Radioembolization With Yttrium-90 Microspheres for Intermediate or Advanced Hepatocellular Carcinoma

Radioembolization With Yttrium-90 Microspheres for Intermediate or Advanced HCC (Hepatocellular Carcinoma) Not Eligible to Curative Approach. A Phase II-b Study.

Rationale: Patients diagnosed with hepatocellular carcinoma (HCC) at an intermediate or advanced stage (according to the BCLC classification system) are not amenable of curative treatment. According to EASL and AASLD guidelines patients with an intermediate stage HCC are treated with trans-arterial chemoembolization (TACE) while patients with an advanced stage HCC are treated with molecular targeted drugs or other combinations according to their liver function. The median survival expected for patients in intermediate-advanced stages ranges from 11 to 20 months.

Purpose of the Study: The purpose of this prospective phase II study is to determine whether or not Radioembolization with Yttrium-90 microspheres (TheraSphere®) provides an anti-tumoral effect and a sensible benefit in terms of time-to-progression (TTP) and survival in patients with good liver function (Child A-B7) and a confirmed diagnosis of Intermediate or Advanced (because of the presence of neoplastic portal thrombosis) Hepatocellular Carcinoma (HCC).

Patients at an intermediate stage (BCLC-B) are currently offered trans-arterial chemoembolisation (TACE) as the standard of care. A recent meta-analysis showed that radioembolization with beta-emitting Yttrium-90-loaded glass microspheres (TheraSphere®) in patients with HCC achieves a median objective response in 79% of cases (range 29-88%) and median survival exceeding 15 months has been reported in patients at intermediate stages who have been treated with TheraSphere®.

In patients with HCC at an advanced stage (BCLC-C) the single treatment that has shown a statistical advantage on overall survival and disease progression is sorafenib, that provides a median survival of 10.7 months. Based on the results reported in literature, the estimated median expected survival of patients with advanced HCC treated by TheraSphere® can be as long as 12 months.

After approval on July 2007 of a treatment protocol of Y-90 for compassionate use by the institutional IRB, at the National Cancer Institute of Milan 40 consecutive patients have been treated with radioembolization with Yttrium-90 microspheres (Theraspheres®) according to the same guidelines of the present prospective phase II protocol. The initial series of 40 patients treated according to a compassionate use of Y-90 has been instrumental for the assessment of the procedure's safety and tolerability. The present study has been targeted to 60 cases including the fist series of 40 "compassionate" patients, due to their adherence to the same inclusion/exclusion criteria of the proposed phase II study.

Inclusion Criteria:

1. Diagnosis of HCC confirmed by histology or non-invasive criteria (EASL/AASLD)
2. Intermediate stage (BCLC-B) HCC: patients with a large or multinodular HCC (single HCC > 5 cm or multiple HCC defined as > 3 nodules > 3 cm), a Child Pugh class A or B7 and no cancer related symptoms (PS=0-1).
3. Advanced stage (BCLC-C) HCC: patients with hepatic vascular involvement (at any tumor number and diameter), a Child Pugh class A or B7, no cancer related symptoms (PS=0-1) and absence of extra-hepatic tumor spread.
4. Cancer-related symptoms within the ECOG 0-1 score
5. Liver function within Child B-7 class
6. Platelets > 50.000/µL
7. WBC > 1500/µL
8. AST/ALT < 5 times the upper limit of normal (U/L)
9. Creatinine < 2.0 mg /dL
10. No indication for any possible curative treatment after multidisciplinary assessment (resection, ablation, transplantation)
11. Signed informed consent

Exclusion Criteria:

1. Child-Pugh class higher than B-7 at entry
2. ECOG performance score ≥ 2 at entry
3. Tumor volume ≥ 50% of liver volume
4. Extrahepatic tumor spread
5. Pulmonary insufficiency
6. Life expectancy of less than 3 months due to HCC or less than 6 months due to any other disease
7. Previous chemoembolization procedure (TACE)
8. Evidence on 99mTc-MAA scan of vascular shunts that can not be corrected by angiographic coil embolization
9. Evidence on 99mTc-MAA scan of lung shunting, with a potential absorbed dose of radiation to the lungs > 30 Gy