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A Randomized Controlled Trial of Multimodality Therapy in the Treatment of Palliative Resectable Hepatocellular Carcinoma With Intrahepatic Vessels Invasion

Phase 3
18 Years
70 Years
Open (Enrolling)
Hepatocellular Carcinoma

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Trial Information

A Randomized Controlled Trial of Multimodality Therapy in the Treatment of Palliative Resectable Hepatocellular Carcinoma With Intrahepatic Vessels Invasion

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third cause of
cancer-related death. At initial diagnosis, surgical resection is considered a potentially
curative modality for HCC[1, 2], with the five-year survival rates for resectable patients
50-60%, however, only about 15% of patients have resectable disease and post-operative
recurrence is common, remaining the main obstacle to long-term survival. On the one hand,
the reason may be the multicentric genesis of HCC or the preoperatively micrometastasis that
can not be resected during operation. Shi M, et al [3] reported that the appropriate
resection margin was >= 2cm. The Liver Cancer Study Group of Japan (LCSGJ) defined[4]:
absolute curative resection included liver resection with 1 cm of free surgical margin in
patients with solitary tumor <= 2cm; relative curative resection included liver resection
without 1 cm of free surgical margin but with the excised tumor tissue in patients with
solitary tumor <= 2cm or liver resection with 1 cm of free surgical margin in patients with
tumor >= 2cm (in either instance, no tumor thrombus may remain in the portal vein, hepatic
vein, or bile duct in images of the remnant liver); relative non-curative resection, in
which all macroscopic tumor tissue is removed; and absolute non-curative resection, which is
liver resection with part of the macroscopic tumor tissue remaining. Either overall survival
rates (OS) or disease-free survival rates (DFS) of HCC patients are higher in curative
resection than in non-curative resection[4]. According to this definition, when the giant
tumor located in middle liver, tumor with lymph nodes adjacent to abdominal aorta
metastasis, multiple lesions (>= 3) or tumor with intrahepatic vessels invasion, the surgery
will be non-curative. On the other hand, post-operative adjuvant therapy is one of the most
effective treatment strategies in improving the survival rates of HCC patients[5].
Unfortunately, only about 15 randomized controlled trials have been reported on the
post-operative adjuvant therapy until now. Most of them were single center, little sample
clinical trials.

Recently, a series of studies have been reported that transcatheter arterial
chemoembolization (TACE) is effective in HCC[6, 7]. Best results are seen in patients with
small tumors and good liver function and 1 year survival has been shown to be of 30-50%. A
recent meta-analysis showed a significant benefit of chemo-embolization with improvement in
two-year survival[6]. TACE is one of most important therapy strategies on HCC. The 2007'
NCCN clinical practice guidelines in oncology has included the TACE throughout the treatment
guideline of unresectable HCC or resectable HCC (for some reason, hepatectomy was not
carried out) or adjuvant therapy post-operative. But there are still lack of RCT studies.

In the patients with palliative resectable HCC, the presence of intrahepatic vessels
invasion was usually regarded as the symbol of cancer cells hematogenous dissemination,
which is associate with short-term recurrence and worse survival. For this special group
patients, some authors insisted that aggressive therapy strategy-initial palliative
hepatectomy followed by TACE and/or local regional treatments was most effective to prolong
the survival of patients.While other authors,however,believed that too aggressive therapy
was not best choice for these patients because of the suppression of immune system after
palliative hepatectomy may potentially accelerate the growth of residual cancer cells. A
relative conservative strategy-transcatheter hepatic arterial chemoembolization combined
local regional treatments without hepatectomy should be used. The optimal therapy strategies
are still in controversial.Only the multiple-center, great sample clinical RCT studies can
answer this question[8]. The purpose of this study is to compare the effects of different
multimodality therapy strategies (initial hepatectomy followed by transcatheter hepatic
arterial chemoembolization and/or local regional treatments compare with transcatheter
hepatic arterial chemoembolization combined local regional treatments without hepatectomy)in
the treatment of palliative resectable hepatocellular carcinoma with intrahepatic vessels

Inclusion Criteria:

- Male or female patients > 18 years and <=70 years of age.

- Patients with palliative resectable HCC (all macroscopic tumor tissue can be
removed), which have been histologically or cytologically documented. Documentation
of original biopsy for diagnosis is acceptable if tumor tissue is unavailable at

- Patients must have at least one lesion that meets both of the following criteria:

- The lesion can be accurately measured in at least one dimension according to
RECIST (Section 10.7).

- The lesion has not been previously treated with local therapy (such as surgery,
radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency
ablation, percutaneous ethanol injection or cryoablation).

- Patients must have the tumor in the liver with intrahepatic vessels(portal
vein/hepatic vein/bile duct) invasion, but all the tumor can be macroscopically

- Patients who have an ECOG PS of 0 or 1.

- Cirrhotic status of Child-Pugh class A only. Child-Pugh status should be calculated
based on clinical findings and laboratory results during the screening period.

Exclusion Criteria:

- Patient compliance is poor.

- The blood supply of tumor lesions is absolutely poor or arterial-venous shunt that
TACE can not be performed.

- The vessels invasion beyond the following extent:

- the main branch of portal vein;

- the inferior vena cava;

- the common hepatic duct.

- 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

- History of cardiac disease:

- congestive heart failure > New York Heart Association (NYHA) class 2;

- active coronary artery disease (myocardial infarction more than 6 months prior
to study entry is permitted);

- cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers,
calcium channel blocker or digoxin;

- uncontrolled hypertension (failure of diastolic blood pressure to fall below 90
mmHg, despite the use of 3 antihypertensive drugs).

- Active clinically serious infections (> grade 2 National Cancer Institute
[NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 3.0).

- Known history of human immunodeficiency virus (HIV) infection.

- Known Central Nervous System tumors including metastatic brain disease.

- Patients with clinically significant gastrointestinal bleeding within 30 days prior
to study entry.

- Distantly extrahepatic metastasis.

- History of organ allograft.

- Drug abuse, medical, psychological or social conditions that may interfere with the
patient's participation in the study or evaluation of the study results.

- Known or suspected allergy to the investigational agent or any agent given in
association with this trial.

- Any condition that is unstable or which could jeopardize the safety of the patient
and his/her compliance in the study.

- Pregnant or breast-feeding patients. Women of childbearing potential must have a
negative pregnancy test performed within seven days prior to the start of study drug.
Both men and women enrolled in this trial must use adequate barrier birth control
measures during the course of the trial.

- Excluded therapies and medications, previous and concomitant:

- Prior use of any systemic anti-cancer treatment for HCC, eg. chemotherapy,
immunotherapy or hormonal therapy (except that hormonal therapy for supportive
care is permitted). Antiviral treatment is allowed, however interferon therapy
must be stopped at least 4 weeks prior randomization.

- Prior use of systemic investigational agents for HCC

- Autologous bone marrow transplant or stem cell rescue within four months of
start of study drug

Type of Study:


Study Design:

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

Outcome Measure:

Overall survival rate

Outcome Time Frame:

1-, 3- and 5-year

Safety Issue:


Principal Investigator

Jin-Qing Li, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Department of Hepatobilliary Surgery, Cancer Center, Sun Yat-sen University


China: Ministry of Health

Study ID:




Start Date:

October 2006

Completion Date:

July 2010

Related Keywords:

  • Hepatocellular Carcinoma
  • Hepatocellular carcinoma
  • Intrahepatic vessels invasion
  • Hepatectomy
  • Transcatheter arterial chemoembolization
  • Local regional treatment
  • Carcinoma
  • Carcinoma, Hepatocellular