SBRT for Liver Cancer Before Liver Transplantation

Not Applicable

Active, not recruiting

• Conditions: Liver Cancer; Liver Transplant Disorder
• Interventions: Radiation: Stereotactic body radiation therapy

• Registration Number: NCT04186234
• Lead Sponsor: The University of Hong Kong

Brief Summary

Hepatocellular carcinoma (HCC) is the second commonest cause of cancer death worldwide. It is the third leading cause of cancer death in Hong Kong. Liver transplantation (LT) is the curative treatment of choice for HCC as it has the advantage of removing the tumour and also the premalignant cirrhotic liver. Milan (solitary tumour \<5cm, or up to 3 tumours, each \<3cm) and University of California San Francisco (UCSF) criteria (solitary tumour ≤6.5cm, up to 3 tumours with none \>4.5cm, and total tumour diameter ≤8cm) provide the benchmark requirements for LT, at which a 5-year survival of \>70% and recurrence rate ranging from 5-15% can be achieved. However, organ shortage and waiting time for liver grafts remain the greatest obstacles for deceased donor liver transplantation (DDLT). It has been reported that the waiting list dropout rate is 7 to 11% at 6 months and 38% at 12 months. Several therapeutic procedures including transarterial chemoembolisation (TACE) and stereotactic body radiation therapy (SBRT) have been studied as bridging therapy before DDLT, aiming at reducing waiting list dropout rate and recurrence after LT, and improving post-transplant survival.

The investigators have carried out a prospective study on HCC patients treated with bridging SBRT before LT. The investigators used dual tracer (18F-fluorodeoxyglucose \[FDG\] and 11carbon-acetate \[ACC\]) positron-emission tomography with integrated computed tomography (PET-CT) and magnetic resonance imaging with gadoxetate disodium as baseline and subsequent imaging assessment before and after SBRT, hoping the PET-CT can help better identify those who benefit from SBRT and to prioritise those with poor response so that they can be better channeled to LT.

Detailed Description

Hepatocellular carcinoma (HCC) is the second commonest cause of cancer death worldwide. It is the third leading cause of cancer death in Hong Kong. Liver transplantation (LT) is the curative treatment of choice for HCC as it has the advantage of removing the tumour and also the premalignant cirrhotic liver. Milan (solitary tumour \<5cm, or up to 3 tumours, each \<3cm) and University of California San Francisco (UCSF) criteria (solitary tumour ≤6.5cm, up to 3 tumours with none \>4.5cm, and total tumour diameter ≤8cm) provide the benchmark requirements for LT, at which a 5-year survival of \>70% and recurrence rate ranging from 5-15% can be achieved. However, organ shortage and waiting time for liver grafts remain the greatest obstacles for deceased donor liver transplantation (DDLT). It has been reported that the waiting list dropout rate is 7 to 11% at 6 months and 38% at 12 months. Several therapeutic procedures including transarterial chemoembolisation (TACE) and stereotactic body radiation therapy (SBRT) have been studied as bridging therapy before DDLT, aiming at reducing waiting list dropout rate and recurrence after LT, and improving post-transplant survival. TACE is the most widely used bridging therapy with tumour necrosis rate of 25-57% on explant pathology.

However it is largely only feasible in patients with Child-Pugh Class A status. SBRT, through the delivery of extremely conformal tumouricidal radiation in a few fractions (usually ≤5) under real-time liver and tumour motion monitoring, is more fashionable. Prospective studies have shown a higher local control rate of 87-100% at 1 year, an overall survival of 60-69% at 2 years after SBRT for unresectable HCC with minimal radiation-induced liver disease (RILD) compared to TACE. Studies have also been made on the use of SBRT as bridging therapy. Computed tomography (CT) and magnetic resonance imaging (MRI) have traditionally been used to diagnose and monitor treatment response for HCC. Their sensitivity and specificity are comparable for lesions \>2cm. MR imaging provides higher soft tissue contrast and addition of liver-specific contrast agent (gadoxetate disodium, Primovist) further improves detection of 1-2cm tumours, demonstrating 92.1% accuracy based on the Milan and UCSF guidelines. However MRI is subject to significant motion artefacts during scanning. 18F-fluorodeoxyglucose (FDG) PET-CT has been extensively studied in HCC staging and treatment response monitoring. Unfortunately, FDG PET-CT is only capable of detecting the more poorly-differentiated component of HCC. It was first found in Hong Kong in 2003 that 11carbon-acetate (ACC) can detect the more well-differentiated component and both FDG and ACC as dual tracers have an incremental value of diagnosing extra-hepatic metastases in comparison to FDG alone. It was further proven by our hepatobiliary surgical team that ACC improved overall sensitivity of diagnosis in the pre-transplant cohort.

Few studies have looked at PET-CT for treatment response evaluation. A previous study has shown that cohorts with higher standardised uptake value (SUV) ratios have higher responses to external radiotherapy than lower SUV ratios cohort. However, the population was small and the treatment regimens were inhomogeneous. Use of FDG PET-CT has been promising in assessing treatment response after TACE and Y-90 microspheres selective internal radiation therapy (SIRT). However, there are very few publications on dual tracer PET-CT scan to evaluate tumour response after SBRT.

In view of the above, the investigators have carried out a prospective study on HCC patients treated with bridging SBRT before LT. The investigators used dual tracer (FDG and ACC) positron-emission tomography with integrated computed tomography (PET-CT) and MRI with gadoxetate disodium as baseline and subsequent imaging assessment before and after SBRT, hoping the dual tracer PET-CT and MRI with gadoxetate disodium can help better identify those who benefit from SBRT and to prioritise those with poor response so that they can be better channeled to LT.

Study Timeline

• Study Start: 2015-01-01
• Study First Submitted: 2019-12-01
• Study First Submitted QC: 2019-12-01
• Study First Posted: 2019-12-04
• Primary Completion: 2023-10-31
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-19
• Last Update Posted: 2024-10-22
• Study Completion: 2025-03-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 71

Inclusion Criteria

Not provided

Exclusion Criteria

1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment or 5 half-lives, whichever is shorter.
2. Has a diagnosis of severe active scleroderma, lupus, other rheumatologic or autoimmune disease within the past 3 months before study recruitment. Patients with a documented history of clinically severe autoimmune disease or a syndrome requiring systemic steroids or immunosuppressive agents will not be allowed on this study. Subjects with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement are not excluded from this study.
3. Has had a prior monoclonal antibody, immunotherapy or immune checkpoint inhibitors before recruitment into this study.
4. Has had prior chemotherapy or targeted small molecule therapy (including sorafenib, lenvatinib, or other anti-vascular endothelial growth factor inhibitor) before recruitment into this study.
5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, indolent lymphomas, or in situ cervical cancer that has undergone potentially curative therapy
6. Has a history of prior solid organ transplants with or without any episodes of graft-versus-host disease.
7. Has a history of allogeneic bone marrow transplantation and peripheral stem cell rescue, with or without any episodes of graft-versus-host disease.
8. Has known extra-hepatic metastases.
9. Has known carcinomatous meningitis (also known as leptomeningeal carcinomatosis)
10. Has an active infection requiring intravenous systemic therapy or hospital admission.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality, including psychiatric or substance abuse disorder, that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 31 weeks after the last dose of trial treatment.
13. Untreated hepatitis B infection. Patients with chronic hepatitis B infection (defined as HBsAg positive) are eligible if they have started anti-viral therapy for at least 1 month and is continuing anti-viral treatment throughout the whole duration of this study.
14. Has experienced Grade 4 toxicity on treatment with prior radiation if done before.
15. Prior systemic therapy utilising an anti CTLA-4 or PD-1/PD-L1 agent or other forms of immunotherapy.
16. Has had prior radiation therapy (defined as >0.5Gy) to the area planning to be treated with SBRT.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Stereotactic body radiation therapy	Stereotactic body radiation therapy	Stereotactic body radiation therapy of 35 to 50 Grays in 5 fractions over 5 to 14 days.

Primary Outcome Measures

Name	Time	Method
Progression-free survival	36 months	Progression-free survival
Best objective response	36 months	Best objective response

Secondary Outcome Measures

Name	Time	Method
Overall survival	36 months	Overall survival

Trial Locations

Locations (1)

Department of Clinical Oncology, Queen Mary Hospital; 🇭🇰 Hong Kong, Hong Kong