Comparison of Stereotactic Body Radiotherapy and Selective Internal Radiation Therapy in Combination With Immunotherapy for Locally-advanced, Unresectable Hepatocellular Carcinomas: an Open-label, Randomized Controlled Trial (BIIRTH)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 106
- 试验地点
- 1
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
The goal of this clinical trial is to compare the safety and efficacy of sequential Transarterial Chemoembolization (TACE) and Stereotactic body radiation therapy (SBRT) versus Y90-radioembolisation (SIRT), followed by systemic therapy in patients with large, locally advanced, unresectable Hepatocellular carcinoma (HCC).
The main question it aims to answer is whether Sequential TACE-SBRT potentially gives longer Progression-free survival (PFS) benefit with similar toxicities as compared with Y90 SIRT.
Participants will be recruited via multidisciplinary meetings (MDTs) with hepatobiliary surgeons, medical hepatologists and radiologists with consistent, strict considerations on eligibility and treatment alternatives. Eligible patients will be randomized in 1:1 ratio to received one of the two treatment arms.
详细描述
Hepatocellular carcinoma (HCC) represents a major global health threat, ranking sixth in worldwide cancer incidence and third in cancer mortalities. Southeast Asia remains endemic, with liver cancer ranking fifth and third in local cancer incidence and mortalities respectively according to the Hong Kong Cancer Registry. While resection, radiofrequency ablation (RFA) and liver transplantation represents chances of cure, only 30% of patients are eligible for curative local intervention upon presentation. Large, locally advanced HCCs represent a distinct population of aggressive clinical courses conferring poor prognoses and are often rapidly symptomatic, with limited treatment options and represent true unmet clinical needs.
1.1 Current Landscape of Locoregional Therapies for Locally Advanced HCC
A substantial population of locally advanced HCC patients die of intra-hepatic treatment failures. Intensifying local treatment strategies has been suggested to improve survival outcomes, hence optimizing locoregional therapy is of paramount importance. Transarterial chemoembolization (TACE) remains the most widely adopted local treatment modality in unresectable HCCs. Growing evidence, however, has demonstrated limited efficacy among large tumours, with reported low response rates of roughly 30% among large (≥5cm) or multinodular HCCs and poor 2-year overall survival of 0% for tumour sizes ≥8 cm.
On the other hand, radiotherapy techniques have evolved, with stereotactic body radiotherapy (SBRT) and selective internal radiotherapy (SIRT) gaining recognition in the treatment of large unresectable HCCs. SIRT has been suggested to be as effective as sorafenib in HCC patients with liver-only involvement with more favourable tumour response and side effect profile. Lately, the American Society for Radiation Oncology (ASTRO) Clinical Practice Guideline on External Beam Radiotherapy (EBRT) for Primary Liver Cancers 2021 recommended EBRT as a potential first-line therapy option in liver-confined, incurable HCCs alongside with catheter-based therapies including TACE and SIRT.
While Y90 SIRT is considered the Hospital Authority's standard in HCC patients with tumours (i) ≥8cm, or (ii) presence of portal vein invasion, or (iii) as a bridge therapy to liver transplantation, there is currently no prospective, head-to-head comparison on the choice of locoregional therapy, and growing evidence urges optimization and standardization of treatment algorithms for locally advanced, unresectable tumours.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients diagnosed with HCC either by histology or by the American Association for the Study of Liver Diseases Criteria (AASLD) 2018
- •Patients age 18-80 years of age with HCCs deemed unresectable at the Multidisciplinary Team Meetings (MDTs) because of the following:
- •R0 resection not feasible e.g. unfavourable tumour location
- •Remnant liver volume <30% in non-cirrhotic patients or 40% in cirrhotic patients
- •Indocyanine green test >15%
- •Patients with Barcelona Clinic Liver Cancer (BCLC) stage B2-4 (unresectable group) or C
- •Tumour sizes of ≥5cm, of which ≥1 is a measurable lesion as defined by the mRECIST criteria
- •Subjects aged 18-80 years of age
- •ECOG performance status of 0-1
- •Predicted life expectancy should be of ≥ 3 months
- •Child Pugh (CP) score of A5-B7
- •Adequate organ and marrow functions, as listed below:
- •Haemoglobin ≥9 g/dL
- •Absolute neutrophil count ≥1,500/uL
- •Platelet count ≥100,000/L
- •Total bilirubin ≤2.0 x upper limit of normal (ULN)
- •Albumin ≥2.8 g/dL
- •ALT ≤3 x ULN
- •Calculated creatinine clearance (eGFR) ≥45 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance
- •Liver volume minus intrahepatic gross tumour volume (GTV) with >700cc
- •Patients with concomitant HBV infection (defined as having HBsAg positive and/or detectable HBV DNA level) must be treated with antiviral therapy (per local institutional practice) to ensure adequate viral suppression (defined as HBV DNA <2,000 IU/mL) prior to enrolment, throughout study duration and continue for at least 6 months following the last dose of local-systemic therapy
- •Informed consent provided
- •Females of childbearing potential or non-sterilized male who are sexually active must use a highly effective method of contraception
- •Females of childbearing potential must have negative serum or urine pregnancy test
排除标准
- •Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured
- •Presence of any extra-hepatic metastases
- •Presence of main portal vein (PV) or inferior vena cava (IVC) involvement
- •Presence of active, uncontrolled varices
- •Presence of active, severe comorbidities including uncontrolled cardiovascular or cerebrovascular diseases or recent events within 6months prior to treatment
- •Received prior non-curative locoregional (including TACE, RT to liver, SIRT) or systemic therapy received for HCC\
- •Prior treatment with any anti-programmed cell death protein-1 (anti-PD-1), PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent, or an antibody targeting other immune-regulatory receptor(s) or mechanism(s)
- •Use of chronic systemic steroid or any other immunosuppressive medication within 14days prior to treatment initiation, except:
- •Intranasal, inhaled, topical steroids, or local steroid injection;
- •Systemic corticosteroids at physiologic doses ≤10mg/day of prednisone or equivalent;
- •Steroids as premedication for hypersensitivity reactions
- •Active or documented autoimmune or inflammatory disorders within 2years, except diabetes type I, vitiligo, psoriasis, or hypo-/hyperthyroid diseases not requiring immunosuppressant(s)
- •Known history of a positive HIV test, primary/acquired immunodeficiency syndrome, or solid organ transplantation
- •Receipt of live, attenuated vaccine within 28 days prior to study treatment
- •Severe hypersensitivity reaction to another monoclonal antibody
- •Presence of any contraindication to TACE not otherwise listed: cisplatin allergy
- •Presence of any contraindication to SBRT not otherwise listed:
- •Maximal size of any one HCC >25 cm
- •Direct tumour extension into gastrointestinal structures (stomach, duodenum, remaining small or large bowel)
- •Presence of any contraindication to SIRT not otherwise listed:
- •Pre-treatment 99mTc-MAA scan >20% lung shunting of hepatic artery blood flow, or a demonstration of radiation exposure to the lungs potentially >25Gy
- •Pre-treatment hepatic angiogram showing potential Y90 microspheres deposition in the gastrointestinal tract or any other organ(s) which is not correctable by catheter embolization techniques.
- •Pregnant or lactating females
研究组 & 干预措施
TACE-SBRT arm
Combination TACE and SBRT followed by immunotherapy
干预措施: Transarterial chemoembolization (TACE) (Procedure)
TACE-SBRT arm
Combination TACE and SBRT followed by immunotherapy
干预措施: Stereotactic Body Radiation Therapy (SBRT) (Radiation)
Y90 SIRT arm
Combination Y90 SIRT followed by immunotherapy
干预措施: Atezolizumab & Bevacizumab (Drug)
Y90 SIRT arm
Combination Y90 SIRT followed by immunotherapy
干预措施: SIRT Yttrium-90 (Radiation)
TACE-SBRT arm
Combination TACE and SBRT followed by immunotherapy
干预措施: Atezolizumab & Bevacizumab (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: defined as the period from the date of starting TACE or Y90-radioembolisation to the time of local, in-field disease progression, or the time of patient death, whichever occurring first; up to 10 years
次要结局
- Toxicities measurement(From start of treatment to progression or death of treated patients; up to 10 years)
- Surgical conversion rate(From treatment to disease progression or death, up to 10 years)
- Overall Survival (OS)(defined as the period from the date of starting TACE or Y90-radioembolisation to the date of patient death; up to 10 years)
- Objective response rate (ORR) per mRECIST criteria(The percentage of patients in each study group achieving a partial response or complete response to intervention arm, from start of TACE or SIRT to date of progression or death; up to 10 years)
- Local Control (LC)(From start of TACE or SIRT to local (target lesion) progression or death, whichever occurs first; up to 10 years)
- Pathological response(From treatment completion to disease progression or death; up to 10 years)
- Factors independently associated with survival outcomes of treated patients(From start of treatment to progression or death of treated patients; up to 10 years)
- Safety outcome measures(From start of treatment to progression or death of treated patients; up to 10 years)
- Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire(From pre-treatment baseline to disease progression or death; up to 10 years)
- European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) Questionnaire(From pre-treatment baseline to disease progression or death; up to 10 years)
- Radiomics(From pre-treatment baseline imaging to the last imaging before the death of treated patients; for up to 10 years)
- Predictive Biomarkers(From pre-treatment baseline blood tests to the last before the death of treated patients; for up to 10 years)
研究者
Wong Sean Man Natalie
Principal Investigator
Tuen Mun Hospital