Transarterial Chemoembolization (TACE) With or Without Stereotactic Body Radiotherapy (SBRT) in Hepatocellular Carinoma

DETAILED OUTLINE OF RESEARCH PROPOSAL

Current State of Knowledge Primary liver cancer, hepatocellular carcinoma (HCC), is a major health problem worldwide. It is the 5th most common cancer and the 3rd most common cause of cancer death in the world. Eighty-five percent of cases occur in developing countries, while in the United States and Canada, it is the fastest growing cancer.

General Treatment Overview: HCC tends to remain within the liver and, therefore, cure with preserved liver function is possible. Surgical resection results in 5-year survival rates of 60%-70%. Liver transplantation can cure both the cancer and underlying liver disease. Four-year survival for HCC within the Milan criteria (single HCC <5 cm or ≤3 HCC <3 cm) is 70%-85% after transplantation. Unfortunately, most patients are not resectable. Transarterial chemoembolization (TACE) has become the mainstay of treatment for unresectable HCC. What makes TACE relatively safe is the liver-unique vascular supply from the portal vein, whereas HCC is supplied almost entirely by branches of the hepatic artery. In a randomized controlled trial for unresectable HCC not suitable for a curative intent, transarterial chemoembolisation or TACE were compared to conservative treatment. TACE induced objective responses (complete and partial response) that were sustained for at least 6 months in 35% of cases. Survival probabilities at 1 year and 2 years were 82% and 63% for TACE, significantly better than 63% and 27% obtained with conservative treatment. Overall survival at 1 and 2 years was also significantly better for the chemoembolization group 57% and 31% vs. 32% and 11%. However, many patients have large tumours and response rates decline rapidly with increasing size. TACE alone results in 2 year overall survivals of 42%, 0 and 0 for lesions 5-7cm, 8-10cm, and >10cm, respectively. Therefore, additional locally ablative treatments are being sought. In the same report, TACE plus radiation results in 2 year overall survivals of 63%, 50% and 17% for lesions 5-7cm, 8-10cm, and >10cm, respectively.

External beam radiotherapy has long been considered to have a very limited role in the treatment of liver tumors. This is due to the fact that the minimum dose required for local ablation exceeded the dose that would result in liver toxicity. The technical development of stereotactic body radiation therapy (SBRT), alone or in combination with TACE, renewed interest in radiation for HCC. This work was done mainly by two groups, in Michigan and Stockholm, who demonstrated that the delivery of high doses of radiation to limited volumes of the liver had promising results in terms of local control and survival with acceptable toxicity. Dr. Lock and his team are one of the first centres to initiate this type of work and currently have one of the largest databases outside of asia. In addition, he leads one of only two groups in Canada able to dose escalate based on radiobiological parameters thereby providing the highest possible doses within known toxicity constraints. For SBRT, advanced techniques are used to very accurately deliver a high total dose to the target in a small number of daily fractions while avoiding dose delivery to surrounding healthy structures. SBRT is offered as an ablative radical local treatment. In total, eleven primary series reported on tumor response and survival of around 300 patients who have been treated with stereotactic body radiation therapy as primary therapy for HCC. The reported percentage of objective responses defined as complete and partial was ≥64% in 7 of 8 series. Median survival between 11.7 and 32 months has been observed. Toxicity, based on multiple case series trials, indicate that the treatment is considered safe. The most common CTC grade 3-4 toxicity was elevation of liver enzymes.

For unresectable cases, both TACE and SBRT have been used safely and with good efficacy as separate treatments. Particularly for larger lesions that are more commonly seen in London, the outcome remains suboptimal compared to surgery. Combined treatment case series have shown dramatic results, but there has not been any randomized trial to compare the value of combining the two modalities. Therefore a clinical study comparing SBRT and SBRT+TACE will be significant as it addresses a common problem in one of the two most deadly cancers.