A Phase III Study in Post-operative HBV-related Hepatocellular Carcinoma
A Phase III Study in Post-operative HBV-related Hepatocellular Carcinoma
Research Objective and Study End Points To evaluate the anti-HBV as well as HCC recurrence
 reducing effects of standard (18 months) lamivudine treatment at time of HBV reactivation
 with hepatitis flare up (HBV DNA > 105 copies/mL and ALT level > 2.0 x UNL) or prophylactic,
 prolong (36 months) adefovir dipivoxil therapy in post-operative HBsAg(+),< 5 cm HCC
 patients, and to compare the results of who group with historical controls (T1297, HBsAg+,< 5
 cm HCC cohort),in terms of the following endpoints.

 1. Primary endpoint:

 the 3-years recurrence rate (excluding those recur within first year).

 2. Secondary endpoints:

 the first 2 year tumor recurrence rates the recurrence-free survival the overall survival.
 anti-viral efficacy, i.e. biochemical response and viral response rate. to correlate the
 changes of viral titer with the clinical outcome in post- operative HCC patients with
 adjuvant lamivudine or adefovir therapy.
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
Inclusion 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.

 -  Pugh-Child's Score < 7.

 -  The serum total bilirubin level are < 2 mg/dl.

 -  The prothrombin times are < 3 sec above normal control.

 -  The platelet are > 7.5 x 104 / mm3.

 -  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.

 Exclusion 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.