Efficacy of Radiation Therapy and Transarterial Chemoembolization (TACE) to Treat Hepatocellular Carcinoma (HCC)

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 controversies.

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 complications.

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 invasion.