Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis§

Authors

  • Vincenzo Mazzaferro,

    Corresponding author
    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    • Gastro-Intestinal Surgery and Liver Transplantation Unit, Istituto Nazionale Tumori IRCCS, via Venezian 1, Milano, 20133 Italy
    Search for more papers by this author
    • fax: (39) 02-23903259

  • Raffaele Romito,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Marcello Schiavo,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Luigi Mariani,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Tiziana Camerini,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Sherrie Bhoori,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Lorenzo Capussotti,

    1. Department of Surgery and Gastroenterology Mauriziano Hospital, Turin, Italy
    Search for more papers by this author
  • Fulvio Calise,

    1. Department of Surgery and Hepatology, Cardarelli Hospital University of Naples, Italy
    Search for more papers by this author
  • Riccardo Pellicci,

    1. Department of Surgery, Santa Corona Hospital Pietra Ligure, Genoa, Italy
    Search for more papers by this author
  • Giulio Belli,

    1. Department of Surgery and Hepatology, Cardarelli Hospital University of Naples, Italy
    Search for more papers by this author
  • Alessandro Tagger,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Massimo Colombo,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
  • Ferruccio Bonino,

    1. Department of Surgery, Biomedical Statistics, Pathology, National Cancer Institute of Milan and Chair of Gastroenterology, Policlinico Foundation, Department of Medicine, University of Milan, Italy
    Search for more papers by this author
    • Potential conflict of interest: Dr. Bonino advises for Roche.

  • Pietro Majno,

    1. Department of Surgery and Liver Unit, University of Geneva, Geneva, Switzerland
    Search for more papers by this author
  • Josep M. Llovet

    1. Hospital Clinic of Barcelona, Spain and Mount Sinai Hospital, New York, NY
    Search for more papers by this author
    • J. M. L. is a Professor of Research Istitut Català de Recerca Avancada, IDIBAPS, Hospital Clinic Barcelona


  • This was an investigator-initiated study. No sponsorship or funding sources for treating patients with interferon-α were solicited. Conversely, thanks to the cooperation of many general practitioners following the home care of the patients referred for surgical removal of hepatocellular carcinoma, the Italian National Health Service supported the cost of treatment in the interferon group as a part of a clinical strategy preventing complications of chronic hepatitis C.

  • Clinical trial registration number: NCT00273247.

  • The following members of the HCC Italian Task Force contributed equally to the study: S. Andreola, A. Antonucci, C. Battiston, J. Coppa, S. LoVullo, R. Miceli, A. Pulvirenti, E. Regalia, A. Russo, N. Zucchini (National Cancer Institute, Milan); R. Polastri, M. Tabone (Mauriziano Hospital, Turin); A. Ascione, F. Sicoli (Federico II Hospital and University of Naples); M. Pasqualini, A. Profeti (S. Corona Hospital, Pietra Ligure-Genoa); A. Belli, A. D'Agostino (S. Maria di Loreto Nuovo Hospital, Naples); M. R. Brunetto, D. Flichman (Cisanello Hospital, Pisa); R. Castoldi, V. Di Carlo (S. Raffaele Hospital, Milan); M. Borzio, G. P. Spina (Fatebenefratelli Hospital, Milan); M. Colledan, M. Strazzabosco (Riuniti Hospital, Bergamo); B. Gridelli, U. Palazzo (ISMETT, Palermo).

Abstract

Tumor recurrence after resection of hepatocellular carcinoma (HCC) can occur early (<2 years) or late (>2 years) as metastases or de novo tumors. Interferon (IFN) has the potential for chemoprevention against hepatitis C virus (HCV)-related cirrhosis. A predetermined group of 150 HCV RNA–positive patients undergoing resection of early- to intermediate-stage HCC was stratified into 80 HCV-pure (hepatitis B anticore antibody [anti-HBc]–negative) and 70 mixed HCV+hepatitis B virus (HBV) (anti-HBc–positive) groups, then randomized to IFN-α (3 million units 3 times every week for 48 weeks [n = 76]) versus control (n = 74). The primary end point was recurrence-free survival (RFS); secondary end points were disease-specific and overall survival. Intention-to-treat and subgroup analysis on adherent patients were conducted. Treatment effects on early/late recurrences were assessed using multiple Cox regression analysis. No patient experienced life-threatening adverse events. There were 28 adherent patients (37%). After 45 months of median follow-up, overall survival was 58.5%, and no significant difference in RFS was detectable between the two study arms (24.3% vs. 5.8%; P = .49). HCC recurred in 100 patients (48 IFN-treated, 52 controls), with a 50% reduction in late recurrence rate in the treatment arm. HCC multiplicity and vascular invasion were significantly related to recurrence (P = .01 and .0003). After viral status stratification, while no treatment effect was apparent in the mixed HCV+HBV population and on early recurrences (72 events), there was a significant benefit on late recurrences (28 events) in HCV-pure patients adherent to treatment (HR: 0.3; 95% CI: 0.09–0.9; P = .04). In conclusion, IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV-pure patients receiving effective treatment. (HEPATOLOGY 2006;44:1543–1554.)

Ancillary