Trial Information

A Phase II Clinical and Mechanistic Study of Radiotherapy for Locally Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Asian countries.
Surgical resection is potentially the only form of curative treatment. However, less than
20% of patients are surgical candidates at diagnosis. Nonsurgical treatment options include
transcatheter arterial chemoembolization (TACE), percutaneous acetic acid or ethanol
injection therapy and radio-frequency ablation. They are sometimes unsatisfactory,
especially for patients with portal vein thrombosis or large infiltrative hepatic tumors.
Repeated treatments are often necessary.

Radiotherapy (RT) for the treatment of HCC has been attempted for more than 4 decades. Early
trials adopted whole liver irradiation but used an inadequate radiation dose. Because of the
unsatisfactory results obtained with this low-dose whole liver irradiation, RT has not long
been considered for the treatment of HCC. Recently, local, not whole, liver RT has been
attempted by several investigators, who have shown that high doses of radiation can be
safely delivered to a portion of the liver alone or in combination with other nonsurgical
modalities. Their results suggest that local RT can be an effective component of the
treatment regimen for HCC.

Development of surrogate markers to monitor the response of HCC to radiotherapy is important
because of the following reasons. First, the response as evaluated by conventional imaging
studies is usually slow and may be unreliable. The maximal response to radiotherapy is often
achieved 6 months after completion of radiotherapy. The slow response to radiotherapy makes
it difficult to modify an ineffective treatment regimen in a more timely fashion to HCC,
especially for patients with low serum a-fetal protein (AFP). Second, intra-hepatic
recurrence outside RT field is a common cause of RT treatment failure. Nearly half of the
patients recur after RT with lesions outside RT fields. Inflammation and normal liver damage
caused by RT may have deleterious effect on tumor control through the release of cytokines
or angiogenic factors. Therefore, the biological consequence of RT in both the tumors and
the non-tumor liver parenchyma shall be carefully evaluated.

Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) may assess hepatic perfusion
parameters which correlate with the severity of cirrhosis and portal hypertension. In
cervical cancer, DCEMRI enables us to evaluate the microcirculation of tumors as well as the
blood perfusion of normal parenchyma. Malignancy, stage and prognosis have all been
correlated with the enhancement parameters in cervical, breast cancers.Several studies have
shown that successful therapies also result in changes in DCEMRI parameters, which may prove
to be a more accurate and earlier indication of response. De Vries et al reported, in rectal
carcinoma patients receiving preoperative radiotherapy, that perfusion index showed a
significant increase in the 1st and 2nd week of treatment. High perfusion index values
correlated with greater lymph node down-staging. Moffat et al also reported increased
apparent diffusion coefficient (ADC) 3 weeks after the initiation of RT in brain cancer
patients who had better local response. Circulating angiogenic factors have been shown to
provide important prognostic information about a variety of cancers (21). Elevated serum
levels of VEGF or bFGF have been associated with increased invasiveness of HCC. Placental
growth factor (PlGF), a homolog of VEGF, has been shown to have a synergistic effect with
VEGF in pathologic angiogenesis, such as angiogenesis induced by cancer or ischemia, but its
prognostic value in human cancers remains unclear.

We would like to correlate functional image studies of blood flow and serum cytokines during
radiotherapy with treatment outcome in hepatocellular carcinoma patients.