Trial Information

A Randomization Trial of Adjuvant Lamivudine/ Adefovir Dipivoxil Against Recurrence in Post-Operative HBV-Related Hepatocellular Carcinoma

Treatment plan and Randomization scheme:

HBsAg+, HCC< 5 cm with curative resection Stratified with HBV DNA < 105 OR ≥ 105 copies/mL
Genotype B or C RANDOMIZATION Prophylactic group Therapeutic control group Adefovir
Dipivoxil 10mg/day x 36 months Lamivudine 100 mg/day x 18 months#, when HBV DNA =/> 105
copies/mL and ALT > 2.0 x UNL

- When YMDD mutant present, switch to Adefovir dipivoxil 10mg/day x 24 months. Selection
of patients

1. Eligibility Criteria (1)Histologically proven hepatocellular carcinoma. (2)HCC
underwent curative resection within 6 weeks before registration. (3)Grossly, the
resection margin should be > 1 cm. (4)Tumors, either single, < 5 cm in size or no
more than 3 for size < 3 cm. (5)Patients must have a performance status of ECOG
score < 2. (6)Patients must have adequate liver reservation and adequate hemogram.
(i)Pugh-Child's Score < 7. (ii)The serum total bilirubin level are < 2 mg/dl.
(iii)The prothrombin times are < 3 sec above normal control. (iv)The platelet are
> 7.5 x 104 / mm3. (v)The WBC are > 3,000 / mm3. (7)Patient must have serum
creatinine < 1.5 mg/dl (8)Cardiac function with NYHA classification < Grade II
(9)HBsAg (+) . (10)Signed informed consent.

2. Ineligibility Criteria

1. Patients who have non-curative resection are not eligible.

2. Resected HCCs with histologically positive margins are not eligible.

3. HCCs with radiological evidence of portal vein thrombus are not eligible.

4. Patients with other systemic diseases which required concurrent usage of
glucoticosteroid or immunosuppressant agent(s) are not eligible.

5. Patients with advanced second primary malignancy are not eligible.

6. Patients with pregnancy or breast-feeding are not eligible.

7. Patients with severe cardiopulmonary diseases are not eligible.

8. Patients with clinically significant psychiatric disorder are not eligible.

9. Patients who had antineoplastic chemotherapeutic or immuno-therapeutic drugs or
corticosteroids within 6 weeks of commencing the protocol are not eligible.

10. Patients who had prior lamividine and/or adefovir dipivoxil therapy are not
eligible.

11. Anti-HCV positive patients are not eligible. Statistical Consideration

Sample size:

With a phase III superior study design, to give an 80% power with a two-sided 5%
significance level, 139 patients per each treatment arm should be included in the
study. If a 10% drop-out rate is included, totally, 309 patients (155 per study
arm) will be required.

Analysis

The objectives are as follows:

1.Primary endpoint: the 3-year recurrence rate (excluding those recur within 1st year)

1. Second endpoints the recurrence-free survival.

2. Second endpoints: the overall survival.

3. Second endpoints: anti-viral efficacy, in terms of sustained biochemical response
rate and viral response rate. To correlate the changes of viral titer with the
clinical outcome 2 RFS and OS are computed from the date of randomization.

(1) In analysis of RFS, patients died without disease recurrence will be censored for
recurrence at the date of death (2) In analysis of OS, an event is defined as death
from any cause. (3) The survival distributions of RFS and OS will be estimated by the
Kaplan and Meier method.

(4) Statistical comparisons of RFS and OS between the two treatment arms will be
performed with the log-rank test.

(5) Cox proportional hazards model will be used to assess the importance of potential
prognostic factors, as well as to test the significance of treatment when adjusting for
factors [39].

3.Tumor size, Liver inflammation, viral status, i.e. HBV genotype and DNA titer