the idea that you can give one and the second one after is an idea that doesn't work very well."

Dr Ducreux concluded by saying that, at this time, TACE "remains the gold standard, but clearly, radioembolization has excellent tolerance, with convincing new data," although a number of potential issues need to be examined further.

The study was funded by Sirtex Medical Ltd. Dr Bouattour has received speaker fees from Bayer and Sirtex Medical and is a member of the advisory boards for Bayer and Bristol-Myers Squibb. No other relevant financial relationships have been disclosed.

19th World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-001, presented 29 June 29, 2017.