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An Open Label, Phase 2 Trial Comparing Sorafenib and 5-fluorouracil/Mitomycin in Hepatocellular Carcinoma With Pulmonary Metastasis

Phase 2
20 Years
80 Years
Open (Enrolling)
Carcinoma, Hepatocellular

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Trial Information

An Open Label, Phase 2 Trial Comparing Sorafenib and 5-fluorouracil/Mitomycin in Hepatocellular Carcinoma With Pulmonary Metastasis

Most HCC patients are diagnosed at advanced stages in Korea, but effective treatment
strategies for advanced HCC have not been established. In particular, optimal treatment
strategy for extrahepatic as well as intrahepatic recurrences following locoregional therapy
(e.g., transarterial chemoembolization, radiofrequency ablation therapy, and percutaneous
ethanol injection) is still a challenging issue. Extrahepatic metastasis has been
encountered more frequently, being more problematic than before in the management of HCC due
to the increased survival with effective locoregional treatments. The lung is the most
common site of extrahepatic metastasis and the surgical resection of pulmonary metastatic
lesions may result in improved survival in selected patients. Previous studies suggested
that aggressive management including resection of the extrahepatic recurrence combined with
locoregional therapy for intrahepatic HCC may offer long-term survival in selected patients
with recurrent HCC following hepatectomy. Such an aggressive strategy has serious
limitation in clinical practice in that extrahepatic recurrence usually present as multiple
lesions. Systemic chemotherapy has been one of the most commonly used treatment modalities
for patients with multiple extrahepatic metastasis. However, chemotherapy using either a
single or combined cytotoxic agents provides only limited benefit for such patients. The
aim of this study is to compare the efficacy of sorafenib to 5-fluorouracil/mitomycin in HCC
patients with pulmonary metastasis whose intrahepatic tumors had been previously controlled
with repeated locoregional therapies before the initiation of systemic chemotherapy.


- Experimental arm(the FM group): Patients receive 5-FU IV continuously over 10 hours on
day 1~6 and mitomycin IV push on day 1~4. Treatment repeats every 28 days.

- Active Comparator arm(the sorafenib group): Patients will receive 2 tablets of
sorafenib (200 mg/tablet) twice daily, orally on a continuous basis.

In all arms, treatment continues in the absence of disease progression or unacceptable
toxicity. During the treatment period, patients will have study visits on Day 1 of every
cycle (every 4 weeks from start of study drug) and will receive CT/MRI assessment every 2
cycles (every 8 weeks). In the event of radiological progression confined to the liver, e.g.
appearance of new nodules in the liver in areas previously not treated by locoregional
therapies, patients will then also be treated with locoregional therapies such as TACE or
local ablation as long as the they may still benefit from treatment. If patients are no
longer amenable to locoregional therapies (in the case of untreatable progression), the
study will be stopped and best supportive care be offered. This will be based on the
investigator's clinical judgment of the subject's status.

Inclusion Criteria:

- Patients with clinical or histological diagnosis of HCC based on the guidelines of
the AJCC

- Patients with at least one, bi-dimensionally measurable, pulmonary metastasis without
intrahepatic viable tumor (Viable tumor is defined as uptake of contrast agent in the
arterial phase of dynamic CT or MRI.)

- Patients who have received previous local therapy treatments (RFA, PEI, cryoablation,
surgery, resection) to non-target lesions are eligible

- Age : 20 years to 80 years

- ECOG Performance Status of 0 to 1

- Child-Pugh class A or B (Child-Pugh score 7)

- Adequate bone marrow, liver and renal function as assessed by the following
laboratory requirements to be conducted within 7 days prior to screening:

- Hb ≧ 9 g/dL

- Absolute neutrophil count > 1000/mm3

- Platelet count ≧ 60,000 /mm3

- Adequate clotting function: INR < 1.5

- Hepatic: AST and ALT < 5 X ULN

- Renal: serum creatinine < 1.7mg/dL

- Bilirubin ≦ 3 mg/dL

Exclusion Criteria:

- Patients with diffuse infiltrative type of HCC that are poorly defined

- Presence of hepatic encephalopathy and intractable ascites

- Patients who are on a liver transplant list

- The patient has received prior systemic chemotherapy

- History of organ allograft

- Active clinically serious infections (> grade 2 NCI-CTC version 3.0), including
spontaneous bacterial peritonitis

- History of cardiac disease: congestive heart failure > NYHA class 2; active coronary
artery disease (myocardial infarction more than 6 months prior to study entry is
allowed), cardiac arrhythmias requiring anti-arrhythmic therapy or uncontrolled
hypertension and diabetes mellitus

- Previous or concurrent cancer that is distinct in primary site or histology from HCC,
EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder
tumors (Ta, Tis & T1). Any cancer curatively treated > 3 years prior to entry is

- HIV infection or AIDS-related illness or serious acute or chronic illness (based on
medical history)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival (PFS)

Outcome Time Frame:

every 8 weeks

Safety Issue:



Korea: Institutional Review Board

Study ID:




Start Date:

November 2010

Completion Date:

July 2016

Related Keywords:

  • Carcinoma, Hepatocellular
  • Carcinoma
  • Carcinoma, Hepatocellular