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Biejia-Ruangan compound and incidence of hepatocellular carcinoma

Published:November 16, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.012

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      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.

      Authors' contributions

      Lei Luo and Wenlong Yang: design. Lei Luo and Xuebing Yao: Manuscript draft. Wenlong Yang: Editing and revision. All the authors read and approved the final version of the manuscript.
      We read with great interest the recent article “Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B” online published at August 18 2022 in Journal of Hepatology.
      • Ji D.
      • Chen Y.
      • Bi J.
      • Shang Q.
      • Liu H.
      • Wang J.B.
      • et al.
      Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B.
      As Chinese hepatologists, we express our gratitude and appreciation to all the researchers in the current study which suggest that adding a traditional Chinese medicine Biejia-Ruangan compound (BRC) to entecavir showed superiority over entecavir used alone in reduction the risk of hepatocellular carcinoma (HCC). It appears to indicate that BRC could be conferred some distinct property in HCC prevention among patient with chronic hepatitis B, but it may be premature to draw any conclusion.
      We reviewed the registration information for this article on the www.clinicaltrials.gov, the original purpose was to investigate whether BRC could attenuate liver fibrosis in patients with hepatitis B, the occurrence of hepatocellular carcinoma was neither included in the initial version (October 18, 2013) of trial protocol nor in the updated version (August 17, 2015). State in another way, it should be alert whether the positive result was come from a coincidence, especially for non-specified endpoints.
      A recent classic example is the interleukin-1β inhibitor--canakinumab, which significantly lowered the rate of recurrent cardiovascular events in patients with previous myocardial infarction. The exploratory results from this study suggested canakinumab exhibited a dose-dependent capacity on reducing incident lung cancer (hazard ratio 0·33, 95% CI 0·18-0·59 for 300mg group, and hazard ratio 0·61, 95% CI 0·39-0·97 for 150mg group), as well as excellent performance on reducing lung cancer mortality (hazard ratio 0·23, 95% CI 0·10-0·54).
      • Ridker P.M.
      • MacFadyen J.G.
      • Thuren T.
      • Everett B.M.
      • Libby P.
      • Glynn R.J.
      Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.
      It seems to imply that anti-inflammatory therapy targeting the interleukin-1β innate immunity had potential on reducing incident lung cancer and lung cancer mortality, noticeably, the finding was not a prespecified clinical endpoint. In the subsequent trials to determine its clinical benefit on non-small cell lung cancer, the addition of canakinumab to the chemotherapy docetaxel failed to pare down the risk of death or disease progression,

      Novartis provides update on Phase III study evaluating canakinumab (ACZ885) as second or third-line treatment in combination with chemotherapy in non-small cell lung cancer. 2021 Mar 09, 2021 [cited 2022 Oct 24]; Available from: https://www.novartis.com/news/media-releases/novartis-provides-update-phase-iii-study-evaluating-canakinumab-acz885-second-or-third-line-treatment-combination-chemotherapy-non-small-cell-lung-cancer

      and failed to demonstrate any benefit when combined with pembrolizumab.
      • Tan D.S.
      • Felip E.
      • Castro G.
      • Solomon B.J.
      • Greystoke A.
      • Cho B.
      • et al.
      Abstract CT037: Canakinumab in combination with first-line (1L) pembrolizumab plus chemotherapy for advanced non-small cell lung cancer (aNSCLC): Results from the CANOPY-1 phase 3 trial.
      The case underscore the importance of prespecified endpoints and to analyze the results with rigorous obedience of the study design.
      Authors attribute the reduction in HCC to the improvement of liver fibrosis with BRC. Most of HCC develops from a context of cirrhosis would make physicians prone to assume that cirrhosis is a predisposing factor for hepatocarcinogenesis, however, recent literature proposed that liver fibrosis and development of HCC are two independent processes with distinct molecular mechanisms rather than a sequential series of events,
      • Garrido A.
      • Djouder N.
      Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma.
      meaning that is hardly to achieve an antitumor effect by anti-hepatic fibrosis. In general, it is unlikely that an agent had originally been developed to anti-hepatic fibrosis while possessing potent efficacy in preventing HCC unexpectedly, particularly there is little experimental study to support that researchers were aware of this regard at the time of trial initial, and lack of persuasive evidence could account for this by far.
      Finally, additional work is needed for elucidating the underlying mechanisms regarding the role of BRC in liver tumorigenesis. More importantly, replication of the preventive efficacy in formal settings of HCC screening among patients with chronic hepatitis B is required.

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        • Chen Y.
        • Bi J.
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        • Wang J.B.
        • et al.
        Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B.
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      1. Novartis provides update on Phase III study evaluating canakinumab (ACZ885) as second or third-line treatment in combination with chemotherapy in non-small cell lung cancer. 2021 Mar 09, 2021 [cited 2022 Oct 24]; Available from: https://www.novartis.com/news/media-releases/novartis-provides-update-phase-iii-study-evaluating-canakinumab-acz885-second-or-third-line-treatment-combination-chemotherapy-non-small-cell-lung-cancer

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        • Castro G.
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        • Cho B.
        • et al.
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