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Spanish researchers raised a red flag regarding observations of unexpected higher rates of hepatocellular carcinoma recurrence following treatment with direct-acting antivirals for hepatitis C virus infection.
Maria Reig MD, PhD
Spanish researchers raised a red flag regarding observations of unexpected higher rates of hepatocellular carcinoma (HCC) recurrence following treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection in results presented at the 2017 International Liver Congress.
Maria Reig MD, PhD, presented data updating results published last year evaluating increased rates of tumor recurrence in patients following successful treatment for HCC and within months of exposure to DAA treatment. At median follow-up of 12.4 months post-initiation of DAA therapy, 77 patients complete response (CR) following HCC treatment. Of those, 24 patients (31.2%) experienced recurrence and 5 patients (6.5%) died.
“These data indicate that there needs to be further research conducted in this area, clarifying the mechanism for the association between liver cancer recurrence and DAA therapy,” Reig said. “Our study offers further support to previous findings that there is an unexpected high recurrence rate of hepatocellular carcinoma associated with DAAs, and that this association may result in a more aggressive pattern of recurrence and faster tumour progression.”
Reig noted tha Conti et al (J Hepatol. 2016;65:727-733), Romano et al (J Hepatol. 2016;64:S1:10A), and Renzulli et al (J Hepatol. 2016;64:S1:223A) have also described more aggressive evolution of HCC after DAA treatment in patients presenting recurrence or de novo HCC.
Median time from initiation of DAA to first HCC recurrence was 3.5 months. Ten patients presented a second recurrence or disease progression. Median time between the first and second events was median 6 months, and 5 more patients died during this time.
The original study evaluated 77 patients beginning DAA for HCV infection in Spanish referral hospitals from 2014 to 2016 who had undergone successful treatment for HCC, and were in CR plus without ‘non-characterized nodules.’ Twenty-eight patients underwent resection for HCC, 41 had ablation, and 8 underwent transarterial chemoembolization. Following DAA, 94.7% of patients achieved sustained virologic response (SVR), indicating viral clearance from the blood.
In the original results, 16 (27.6%) patients developed radiologic tumor recurrence within a median follow-up of 5.7 months after beginning DAA treatment. Three of these patients died.
In the updated data, researchers also observed that some patients were developing more aggressive disease in addition to elevated recurrence rates. At baseline, 75 patients had stage BCLC-0/A 0 tumors and 2 patients had tumors classified as BCLC-B. Stage 0/A describes resectable asymptomatic tumours and BCLC-B tumors are considered intermediate stage.
Among the 21 patients who experienced subsequent HCC recurrence, 19 patients had BCLC 0-A and 2 patients had BCLC-B stage tumors at DAA treatment initiation. Upon recurrence, 10 patients remained as BCLC A stage but 11 patients demonstrated deteriorating stages.
Among patients with initial stage BCLC-0, 2 patients evolved to BCLC-A and one patient to BCLC-D. In patients with stage BCLC-A, one patient went to BCLC-B, 3 evolved to BCLC-C, and 2 patients progressed to BCLC-D. Among the patients staged BCLC-B, one patient remained BCLC-B after recurrence but the other evolved to BCLC-C.
Researchers adjusted treatment modalities in response to the more aggressive disease staging. Because 6 patients had experienced progression within the immediate 6 months of treatment for HCC recurrence, only 8 (37.5%) were treated with resection, ablation, or liver transplantation. Ten patients (45.8%) received systemic/locoregional treatment and 3 (16.7%) received best supportive care.
Thomas Baumert MD, University of Strasbourg, France, is investigating the mechanism behind the development of liver cancer after HCV cure (ILD 2017 abstract PS-039). In results presented at the Congress, he said that epigenetic and transcriptional changes caused by interaction of the virus with histones are only partially reversed by DAAs and persist after HCV cure, and may act in concert with oncogenes to drive HCC development.
Massimo Colombo MD, Milan, Italy, discussed abstracts, including Dr. Reig´s, being presented at ILC. He asked whether treatment affects recurrence since factors such as patient age and not achieving SVR have also been associated with HCC recurrence. One possible explanation is that DAA treatment can be tolerated by patients with more advanced HCV disease and HCC recurrence following DAA is unrelated to the treatment, but is an expression of disease progression in patients that were at high risk prior at baseline.
“This controversy will only be fully resolved when we have data from prospective studies,” Colombo said.
Reig M, Mariño Z, Perelló C, et al. Tumour recurrence after Interferon-free treatment for hepatitis C in patients with previously treated hepatocellular carcinoma discloses a more aggressive pattern and faster tumour growth. Presented at: 2017 International Liver Congress; April 19-23, 2017; Amsterdam, Netherlands. Abstract PS-031.