Postoperative Adjuvant Therapy With Recombinant Interferon-Alpha Following Curative Resection of HCC
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      We conducted a randomized controlled trial of adjuvant interferon therapy in patients with
      predominantly hepatitis B-related hepatocellular carcinoma (HCC) to investigate whether the
      prognosis after hepatic resection could be improved. Since February 1999, patients with no
      residual disease after hepatic resection for HCC were randomly assigned with stratification
      by pTNM stage to receive no treatment (control group), interferon alpha-2b 10 MIU/m2 (IFN-I
      group) or 30 MIU/m2 (IFN-II group) thrice weekly for 16 weeks. Enrollment to the IFN-II group
      was terminated from January 2000 because adverse effects resulted in treatment
      discontinuation in the first 6 patients. By June 2002, 40 patients each had been enrolled
      into the control group and IFN-I group. The baseline clinical, laboratory and tumor
      characteristics of both groups were comparable. The 1- and 5-year survival rates were 85% and
      61%, respectively for the control group and 97% and 79%, respectively for the IFN-I group
      (P=0.137). After adjusting for the confounding prognostic factors in a Cox model, the
      relative risk of death for interferon treatment was 0.42 (95% CI 0.17 - 1.05; P=0.063).
      Exploratory subset analysis showed that adjuvant interferon had no survival benefit for pTNM
      stage I/II tumor (5-year survival 90% in both groups; P=0.917) but prevented early recurrence
      and improved the 5-year survival of patients with stage III/IVA tumor from 24% to 68%
      (P=0.038). In conclusion, in a group of patients with predominantly hepatitis B-related HCC,
      adjuvant interferon therapy prevented early recurrence and improved survival in those with
      pTNM stage III/IVA tumors.
    

Detailed description: 
      1. Background

           Hepatocellular carcinoma (HCC) is the second commonest cause of cancer death in Hong
           Kong and the majority are hepatitis B related. Hepatic resection has remained the only
           therapeutic option that can offer these patients a chance of long-term survival.
           Although the safety of hepatectomy has improved, postoperative recurrences are frequent.
           Depending on the size of the primary tumors, recent reports from Japan, France and Hong
           Kong1 showed that the postoperative recurrence rate was 20 to 64% at one year and 57 to
           81% at 3 years.

           While the hepatic remnant is the predominant site of recurrence, involvement of
           extrahepatic organs was not infrequent. There are three possible mechanisms for the
           development of recurrent disease:

           i) residual tumor cells due to an inadequate resection margin ii) subclinical metastasis
           that occurs before or during hepatic resection iii) metachronous multicentric
           hepatocarcinogenesis which may be related to the underlying necroinflammation of chronic
           active hepatitis and oncogenic activities of hepatitis viruses.

           The surgeon's attempt to prevent recurrence by more extensive resection is prohibited by
           the need to preserve hepatic function. Futhermore, even a major hepatic resection cannot
           guarantee freedom from recurrence since metachronous multicentric tumors can develop in
           the entire liver. Theorectically, total hepatectomy and liver transplantation removes
           both the subclinical metastases in the liver and prevent metachronous lesions.
           Unfortunately, with immunosuppressive therapy, recurrences are frequent and tumors grow
           more rapidly, thus, illustrating the importance of the host immune surveillance in
           preventing the development of recurrence.

           The use of postoperative regional and systemic chemotherapy has been reported. Although
           retrospective studies have shown encouraging results, there are only limited number of
           prospective trials. The favourable result of the use of oral
           1-hexylcarbomyl-5-fluorouracil in a multi-center trial as reported by Yamamoto and
           colleagues was questionable since treatment was suspended due to side-effects in 44% of
           the patients. Our single-center prospective randomised study performed at Queen Mary
           Hospital (QMH) using a combination of transarterial chemoembolisation and systemic
           epirubicin showed a higher extrahepatic recurrence rate and worse outcome with the use
           of adjuvant chemotherapy. The reasons for the failure of adjuvant chemotherapy include:

           i) HCC is slow-growing and hence cytotoxic drug resistant. ii) the associated liver
           cirrhosis limits the maximum tolerated intensity of chemotherapy iii) the anticancer
           agents may adversely affect the host immunity

        2. Interferon alpha-2b

           Interferon alpha-2b is a recombinant form of human interferon. Interferons are cytokines
           possessing anti-viral, anti-proliferative and immunodulatory effects. Interferon may
           halt the replication of both hepatitis B and hepatitis C virus, thus, reducing the
           severity of the chronic active hepatitis. The histologic activity of chronic active
           hepatitis is an important risk factor for recurrence related to metachronous
           multicentric hepatocarcinogenesis and the use of interferon has been shown to reduce the
           incidence of HCC in patients with cirrhosis due to hepatitis C and possibly hepatitis B.

           Interferon has a powerful anti-proliferative effect on hepatoma cell-line PLC/PRF/5 in a
           dose-dependent manner both in-vitro and in-vivo. The use of interferon has been applied
           to patients with inoperable HCC with a tumour regression rate and survival rate superior
           to that of placebo-control or chemotherapeutic agents such as doxorubicin.

           Peripheral blood mononuclear cells from patients with HCC have considerably reduced
           cytotoxicity against hepatoma cell lines. Interferon has been shown to normalise the
           T-lymphocyte subpopullation and enhance the cytotoxic activity against an
           HBsAg-producing hepatoma cell line in-vitro.

        3. Interferon adverse effects

           Interferon alpha-2b is registered for treatment of HCC and chronic hepatitis B in Hong
           Kong. In patients with unresectable HCC, interferon has a much lower incidence of fatal
           side-effects when compared to doxorubicin. Most patients experience flu-like symptoms
           including fever, headache, fatigue and myalgia which usually subside spontaneously with
           continuation of treatment. Less common but more serious adverse effects include
           alopecia, leukopenia, thrombocytopenia, depression, irritability, and mental
           deterioration. The adverse effects are dose-dependent and the majority are reversible
           with a reduction in dosage. The use of high-dose interferon has been well-tolerated in
           clinical trials involving patients with unresectable HCC.

        4. Rationale

      Interferon has anti-viral, anti-proliferative and immunodulatory activities. It has been used
      clinically in the treatment of unresectable HCC as well as viral hepatitis B and C. It can
      potentially reduce the incidence of recurrence due to residual tumour cells or metachronous
      multicentric disease in patients after resection for HCC.
    

Intervention name(s): Interferon alpha-2b
Intervention type(s): Drug
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: liver cancer; hepatectomy; survival; recurrence