Angelo Sangiovanni1, Eleonora Alimenti2, Riccardo Gattai3, Roberto Filomia4, Elisabetta Parente5, Luca Valenti6, Luca Marzi7, Gaia Pellegatta8, Guglielmo Borgia9, Martina Gambato10, Natalia Terreni11, Ilaria Serio12, Luca Belli13, Filippo Oliveri3, Sergio Maimone4, Matteo Brunacci8, Roberta D'Ambrosio2, Laura Virginia Forzenigo14, Francesco Paolo Russo10, Mariagrazia Rumi15, Michele Barone5, Anna Ludovica Fracanzani6, Giovanni Raimondo4, Edoardo Giovanni Giannini8, Maurizia Rossana Brunetto16, Erica Villa7, Elia Biganzoli17, Massimo Colombo18, Pietro Lampertico19. 1. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy. Electronic address: angelo.sangiovanni@policlinico.mi.it. 2. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy. 3. Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, University Hospital of Pisa, Pisa, Italy. 4. Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy. 5. Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy. 6. Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 7. Gastroenterology Unit, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy. 8. Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy. 9. Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples 'Federico II', Naples, Italy. 10. Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy. 11. Division of Gastroenterology, Valduce Hospital, Como, Italy. 12. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. 13. UOC Epatologia e Gastroenterologia, Ospedale Niguarda, Milan, Italy. 14. Unit of Radiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 15. Division of Hepatology, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy. 16. Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, University Hospital of Pisa, Pisa, Italy; Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 17. Department of Clinical Sciences and Community Health & DSRC, University of Milan, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 18. Center of Translational Research in Hepatology, Humanitas Hospital, Rozzano, Italy. 19. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Abstract
BACKGROUND & AIM: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. PATIENTS AND METHODS: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. RESULTS: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47-6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23-7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05-3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08-4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35-6.09; p = 0.006) were associated with HCC recurrence. CONCLUSION: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. LAY SUMMARY: This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.
BACKGROUND & AIM: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. PATIENTS AND METHODS: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. RESULTS: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47-6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23-7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05-3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08-4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35-6.09; p = 0.006) were associated with HCC recurrence. CONCLUSION: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. LAY SUMMARY: This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.
Authors: Cristina Maria Muzica; Carol Stanciu; Laura Huiban; Ana-Maria Singeap; Catalin Sfarti; Sebastian Zenovia; Camelia Cojocariu; Anca Trifan Journal: World J Gastroenterol Date: 2020-11-21 Impact factor: 5.742
Authors: Chung Sang Tse; Ju Dong Yang; Omar Y Mousa; Kevin M Nelson; Surakit Pungpapong; Andrew Keaveny; Bashar A Aqel; Hugo Vargas; Rolland C Dickson; Kymberly Watt; Gregory J Gores; Lewis R Roberts; Michael D Leise Journal: Transplant Direct Date: 2020-12-08
Authors: Jun Yong Park; Sang Gyune Kim; Hae Won Yoo; Young Kul Jung; Sae Hwan Lee; Moon Young Kim; Dae Won Jun; Jae Young Jang; Jin Woo Lee; Oh Sang Kwon Journal: Sci Rep Date: 2022-01-07 Impact factor: 4.379