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SBRT for Liver Cancer Before Liver Transplantation

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ClinicalTrials.gov Identifier: NCT04186234
Recruitment Status : Recruiting
First Posted : December 4, 2019
Last Update Posted : December 9, 2019
Sponsor:
Collaborator:
Pamela Youde Nethersole Eastern Hospital
Information provided by (Responsible Party):
Dr. Victor H.F. Lee, 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) 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.


Condition or disease Intervention/treatment Phase
Liver Cancer Liver Transplant Disorder Radiation: Stereotactic body radiation therapy Not Applicable

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 (gadoxetic acid, 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) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Stereotactic body radiation therapy as bridging therapy before liver transplantation for hepatocellular carcinoma
Masking: None (Open Label)
Masking Description: Inapplicable
Primary Purpose: Treatment
Official Title: Prospective Study of Stereotactic Body Radiation Therapy as Bridging Therapy for Hepatocellular Carcinoma Patients on Waiting List for Liver Transplantation
Actual Study Start Date : January 1, 2015
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Stereotactic body radiation therapy
Stereotactic body radiation therapy of 35 to 50 Grays in 5 fractions over 1 to 2 weeks.
Radiation: Stereotactic body radiation therapy
Stereotactic body radiation therapy of 30 to 50 Grays in 5 fractions before liver transplantation




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: 36 months ]
    Progression-free survival


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 36 months ]
    Overall survival


Other Outcome Measures:
  1. Best objective response [ Time Frame: 6 months after stereotactic body radiation therapy ]
    Best objective response

  2. Toxicity profile [ Time Frame: 36 months ]
    Toxicity profile



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have histologically or radiologically confirmed HCC. For radiological diagnosis of HCC, a contrast-enhanced computed tomography or magnetic resonance imaging is mandatory to demonstrate the early arterial enhancement in arterial phase and contrast washout in the porto-venous phase on the imaging.
  2. Patients' HCC must be within Milan criteria (solitary tumour <5cm, or up to 3 tumours, each <3cm) or University of California San Francisco (UCSF) criteria (solitary tumour ≤6.5cm, up to 3 tumours with none >4.5cm, and total tumour diameter ≤8cm)
  3. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorisation (e.g. Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
  4. Between 18 and 70 years of age on the day of signing informed consent.
  5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  6. Demonstrate adequate organ function as defined in Inclusion Criteria 7, all screening labs should be performed 28 days prior to study registration up to the first dose of study drug.
  7. Adequate serum hematological functions defined as:

    - Absolute neutrophil count (ANC) ≥1.0 x 10^9/l

  8. Platelet ≥20 x 10^9/l
  9. Hemoglobin ≥9 g/dL
  10. Adequate serum biochemistry functions defined as:

    - Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).

  11. Serum Aspartate transaminase (AST) or alanine transaminase (ALT) (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
  12. Child-Pugh score of 8 or less.
  13. Measured creatinine clearance >40 mL/min or Calculated creatinine clearance>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
  14. International Normalized Ratio (INR) or Prothrombin Time (PT) <=1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Activated Partitional Thromboplastin Time (aPTT) <=1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
  15. Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours of study enrollment up to administration of the dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  16. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 31 weeks after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. The following age-specific requirements apply:
  17. Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  18. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  19. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 31 weeks after the last dose of study therapy.
  20. We will allow prior radiation to other sites, with no washout period, prior to study entry as long as the high dose regions of the prior and proposed radiation fields do not overlap. In patients where the prior high dose area would overlap with the high dose area of the intended radiation, a 4 month washout period will be required. The safety of such treatment will be at discretion of the treating radiation oncologist.
  21. Prior central nervous system (CNS) radiation is allowed as long as cumulative radiation doses do not exceed tolerance of critical structures as judged by the treating radiation oncologist.
  22. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  23. Must have a life expectancy of at least 12 weeks.

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 had a prior monoclonal antibody, immunotherapy or immune checkpoint inhibitors before recruitment into this study.
  3. Has had prior chemotherapy or targeted small molecule therapy (including sorafenib or other anti-vascular endothelial growth factor inhibitor) within 3 weeks prior to administration of the study drug or who has not recovered (i.e., <=Grade 1 or at baseline) from adverse events due to a previously administered agent.
  4. 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
  5. Has a history of prior solid organ transplants with or without any episodes of graft-versus-host disease.
  6. Has a history of allogeneic bone marrow transplantation and peripheral stem cell rescue, with or without any episodes of graft-versus-host disease.
  7. Has clinically significant or symptomatic ascites requiring either diuretic therapy or paracentesis.
  8. Has known carcinomatous meningitis (also known as leptomeningeal carcinomatosis).
  9. Has an active infection requiring intravenous systemic therapy or hospital admission.
  10. 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.
  11. 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.
  12. Has a known history of Human Immunodeficiency Virus (HIV) Type 1 or 2 antibodies. Routine checking for Anti-HIV Type 1 or Anti-HIV Type 2 is not mandatory.
  13. Untreated hepatitis B infection. Patients with chronic hepatitis B infection (defined as surface antigen 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 received a live vaccine 30 days prior to the first dose of trial treatment.
  15. Has experienced Grade 4 toxicity on treatment with prior radiation.
  16. Has experienced Grade 3-4 intracranial toxicity (hypophysitis or central nervous system toxicity) with either prior intracranial radiation, anti programmed cell death-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor therapy.
  17. Prior systemic therapy utilizing an anti CTLA-4 or PD-1/PD-L1 agent or other forms of immunotherapy.
  18. Has had prior radiation therapy (defined as >1 Gray) to the area planning to be treated with SBRT.
  19. Major surgical procedure (as defined by the Investigator) within 28 days of stereotactic body radiation therapy. Note: Local surgery of isolated lesions for palliative intent is acceptable.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04186234


Contacts
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Contact: Victor Lee, MD 852-2255-4352 vhflee@hku.hk
Contact: Ka On Lam, FRCR 852-2255-4352 lamkaon@hku.hk

Locations
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Hong Kong
Department of Clinical Oncology, Queen Mary Hospital Recruiting
Hong Kong, Hong Kong
Contact: Victor Lee, FRCR    852-2255-4352    vhflee@hku.hk   
Contact: Ka-On Lam, FRCR    852-2255-4352    lamkaon@hku.hk   
Sub-Investigator: Tiffany Wong, MS         
Sub-Investigator: Ka On Lam, FRCR         
Sponsors and Collaborators
The University of Hong Kong
Pamela Youde Nethersole Eastern Hospital
Investigators
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Principal Investigator: Victor Lee, MD Department of Clinical Oncology, The University of Hong Kong, Hong Kong

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Responsible Party: Dr. Victor H.F. Lee, Clinical Associate Professor, The University of Hong Kong
ClinicalTrials.gov Identifier: NCT04186234    
Other Study ID Numbers: UW 15-191
First Posted: December 4, 2019    Key Record Dates
Last Update Posted: December 9, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data will not be routinely available to other researchers unless if our site is invited by other parties for individual patient data meta-analysis

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. Victor H.F. Lee, The University of Hong Kong:
Liver cancer
Stereotactic body radiation therapy
Bridging therapy
Liver transplantation
Additional relevant MeSH terms:
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Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Liver Extracts
Hematinics