Treatment With IFN After Curative Resection of HCC in HCV-Related Cirrhosis
Condition: Hepatocellular Carcinoma; Hepatitis C Virus Infection; Liver Cirrhosis; Interferon Treatment; Hepatic Resection
MeSH terms: Hepatitis C; Carcinoma; Carcinoma, Hepatocellular; Liver Cirrhosis; Fibrosis
Study type: Interventional
Phase: Phase 3

Summary: 
      We conducted a randomized controlled trial of adjuvant interferon (IFN) therapy in patients
      with hepatitis-C virus (HCV)-related cirrhosis who underwent curative resection of
      hepatocellular carcinoma (HCC) to investigate whether IFN could reduce or delay the incidence
      of recurrent tumor (secondary/tertiary prevention of HCC). Patients were randomly assigned to
      treatment with IFN (3MU thrice/wk /48 weeks) vs. no treatment after curative resection of
      HCC(control group)
    

Detailed description: 
      Background

      Primary liver cancer (hepatocellular carcinoma, HCC) remains a major cancer-related cause of
      death with an estimated incidence of 1 million cases per year worldwide and particular
      endemic distribution related to chronic hepatitis carriers. Post-necrotic cirrhosis due to
      chronic infection by HBV and HCV is the leading background for HCC development with a yearly
      rate of 3% and a 5-year probability of survival of 20%.

      Liver surgery, resection or transplantation, appears the only chance of curative treatment of
      the tumor, but feasibility is still ranging from 15 to 30% in Western countries at time of
      diagnosis. Several alternative treatments are available but their potential curative effects
      are lacking, due to the absence of controlled trials.

      Liver resection is claimed to be feasible in order 15-30% of patients with HCC with mortality
      reported in major centers extremely low (5%). Technical and biological devices developed in
      the setting of OLT can now support the limited reserve of cirrhotic livers after resection.

      Regulated segmentectomy is advisable with removal of the whole portal territory belonging to
      the tumor. Single nodule tumors (< 5 cm) and compensated cirrhosis (Child class A) are
      accepted as the best candidates for liver resection that now can be performed with minimal
      blood loss, and minimal ischemia damage. Intraoperative ultra sound examination is now
      routinely used as the golden standard for staging and detection of previously undiscovered
      neoplastic nodules. Hepatic decompensation with ascites development, cholestasis and variceal
      bleeding within three months from surgery are the main negative prognostic factors for
      patient survival. Five years survival exceed 50% but tumor recurrences due to cirrhosis
      persistence could exceed 30% after three years of follow-up. Several attempts to reduce
      recurrence through antiangiogenetic and antiproliferative agents have been proposed.

      In the present project a prospective randomized trial of Interferon (as antiproliferative
      drug) versus control in anti-HCV positive patients will investigate in homogeneous categories
      of resected tumor possible variation in the natural history and namely a reduction of
      recurrence rate after curative resection.

      Purpose and Study Design

      The trial was intentionally designed in 1997 as an unresticted collection of patients with
      histologically proved HCC and a HCV-related cirrhosis selected for surgical resection of the
      tumor in 4 experienced surgical Liver Units in Italy. Eligible patients were stratified on
      the basis of concomitant anti-core antibodies against HBV (anti-HBc) into two populations:
      "pure HCV" (HCV-RNA:positive, anti-HBc:negative) and "mixed HCV+HBV" (HCV-RNA:positive,
      anti-HBc:positive). Within each strata patients were then randomized in a 1:1 ratio to
      treatment with α-interferon (IFN) vs. no treatment (control). No restriction criteria were
      applied to tumor stage, as far as the resection of HCC was judged as potentially curative at
      pre-operative staging, intra-operative ultrasound and post-operative pathology (clearance of
      surgical margins).

      The study was originally designed for lymphoblastoid α-interferon; then soon after trial
      approval by the NCI-Milan Scientific and Ethic Committee (#98-016) the protocol was amended
      for allowing also the use of recombinant α-2a (Roferon-A, Hoffmann-La Roche, Nutley NJ) or α
      -2b interferon (Intron-A, Schering-Plough, Kenilworth, NJ). The latter was eventually the
      preferred form. Patients allocated to treatment received IFN 3 MU/thrice weekly for 48 weeks
      starting within 6 weeks from the operation. The severity of adverse events during treatment
      were monitored and rated. Therapy was discontinued in case of life-threatening adverse event
      or in case of HCC recurrence during treatment. For severe events other than anemia the IFN
      dose was reduced by 50%; full dose could be resumed after the event was resolved or
      discontinued if the effect persisted. The percentage of the total predicted dose of IFN
      actually assumed by each patients was recorded. Patients assuming at least 80% of the total
      dose of IFN and treated for at least 80% of the expected duration of therapy were a priori
      defined as adherent to therapy.

      Recurrences were a priori defined as "early" or "late" whether or not they occurred within 2
      years from the surgical removal of the HCC. In fact early recurrence were related to
      intra-hepatic metastases of the primary tumor possibly missed at the time of therapy, while
      late recurrence might be due to new cancer foci related to the persistence of HCV-related
      carcinogenetic factors.

      Primary endpoint of this randomized clinical trial (RCT) was recurrence-free survival (RFS)
      while the secondary endpoint were disease-specific survival (DSS) and overall survival (OS).
      Further secondary endpoints were the assessment of IFN tolerability in post-surgical patients
      and the observation of prognostic factors related to early or late recurrence. Adherent
      patients were considered for a subgroup analysis focused on patients who effectively received
      the treatment designed to prevent HCC recurrence.

      Enrolment for the trial started on June 1998. By December 2002 the predicted sample size of
      150 randomized patients was completed ("pure HCV": 80 and "mixed HCV+HBV": 70). The baseline
      clinical, laboratory and tumor characteristics of the two arms and viral strata were
      comparable. After 45 months of median follow-up the three- and five- years survival rates
      were 69% and 52.4% respectively for the control group and 77.3% and 63.6% respectively for
      the IFN group (P= 0.471) . At the univariate analysis tumor multiplicity (>1 nodule) and
      vascular invasion were significantly related to recurrence. After adjustment of the relative
      weight of prognostic factors in a series of Cox models and cumulative incidence curves
      calculated on pattern of recurrence, a benefit of IFN was observed on late recurrence
      occurring in the pure-HCV patients adherent to treatment (hazard rate: 0.3; 95% Confidence
      interval:0.09-0.9, P=0.04).

      In conclusion, although adjuvant IFN failed to show a generalized effect on prevention of HCC
      recurrence after curative resection, it effectively reduced late recurrence due to new tumor
      foci in pure-HCV patient adherent to therapy (i.e.: receiving at least 80% of IFN dose for at
      least 80% of time).
    

Intervention name(s): Interferon alpha-2b
Intervention type(s): Drug
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment