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Management of portal hypertension in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma

Published:February 16, 2022DOI:https://doi.org/10.1016/j.jhep.2022.02.004

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      • Baveno VII – Renewing consensus in portal hypertension
        Journal of HepatologyVol. 76Issue 4
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          To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD – defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled “Personalized Care for Portal Hypertension”.
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      • Reply to: ‘Management of portal hypertension in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma’
        Journal of HepatologyVol. 77Issue 2
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          We read with interest the comments of Drs. Ollivier-Hourmand, Alaire and Cervoni, who wrote a letter on behalf of the ‘Club Francophone pour l’Etude de l’Hypertension Portale’ commenting on the management of portal hypertension in the specific group of patients with hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Beva).1
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      To the Editor:
      Management of portal hypertension in the setting of advanced hepatocellular carcinoma (HCC) was not raised by Baveno VII renewing consensus in portal hypertension.
      • De Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Thomas Reiberger T.
      • Cristina Ripoll C.
      on behalf of the Baveno VII Faculty
      Baveno VII-Renewing consensus in portal hypertension.
      The “Club Francophone pour l’Etude de l’Hypertension Portale” would like to take the opportunity to discuss this issue.
      The combination of atezolizumab and bevacizumab which is the current first-line therapy for advanced HCC
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevaci- zumab in unresectable hepatocellular carcinoma.
      may expose patients to bleeding complications related to portal hypertension. Phase II studies of bevacizumab monotherapy in HCC have shown a 10% rate of variceal bleeding.
      • Fang P.
      • Hu J.H.
      • Cheng Z.G.
      • Liu Z.F.
      • Wang J.L.
      • Jiao S.C.
      Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carci- noma: a systematic review of phase II trials.
      This risk was lower in the IMbrave150 study, with only 3.65% of hemorrhages secondary to gastric or oesophageal varices in the atezolizumab + bevacizumab arm compared to 1.28% in the sorafenib arm (https://clinicaltrials.gov/ct2/show/results/NCT03434379; last update posted: December 30, 2021), but similar to other phase III data.
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevaci- zumab in unresectable hepatocellular carcinoma.
      ,
      • Allaire M.
      • Rudler M.
      • Thabut D.
      Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses.
      In IMbrave 150, patients were excluded in case of bleeding related to portal hypertension in the last 6 months or in the absence of efficient prophylaxis. Therefore in « real life », a meticulous evaluation of bleeding risk secondary to portal hypertension is needed and primary prophylaxis is essential when indicated before starting combination therapy.
      • Gordan J.D.
      • Kennedy E.B.
      • Abou-Alfa G.K.
      • Beg M.S.
      • Brower S.T.
      • Gade T.P.
      • et al.
      Systemic therapy for advanced hepatocellular carcinoma: ASCO guidelines.
      The recent Baveno VII consensus for portal hypertension recommends non-selective beta blockers (NSBBs) in compensated cirrhosis with clinically significant portal hypertension (CSPH) defined by the presence of either gastroesophageal varices, or ascites, or portosystemic collateral vessels or liver stiffness measurement (LSM) ≥25 kPa or hepatic venous pressure gradient ≥10 mmHg.
      • De Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Thomas Reiberger T.
      • Cristina Ripoll C.
      on behalf of the Baveno VII Faculty
      Baveno VII-Renewing consensus in portal hypertension.
      In patients without CSPH, screening endoscopy is indicated either if platelets ≤150,000/mm3 or LSM ≥20 kPa. Other patients can be followed by yearly repetition of LSM and platelet count. If varices are present, primary NSBB prophylaxis is indicated in first line whatever the size. In case of NSBB contraindication or intolerance, endoscopic band ligation (EBL) must be alternatively performed for high-risk varices.
      However, in case of advanced HCC, with or without portal obstruction, Baveno VII criteria are not applicable since LSM and platelet count may be modified by the tumor and portal hypertension may rapidly worsen so that the annual rhythm of follow-up by LSM and platelets is not appropriate.
      • Allaire M.
      • Rudler M.
      • Thabut D.
      Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses.
      Therefore, before starting bevacizumab, a screening endoscopy in the 6 previous months is mandatory.
      • Gordan J.D.
      • Kennedy E.B.
      • Abou-Alfa G.K.
      • Beg M.S.
      • Brower S.T.
      • Gade T.P.
      • et al.
      Systemic therapy for advanced hepatocellular carcinoma: ASCO guidelines.
      Likewise, when primary prophylaxis is not indicated, screening endoscopy should be considered yearly.
      One other concern is primary prophylaxis in case of NSBB contraindication or intolerance. In patients treated with bevacizumab, EBL is the alternative to NSBBs, but we have to keep in mind that it may not be so safe. Indeed 10 to 12 days after EBL, ulcer bleeding occurs in 4.6%, with an increased risk in patients with HCC (hazard ratio 8.84; 95% CI 2.85-27.02).
      • Dueñas E.
      • Cachero A.
      • Amador A.
      • Rota R.
      • Salord S.
      • Gornals J.
      • et al.
      Ulcer bleeding after band ligation of esophageal varices: risk factors and prognosis.
      Bevacizumab could further delay post-EBL ulcer healing as well as bleeding control. Given this potential side effect, a 4-week interval is usually recommended after surgery before starting bevacizumab, which can be reduced to 7 to 14 days for less invasive procedures.
      • Erinjeri J.P.
      • Fong A.J.
      • Kemeny N.E.
      • Brown K.T.
      • Getrajdman G.I.
      • Solomon S.B.
      Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement.
      ,
      • Kriegel I.
      • Cottu P.H.
      • Fourchotte V.
      • Sanchez S.
      • Fromantin F.
      • Kirov K.
      • et al.
      Wound healing and catheter thrombosis after implantable venous access device placement in 266 breast cancers treated with bevacizumab therapy.
      Moreover, varices eradication requires 3 to 4 EBL sessions repeated at intervals of 2 or 3 weeks,
      • Lo G.H.
      • Lai K.H.
      • Cheng J.S.
      • Chen M.H.
      • Huang H.C.
      • Hsu P.I.
      • et al.
      Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial.
      which may impact HCC treatment initiation. In our expert opinion, atezolizumab + bevacizumab treatment should not be delayed until complete eradication, and combination therapy can be started 2 weeks after a first EBL session in the absence of post-EBL ulcer bleeding.
      The last concern is that, if acute bleeding occurs during atezolizumab + bevacizumab treatment, secondary prophylaxis with NSBBs and EBL must be started and HCC treatment may be modified. In patients who maintained an ECOG performance status 0/1 and remained compensated after bleeding, it is not clear for how long bevacizumab should be interrupted due to the risk of slower healing of ulcers and bleeding recurrence. Other questions are still pending. Should atezolizumab be continued in monotherapy until variceal eradication? Is there a definitive contraindication to this combination therapy? Should other anti-VEGF therapy such as tyrosine kinases inhibitors (TKIs) be preferred as this treatment was associated with a decrease in portal hypertension in preclinical models
      • Allaire M.
      • Rudler M.
      • Thabut D.
      Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses.
      ? To date, strong clinical evidence is lacking to consider that TKIs would be safer than continuing atezolizumab + bevacizumab in this situation. Moreover, other combination therapies will probably be available soon. Tremelimumab + durvalumab recently showed promising results (Gastrointestinal Cancer Symposium of the American Society of Clinical Oncology, January 2022) and the results of pembrolizumab + lenvatinib are still pending. The decision should obviously take into account, case by case, the initial response to immunotherapy.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors' contributions

      Guarantor of the article: Isabelle Ollivier-Hourmand. Isabelle Ollivier-Hourmand drafted the manuscript. Manon Allaire contributed to the critical revision of the manuscript. Jean Paul Cervoni contributed to the critical revision of the manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      Governing Board members of the “Club Francophone pour l’Etude de l’Hypertension Portale”:
      Delphine Weil, Violaine Ozenne, Pierre Emmanuel Rautou, Charlotte Bouzbib, Sabrina Sidali, Frédéric Oberti, Maeva Guillaume, Paul Castellani, Paul Calame, Sandrine Barge, and Christophe Bureau.

      Supplementary data

      The following are the supplementary data to this article:

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