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A Phase II Trial of Radiation Therapy, Followed by Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma Invading 1st or 2nd Order Branch of Portal Vein

Phase 2
18 Years
69 Years
Not Enrolling
Hepatocellular Carcinoma

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Trial Information

A Phase II Trial of Radiation Therapy, Followed by Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma Invading 1st or 2nd Order Branch of Portal Vein

Hepatocellular carcinoma (HCC) invading portal vein represents or predisposes to several
disastrous clinical conditions. First, obstruction of portal vein per se or accompanying
large arterio-portal shunts can cause a rapid deterioration of hepatic function and
development of portal hypertension complications. Second, vascular invasion itself is a risk
factor for future extrahepatic metastasis. Third, severe complications including hepatic
failure may develop after transarterial chemoembolization (TACE) since both hepatic arterial
and portal venous blood flows can be interrupted simultaneously. For these reasons, TACE is
not routinely recommended in this clinical setting, although there have been some

Patients with HCC invading portal vein have a dismal prognosis. In an Asian prospective
randomized trial evaluating the efficacy of TACE, the median survival of HCC patients with
unilobar portal vein invasion was only 2.6 months in control group. Though it was 5.1 months
in TACE group, the difference was not significant statistically. Recent two phase III
randomized placebo-controlled trials revealed that sorafenib can prolong the patient's
survival in the Barcelona Clinic Liver Cancer (BCLC) advanced stage that includes HCC
invading portal vein, and thereby the guideline endorsed by the American Association for the
Study of Liver Diseases (AASLD) recommended it as a standard therapy for these patients.
However, before the advent of sorafenib, many treatment modalities had been used in Asian
countries for these patients. Examples are surgical resection, TACE, hepatic arterial
infusion chemotherapy, or radiation therapy (RT). Accordingly, guidelines of many Asian
countries still adopt these therapies for patients with portal vein invasion, despite there
being no solid evidence.

Radiation was traditionally thought to have a limited role in the treatment of HCC. This
concept partly resulted from the limited ability to deliver lethal doses using external beam
techniques in the past, since the whole-liver tolerance to radiation was reported to be low.
However, recent use of three- or four-dimensional conformal radiation therapy (RT) has
permitted the delivery of higher doses of radiation to intrahepatic tumors with no increase
or even decrease of radiation-induced toxicities. Accordingly, several recent retrospective
studies performed in Asia have suggested that RT combined with transarterial chemoinfusion
(TACI) or TACE may have a beneficial effect in HCC patients with portal vein invasion. In
our retrospective analysis, the median survival in CTP A patients with unilobar portal vein
invasion treated with RT and TACE/I was over 22 months, which was obviously longer than the
reported median survival in advanced stage patients by BCLC staging system. The median
survival was 6 months in patients who were treated only with TACE/I. However, the survival
benefit was not obvious in patients with main portal vein invasion.

Despite these encouraging data, radiation-induced hepatotoxicity is still the major obstacle
for the widespread use of RT for the treatment of HCC even with the 3D- or 4D-conformal
radiation therapy. The reported incidence of hepatotoxicity after RT was up to 15-20%, but
about half of the cases were in fact related to hepatitis B virus (HBV) reactivation, which
is preventable with preemptive antiviral therapy. Other factors such as the area of RT field
or dose may be related to the occurrence of hepatotoxicity. Techniques to deliver radiation
beam are also important and tracking of respiratory movement (4D-RT) can minimize

In our center, radiation therapy is mostly focused on the tumor portions invading portal
vein to deliver a sufficient radiation dose and to minimize toxicity. With this approach, we
control the tumor portions invading portal vein with RT and remnant parenchymal portions of
tumors with TACE. Though TACE also carries a risk of hepatic failure in HCC patients with
portal vein invasion, our retrospective analysis (submitted data) showed that it can be
performed safely in CTP A patients with HCC invading 1st or 2nd order branch of portal vein
if the tumor volume is less than 1/2 of total liver volume. Grade 3 or 4 hepatotoxicity
developed in 10% of patients. Although there were slight differences in the protocols,
several other studies have also reported the effectiveness and safety of this approach.

However, there are still limitations in interpreting pre-existing data. Since most have been
retrospective studies, there could be a high probability that treatment-related toxicities
were underestimated and an intention-to-treat analysis was not performed. And also, there
have been a wide variability in treatment schedule, or evaluating response to treatment
and/or treatment-related toxicities among studies.

Therefore, in this study, we are to prospectively evaluate patient's survival, tumor
response, and safety of RT followed by TACE in Child A patients with unilobar portal vein

Inclusion Criteria:

- 18 and older than 18 years, and less than 70 years

- Histologically diagnosed HCC, or clinically diagnosed HCC based on the American
Association of Study of Liver Disease (AASLD) noninvasive diagnostic criteria for HCC
larger than 2 cm in diameter (Patients with chronic HBV or HCV infection, and/or
evidence of liver cirrhosis, and typical enhancement pattern (arterial enhancement
and portal or delayed washout) on dynamic computed tomography (CT) or magnetic
resonance imaging (MRI), or mass with serum alpha fetoprotein level more than 200

- Treatment naïve HCC patients or patients who received a locoregional therapy(-ies)
(radiofrequency ablation, percutaneous ethanol injection, surgical resection; TACE is
not allowed) to nontarget lesion at least 3 months prior to baseline scan

- HCC invasion to 1st or 2nd order branch of portal vein

- HCC greater than 2 cm and the tumor volume should be less than half of total liver

- CTP score 6 or less than 6 (Child A class only)

- ECOG performance status 0 or 1

- Women with childbearing potential and men must agree to use adequate contraception
prior to study entry and during study participation

- Patients who refuse to use sorafenib

- The patient must give written, informed consent

Exclusion Criteria:

- Age of 70 and older, or younger than 18

- HCC less than 2 cm, or tumor volume larger than half of total liver volume

- Invasion to both right and left portal veins, or main portal vein

- Invasion to hepatic vein or inferior vena cava

- Presence of extrahepatic metastasis

- Recurred HCC after liver transplantation

- Prior history of any treatment to target lesion

- Any history of previous RT, TACE, sorafenib or other systemic therapy

- Prior locoregional therapy (radiofrequency ablation, percutaneous ethanol injection
therapy, surgery) within 3 months before baseline scan

- CTP score more than 6 (Child class B or C)

- ECOG performance status more than 1

- Presence of ascites or encephalopathy

- Absolute neutrophil count less than 1,000/mm3

- Platelet count less than 60,000/mm3

- INR of prothrombin time more than 1.5

- Serum creatinine more than 1.5 mg/dL

- AST or ALT more than 5x upper limit normal(ULN)(200 IU/L)

- Bilirubin more than 3 mg/dL

- Recent gastrointestinal bleeding including variceal bleeding within 3 months

- History of active gastro-duodenal ulcers within the past 6 months. However, the
patient is eligible if a more recent gastroscopy shows complete healing of ulcers.

- Major surgery or serious non-healing wounds within 3 months of start of RT

- Pregnancy or breastfeeding. All female patients with childbearing potential must have
a negative pregnancy test within 7 days prior to enrollment.

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

- Any active clinically serious infections (Grade 3, CTCAE version 4.0)

- History of human immunodeficiency virus (HIV) infection

- History of organ allograft

- Patients who agree to use sorafenib

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Time to tumor progression

Outcome Description:

At the visiting time of D8, D15, D22, and D29, patients can visit at the outpatient clinic within the window period of ± 1 week. In addition, at the visiting time of D43, D71, D99, and W18, patients can visit at the outpatient clinic within the window period of ± 2 week. Progression of target region or appearance of new lesion will be checked at every visit.

Outcome Time Frame:

participants will be followed for the duration of hospital stay and outpatient visit, an expected average of 18 weeks

Safety Issue:


Principal Investigator

Han Chu Lee, M.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine


Korea: Institutional Review Board

Study ID:




Start Date:

October 2011

Completion Date:

December 2013

Related Keywords:

  • Hepatocellular Carcinoma
  • patient's survival
  • tumor response
  • safety
  • Carcinoma
  • Carcinoma, Hepatocellular