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HCC and HCV - new Treatments

by Gerond Lake-Bakaar, MD. PhD | May 26th, 2018

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Immunotherapy Prolongs Hepatocellular Carcinoma Survival

Neil Osterweil

April 18, 2018

PARIS — For patients with hepatocellular carcinoma, adjuvant immunotherapy with autologous cytokine-induced killer cells significantly extends 5-year recurrence-free and overall survival, data from a follow-up extension study show.

"Surprisingly, the gain in survival was even after withdrawal of finite-duration immunotherapy," said Jeong-Hoon Lee, MD, PhD, from Seoul National University College of Medicine in South Korea.

The immunotherapy uses T-lymphocytes derived from a patient's peripheral blood. They are expanded ex vivo with cytokines and cytotoxic T-cells, and then reinfused into the patient at fixed intervals.

Lee reported follow-up results from a study of immunotherapy in patients with hepatocellular carcinoma treated with surgical resection, radiofrequency ablation, or percutaneous ethanol injection at university-affiliated hospitals in Korea here at the International Liver Congress 2018.

 

The original study showed that the primary end point of median recurrence-free survival was better with immunotherapy than with no adjuvant therapy (44 vs 30 months; hazard ratio [HR], 0.63; P = .010), as were the secondary end points of all-cause mortality (HR, 0.21; 95% confidence interval [CI], 0.06 - 0.75; P = .008) and hepatocellular carcinoma-related death (HR, 0.19; 95% CI, 0.04 - 0.87; P = .02) (Gastroenterology. 2015;148:1383-1391.e6).

Adverse events were significantly more common in the immunotherapy group than in the control group (62% vs 41%; P = .002), but the difference in serious adverse events between groups was not significant (7.8% vs 3.5%; P = .15).

In the immunotherapy group, cytokine-induced killer cells 200 mL were administered intravenously over a period of 60 minutes. The 16 treatments were delivered once weekly for the first 4 weeks, followed by four treatments every 2 weeks, four treatments every 4 weeks, and then four treatments every 8 weeks.

In the extension study, participants in the original study — 89 from the immunotherapy group and 73 from the control group — were followed out to a median of 68.5 months.

 

At 5 years, median recurrence-free survival continued to be better in the immunotherapy group than in the control group (44.8% vs 33.1%; HR, 0.67, P = .009), as did overall survival (HR 0.33; P = .006) and cancer-specific survival (HR, 0.33; = .02).

Most of the benefit was in patients with tumors at least 2 cm in size (HR, 0.66; = .035). Although there appeared to be some recurrence prevention in patients with lesions smaller than 2 cm, the difference was not statistically significant, possibly because of the relatively small sample size.

It is possible that the prolonged antitumor activity of cytokine-induced cells promotes long-lasting memory T-cells and memory natural killer cells, Lee explained. In fact, the cells themselves are a form of terminally differentiated memory T-cells, he added.

Cost is a barrier to the widespread adoption of this approach, he acknowledged, noting that in Korea, the procedure is not currently reimbursable.

 

Despite the cost, any effective and safe adjuvant therapy would be welcome in the management of patients with hepatocellular carcinoma, said Ronald Sokol, MD, from the University of Colorado School of Medicine in Aurora. To date, nothing has been proven to reduce the risk for recurrence.

"Once again, the results are quite impressive," Sokol told Medscape Medical News.

"In cancer trials, if you prolong your survival without recurrence by 14, 16, 18 months, that's frequently considered a very significant interval, particularly when drug combinations are eventually used and extend cancer-free survival," he said.

 

This study was supported by Green Cross Cell. Lee and Sokol have disclosed no relevant financial relationships.

International Liver Congress (ILC) 2018: Abstract GS-008. Presented April 13, 2018. Follow Medscape Gastro on Twitter @MedscapeGastro and Neil Osterweil @NeilOsterweil

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More Than Okay to Reduce Sorafenib Dose for Liver Cancer

Nick Mulcahy

September 15, 2017

In the treatment of hepatocellular carcinoma (HCC), it's "safe and reasonable" to start sorafenib (Nexavar, Bayer) at reduced dosages, conclude authors of a new retrospective analysis of nearly 5000 patients.

Reduced dosing was not associated with inferior overall survival compared with standard dosing, report the study authors, led by Kim Reiss Binder, MD, a medical oncologist at the University of Pennsylvania in Philadelphia.

Notably, the less intense dosing also had some benefits — a reduced pill burden and about $3000 in reduced costs, as well as a trend toward decreased discontinuation of sorafenib due to adverse events.

"It's important to remember that the reduced dose patients will ramp up as they show they can handle it," said Dr Reiss Binder in a press statement.

 

Patients' ability to handle sorafenib, which is the only approved first-line therapy for HCC, is a challenge because of toxicity. Previous research has shown about one third of patients permanently discontinue the drug (Int J Clin Pract. 2014;68:609-617). The standard dose is 400 mg twice daily.

The study's good news about overall survival is highly relevant as clinicians are increasingly starting patients at a lower initial dose. The authors report that full-dose initial prescriptions accounted for 78% of all new sorafenib prescriptions in 2007 but decreased to 51% in 2014.

The new study was published online September 5 in the Journal of Clinical Oncology.

"This paper confirms what we have experienced," said Sunyoung Lee, MD, PhD, a medical oncologist at the Roswell Park Cancer Institute in Buffalo, New York, who was not involved with the study.

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Triple Combo of drugs for Hepatitis C      

https://www.medpagetoday.com/gastroenterology/hepatitis/65708

A combination of three drugs that act directly to block hepatitis C (HCV) replication successfully cured most patients who had previously failed therapy with such agents, researchers reported.

In two phase III trials, the investigational combination of sofosbuvir, velpatasvir, and voxilaprevir cleared the virus in 96% and 98% of patients, regardless of whether they had compensated cirrhosis or not, according to Marc

Adverse events associate with the combination were mild and similar to those seen among patients getting a placebo or the approved combination of sofosbuvir and velpatasvir (Epclusa), Bourlière and colleagues reported in the June 1 issue of the New England Journal of Medicine.

While retreatment options are available for patients with chronic HCV who have failed previous treatment with an interferon-containing regimen, there is no approved treatment for those whose treatment with direct-acting antiviral agents (DAAs) was unsuccessful.

Although the DAA regimens are highly effective, with cure rates in many cases of more than 95%, the sheer number of people with chronic HCV -- estimated to be some 150 million around the world -- means that a substantial number will fail therapy and need retreatment.

To help fill the gap, Bourlière and colleagues tested the three-drug combination in two trials -- dubbed POLARIS-1 and POLARIS-4 -- whose central difference was that patients in POLARIS-1 had failed therapy with an NS5A inhibitor, while those in POLARIS-4 had unsuccessful treatment with DAAs attacking other viral targets.

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Hepatitis C Treatments Reduce Transplants

Therapies also appear to reduce liver-related mortality

  • by Ed Susman, Contributing Writer, MedPage Today
  • This article is a collaboration between MedPage Today® and:

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
 

PARIS -- Since use of direct acting antiviral combination therapies for hepatitis C virus (HCV) infection became widespread, the need for liver transplantation for patients with the infection has plummeted, researchers reported here.

In 2007, HCV infection was listed as the reason for 23.87% of all liver transplants in Europe, and that remained constant through 2014 when the impact of direct acting antiviral medications began to hit, said Chiara Mazzarelli, MD, of A.O. Ospedale Niguarda Ca'Granda, Milan, Italy.After that, the proportion dropped sharply each year, to the point that in 2017 about 10.6% of transplants were performed for HCV (P<0.0001).

"In contrast, the demand for livers for patients with NASH (nonalcoholic steatohepatitis) is increasing," Mazzarelli said in her late-breaker presentation at the International Liver Conference, sponsored by the European Association for the Study of the Liver. Liver transplantation for alcohol-related cirrhosis and for hepatitis B infection has remained consistent across the 11-year study period, she said.

She indicated that the reduction in transplantation observed among European patients would likely be similar in the United States and North America.

"In Europe the percentage of liver transplantations performed because of hepatitis C virus infection is rapidly declining," Mazzarelli said at a press conference. "This trend is expected to continue with the increasing access to direct acting antiviral therapy. For the first time after many years, survival of hepatitis C virus transplant recipients is improving thanks to the advent of direct acting antivirals."

"This important study does put into perspective the impact of treatment and shows that treatment can result in really relevant outcomes," said press conference moderator Markus Cornberg, MD, of Hannover Medical School in Germany.Mazzarelli scrutinized data from the European Liver Transplant Registry, identifying 36,382 adult liver transplantations which were performed between January 2007 and June 2017 due to hepatitis C, hepatitis B, alcohol and NASH.

The researchers stratified time periods based on treatment options for hepatitis C, with the period from 2007 to 2010 identified as the interferon era; the period from 2011 to 2013 as the protease inhibitor era, and the period from 2014 to 2017 as the direct acting antiviral era. During the first two periods, the numbers of liver transplantations in Europe ranged from about 2,600 to around 3,000 a year. That number fell to 2,271 in the first half of 2017, driven mainly by the precipitous drop in HCV infection etiology for transplant, she said.

A similar fall was observed for patients with decompensated liver disease as a result of HCV, and a mirroring fall in cases of transplant needed for patients who developed primary hepatocellular carcinoma secondary to hepatitis C.

Mazzarelli said that the decline in the need for a liver transplant was more evident in patients with HCV-related decompensation – a reduction of more 68.8% – than in those patients who were diagnosed with hepatocellular carcinoma associated with HCV where the reduction was about 34%.

Patients who underwent liver transplantation in the direct acting antiviral era also had significantly better survival after transplant when compared with the other periods. About 76.9% of patients in the direct acting antiviral period lived at least 3 years compared with about 70% of patients in the protease era and 65.1% of those who were transplanted during the interferon era (P<0.0001).

 
 

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