A Phase II Study of Radiotherapy for Locally Advanced Hepatocellular Carcinoma (HCC)
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Study type: Interventional
Phase: Phase 2

Summary: 
      1. This is a phase II study of radiotherapy for patients with locally advanced HCC.

        2. Patients whose tumor(s) are not suitable for other local treatment, such as surgery,
           trans-arterial chemoembolization (TAE), ethanol injection, or radiofrequency ablation.
           will be enrolled.

        3. Radical radiotherapy will be started after pre-treatment evaluation. The total dose of
           RT will be 50Gy in 25 fractions to local tumor(s).

        4. Dynamic contrast enhanced MRI and serum samples will be done at the following time
           points to assess the change in tumor perfusion: (1) before the start of thalidomide
           treatment; (2) 2weeks after radiotherapy begins; and (3) 1 month after radiotherapy
           completes. DCEMRI will then be done every 3 months until disease progression.

        5. The study was designed to evaluate the response rate and tolerability of radical
           radiotherapy for locally advanced HCC. The sample size was determined by the expected
           incidence of grade 4 toxicity and response rate of radiotherapy for locally advanced
           HCC. Since the grade 4 toxicity of radiotherapy alone is 10%, the response rate is 60%
           we need at least 12 patients to evaluate for the treatment.
    

Detailed description: 
      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.
    

Intervention name(s): radiotherapy
Intervention type(s): Procedure
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: radiotherapy; dynamic contrast enhanced MRI; hepatocellular carcinoma