Phase Ⅲ Randomized Trial in Postoperative Hepatocellular Carcinoma
Phase Ⅲ Randomized Trial in Postoperative Hepatocellular Carcinoma
* OBJECTIVES

 1. To investigate whether adjuvant IFN-α therapy can delay or reduce the 2-5 years
 recurrence rate in curatively resected HCC .

 2. To examine whether adjuvant IFN-α therapy can prolong the disease-free survival in
 curatively resected HCC.

 3. To determine the safety and tolerance of adjuvant IFN-α therapy in postoperative HCC
 with or without cirrhosis.

 4. To investigate the change of activity of HBV and HCV in postoperative HCC patients with
 adjuvant IFN-α therapy.

 5. To correlate the changes of viral status with the clinical outcome in post-operative HCC
 patients with adjuvant IFN-α therapy.
1. TREATMENT PLAN

 1.1 Eligible patients are randomized to receive adjuvant IFN-α for 53 wks or 1.2
 Administration of IFN-α 1.21 IFN-α will be started after randomization. 1.22 IFN-α will
 be administered by subcutaneous injection at the bed time. 1.23 Escalation of IFN-α
 dosage. 1.231 During the first 2 days, 1 x 106 u/day will be given. 1.232 If tolerable,
 the dose of IFN-α will be escalated to 3 x 106 u/day in days 3 and 4, and to 5 x 106
 u/day at day 5.

 1.24 After dose escalation, IFN-α 5 x 106 u/day will be given in the following ways
 1.241 induction therapy: 5 times per week for the first 4 weeks, followed by 1.242
 maintenance therapy: 3 times per weeks for additional 48 weeks. 1.25 Modification of
 IFN-α dosage 1.251 In the presence of any moderate adverse events (as listing in
 Appendix II) it required a dose reduction to 3 x 106 u/day.

 1.2511 If any moderate adverse events occur at the 3 x 106 u/day level, the patients
 will be withdraw from the study; 1.252 In the presence of any severe adverse events (as
 listing in Appendix II), it requires immediate discontinuation of therapy; 1.2521 IFN-α
 will be discontinued until a return to baseline or moderate toxicity. Then IFN-α will be
 reinstituted at the dose level of 3 x 106 u/day; 1.2522 If moderate or severe adverse
 events occur at the 3 x 106 u/day level, the patients will be withdraw from the study.

 1.253 Flare-up of hepatitis activity, as manifested by increment of serum transaminase
 per se is not an indication for dose modification; 1.254 If symptoms/signs (S/S) of
 hepatic decompensation occur after the presence of ALT flare-up during IFN-α therapy,
 the drug will be held.

 1.2541 The presence of two of following five criteria is considered as evidence of
 hepatic decompensation: 1.25411 Presence of ascites; 1.25412 Presence of hepatic
 encephalopathy; 1.25413 hypoalbuminemia with serum albumin < 3 g/dl; 1.25414
 hyperbilirubinemia with serum bilirubin > 3 mg/dl; 1.25415 Prolongation of prothrombin
 time with PT > 2 sec above base-line. 1.2542 Serial workup have to be taken to rule out
 the presence of other predisposing factor (such as spontaneous bacterial peritonitis,
 constipation, electrolyte imbalance,...ect) to cause the S/S of hepatic decompensation.
 If any, start specific treatment.

 1.2543 If S/S of hepatic decompensation recovered with a return of serum ALT to ≦1.5
 times upper limit of normal range, IFN-α will be restarted at the level of 3 x 106 u/day
 and escalated to 5 x 106 u/day within 1 week.

 1.2544 If S/S of hepatic decompensation recovered with persistent elevation of serum ALT
 > 1.5 times upper limit of normal range, IFN-α will be given and maintained at the level
 3 x 106 u/day 3 times per week.

 1.2545 After excluding other specific etiologies and S/S of hepatic decompensation
 persist longer than 4 weeks, patients will be withdrawn from the study.

 1.2546 Recurrent episodes of hepatic decompensation will be considered as severe adverse
 events and managed as listing in section 5.252.

 1.255 If symptoms/signs (S/S) of hepatic decompensation occur in the absence of ALT
 flare-up, the patients will be managed as listing in section 5.252.

 1.256 In the presence of severe bacterial infection such as: bacterial peritonitis,
 bacterial pneumonia, and .. etc., IFN-a will be held until resolution of infection after
 adequate antibiotics therapy. Then the patients will be managed as listing in section
 5.252.

 1.26 Before IFN-α, if necessary patients will be pretreated with acetaminophen 500 -
 1,000 mg, q 6 hours for 4 doses, started 12 hours before IFN-α administration to
 alleviate the associated flu-like symptoms.

 1.3 Adverse Drug Reaction (ADR) Reports 1.31 Any life threatening and/or unexpected and
 serious (grade 3 or 4) toxicity will be reported within 48 hours to the principal
 investigator: Li-Tzong Chen M.D. Cancer Clinical Research Center, National Health
 Research Institutes, A191 Ward Veteran General Hospital Taipei, 201, Shih-Pai Road, Sec
 2, Taipei 112, Taiwan Tel:886-2-8712121-2737; Fax: 886-2-8716467; and/or Per-Jei Chen,
 M.D., Ph.D. Department of Internal Medicine, National Taiwan University Liver Disease
 Research Center, National Taiwan University Hospital. Tel: 886-2-3970800-7072 Fax:
 886-2-3317624. The initial contact should be made by calling the Coordinate Center of
 TCOG,at 886-2-7852459. A written report will follow within 7 working days.

 1.32 A written report will be submitted within 7 working days describing any
 life-threatening or lethal (grade 4 or 5) known reactions (except for grade 4
 myelosuppression), and any grade 2 or 3 unknown reactions. The address for submitting
 ADR reports is: Coordinate Center of TCOG, National Health Research Institutes in
 Biomedical Science, Academia Sinica, Taipei, Taiwan.

 1.33 Above toxicity grading is according to the ECOG toxicity criteria (Appendix III)

 2.0 Evaluation

 The following tests should be performed within 2 weeks before the initiation of therapy
 ( as the baseline data) and then repeated as request following the initiation of
 therapy.

 2.1 Physical examination and comprehensive history are recorded bi-weekly during
 induction period (first month) and monthly during maintenance therapy (for one year).
 After first year, patients will be followed bi-monthly. After 6 years , patients will be
 followed 3 monthly.

 2.2 Complete blood count and liver functional tests (bilirubin direct/indirect, AST/ALT
 and alkaline phosphatase/gGT albumin AC sugar) will be checked bi-weekly during
 induction period (first month) and monthly during maintenance therapy (for one year).
 After first year, patients will be followed bi-monthly. After 6 years, patients will be
 followed 3 monthly..

 2.3 Chest PA every 4 months for one year and then every 6 months. 2.4 ECG for those with
 history of cardiac disease at time of symptom recurrence.

 2.5 a-fetoprotein will be checked monthly for one year and then bi-monthly. After 6
 years, patients will be followed 3 monthly.

 2.6 Abdominal sonography every 2 months. After 6 years, patients will be followed 3
 monthly.

 2.7 Abdominal computed tomography performed every 12 months or whenever abdominal
 sonography shows suspicious recurrent lesions.

 2.8 Any suspicious lesion found on abdominal sonography and/or computed tomography
 should undergo angiography and sono-guided biopsy for histological examination.

 2.9 UGI endoscopy at the time of UGI bleeding or dyspepsia. [CANCEAL] 2.91 Preoperative
 endoscopy is acceptable as the base-line data. [CANCEAL] 2.10 Bone scan at the time of
 symptoms suggest the occurrence of bony metastases.

 2.11 Serum for HBV and HCV status study collected bi-monthly. 2.12 HBeAg and anti-HBe
 will be checked every 4 months in those with HBeAg(+). After 6 years, patients will be
 followed 6 monthly.

 2.13 HBsAg will be checked every 6 months in those with HBsAg(+).

 3.0 Off-study Criteria 3.1 Development of a serious medical condition which makes
 administration of IFN-α life threatening.

 3.11 Patients present with S/S of hepatic decompensation should be managed as list in
 sections 5.2544 and 5.2545.

 3.12 as those listed in 5.2511 and 5.2522. 3.2 Occurrence of tumor recurrence. 3.3
 Non-compliance by a patient with protocol requirement. 3.4 Patient refusal further
 therapy. 3.5 Patient death. 3.6 Interruption of IFN-α therapy >4 weeks

 4.0 Statistical Consideration 4.1 Sample size Review of literatures showed that the
 2-year survival rate of post-operative HCC was 25% to 60% [7-14]. We estimate that
 adjuvant IFN-α can improve the 2-year survival rate from 50% to 70%. According to the
 methods of Casagrande et al.[129], to give a 90% power for detecting the increase of 20%
 for a two-sided statistical significance test, 134 patients for each of the two
 treatment arms are needed. 4.2 Randomization Patients are stratified into two strata :
 one with HBsAg(+),another with HBsAg(-) but with anti-HCV(+). Randomization of patients
 into control or treatment group is taken within each stratum. Balanced block sizes of
 two strata for randomization are different. 4.3 Analysis 4.31 The primary objectives are
 as follows: 4.311 To determine if adjuvant IFN-α can reduce or delay the occurrence in
 curatively resected HCC. 4.312 To determine if adjuvant IFN-α prolong disease-free
 survival (DFS) and/or overall survival (OS) in curatively resected HCC. 4.313 To
 determine the safety and tolerance of IFN-αin post-operative H.C.C patients. 4.314 To
 evaluate the anti-viral activity of IFN-α in post-operative HCC patients. 4.32 DFS and
 OS are computed from the date of randomization. 4.321 In analysis of DFS, patients died
 without disease recurrence will be censored for recurrence at the date of death. 4.322
 In analysis of OS, an event is defined as death from any cause. 4.323 The survival
 distributions of DFS and OS will be estimated by the Kaplan and Meier method [130]. 4
 4.324 Statistical comparisons of DFS and OS between the two treatment arms will be
 performed with the log-rank statistic [131]. 4.325 Cox proportional hazards model [132]
 will be used to assess the importance of potential prognostic factors, as well as to
 test the significance of treatment when adjusting for factors. 4.33 Tumor size, Liver
 inflammation, viral status such as HBsAg. anti- HCVand

 -  Patient's Specific Factor:

 Performance status Age Sex Family history of HCC and liver diseases. Esophageal varices
 Prior Hx of esophageal varices bleeding Serum ALT (SGPT) level Serum albumin level
 Pre-operative serum α-FP level

 -  Underlying Liver Disease's Specific Factors:

 HBsAg (by RIA) HBeAg (by RIA) anti-HBc anti-δ antibody anti-HCV antibody Severity of
 underlying liver disease in nontumor portion Concurrent management of esophageal varices

 -  Tumor's Specific Factors:

 Presence of capsule Tumor type Venous invasion Tumor size (the largest in multiple
 lesions) Histological grading will be treated as potential prognostic factors.

 4.4 Interim Analysis The interim analyses will be conducted according to the alpha
 spending function approach proposed by DeMets and Lan (1994) which provides flexibility
 about the time for interim analysis. The a1 spending function, which generates the
 approximate O'Brien-Fleming boundaries (O'Brien and Fleming, 1979), will be used for a
 conservation termination at the early stage of the study. In addition, the method of
 B-value developed by Lan and Wittes (1988), Li (1998) will be used to monitor the data
 and to compute the conditional probability of detecting either a positive or negative
 treatment effect at the scheduled end of the study given the present status. The primary
 efficacy endpoint for the interim analyses is the time to occurrence of second primary
 tumors. The toxicity will be monitored constantly throughout the study. The conduct of
 interim analyses and dissemination of the results of the interim analysis will follow
 the TCOG Data and Safety Monitoring guidelines for confidentiality. The TCOG Data and
 Safety Monitoring Committee will review the results of interim analyses for a possible
 early termination of the trial.
-  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. Patients must be younger than 70 year-old.

 5. Patients must have a performance status of ECOG score < 2.

 6. Patients must have adequate liver reservation and adequate hemogram.

 7. Pugh-Child's Score < 7.

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

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

 10. The platelet are > 10 x 104 / mm3.

 11. The WBC are > 3,000 / mm3.

 12. Patient must have serum creatinine < 1.5 mg/dl

 13. Cardiac function with NYHA classification < Grade II

 14. Known HBV or HCV status.

 15. 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
 glucocorticosteroid or immunosuppressant agent(s) are not eligible.

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

 6. Patients with pregnacy 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.