Radiotherapy/Apatinib for Adjuvant Treatment of HCC Patients receIved Curative reSEction With Microvascular Invasion

Study Overview
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Brief Summary
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RAISE is a multicenter phase II randomized 2x2 factorial trial. The purpose is to further investigate both the efficacy and safety of the radiotherapy/apatinib for adjuvant treatment of HCC patients accepted radical resection with microvascular invasion.

Detailed Description
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RAISE trial will recruit 160 patients, and they will be randomized (1:1:1:1) to four groups (radiotherapy group, apatinib group, radiotherapy+apatinib group and control group). Patients in radiotherapy group will receive Intensity Modulated Radiation Therapy (IMRT) at a dose of 50Gy/25fraction after randomization. Patients in apatinib group will receive oral apatinib at an initial dose of 500mg/qd until recurrence, patient withdrawal or unacceptable toxic effects. Patients in radiotherapy+apatinib group will receive Intensity Modulated Radiation Therapy (IMRT) at a dose of 50Gy/25fraction after randomization and after radiotherapy they will receive oral apatinib at an initial dose of 500mg/qd until recurrence, patient withdrawal or unacceptable toxic effects. Patients on the control arm will be actively monitored after randomization.

Official Title
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Radiotherapy/Apatinib for Adjuvant Treatment of Hepatocellular Carcinoma Patients Accepted Curative Resection With Microvascular Invasion: a 2x2 Factorial Design Study

Conditions
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Hepatocellular Carcinoma, Radiotherapy, Apatinib, Hepatectomy

Intervention / Treatment
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* Radiation: Radiotherapy
* Drug: Apatinib
* Drug: Radiotherapy+apatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18--75； Primary treatment of HCC patients was treated with curative surgery. Postoperative pathology was diagnosed as hepatocellular carcinoma with microvascular invasion； No residual and new lesions, no lymph node ,local and distant metastasis were detected after 4 weeks of postoperative ultrasound and enhanced CT/MRI. ECOG 0/1 ; Child-Pugh score 5-6; A life expectancy of 6 months or more； Adequate haematological, liver and renal function Neutrophil count ≥1.5 x 109/L; platelet count> 60 x 109/L; Haemoglobin concentration≥9.0 g/dL; Serum albumin≥ 3.0 g/dL; A total bilirubin of less than 1.5 times upper limit of normal; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 3 times upper limit of normal; Prothrombin time ≤3s above the control Serum creatinine concentration of 1.5 times the upper limit of the normal range or less; CCR ≥60ml/min Written informed consent Exclusion Criteria: with tumor thrombus in the portal veins, hepatic veins, or bile ducts on preoperative radiological imaging >3 tumor nodules in patients with multi-nodular HCC have been treated with radiotherapy, TACE and ablation subjects for pregnant or lactating women or family planning for two years with HIV, HCV, syphilis infection; with other malignant tumors or other malignant tumors within 5 years of entry; organ transplant within 5 years of entry; serious heart, kidney function and other serious organ dysfunction; participated in clinical trials of other drugs within 12 months of entry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2X2 factorial design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy<br>Patients in radiotherapy group will receive Intensity Modulated Radiation Therapy (IMRT) at a dose of 50Gy/25fraction after randomization. After radiotherapy, patients on the control arm will be actively monitored. | Radiation: Radiotherapy<br>* Patients in radiotherapy group will receive Intensity Modulated Radiation Therapy (IMRT) at a dose of 50Gy/25fraction after randomization.<br>* Other names: RT;|
| Experimental: Apatinib<br>Patients in apatinib group will receive oral apatinib at an initial dose of 500mg daily until recurrence,death, patient withdrawal or unacceptable toxic effects. | Drug: Apatinib<br>* Patients in apatinib group will receive oral apatinib at an initial dose of 500mg daily until recurrence, death,patient withdrawal or unacceptable toxic effects. At the first occurrence of grade 3 or 4 toxicities, apatinib was delayed until recovery to grade 2 or below, and then treatment was resumed with a reduction to 500 mg and 250 mg taken on alternate days. At the second occurrence of grade 3 or 4 toxicities, apatinib was delayed until recovery to grade 2, and then treatment was resumed with a reduction to 250 mg once daily.<br>* Other names: Anti-angiogenic therapy;|
| Experimental: Radiotherapy and apatinib<br>Patients in radiotherapy+apatinib group will receive Intensity Modulated Radiation Therapy (IMRT) at a dose of 50 Gy/25 fraction after randomization and after radiotherapy they will receive oral apatinib at an initial dose of 500mg/qd until recurrence,death,patient withdrawal or unacceptable toxic effects. | Drug: Radiotherapy+apatinib<br>* Patients in radiotherapy+apatinib group will receive Intensity Modulated Radiation Therapy (IMRT) at a dose of 50 Gy/25 fraction after randomization and after radiotherapy they will receive oral apatinib at an initial dose of 500mg daily until recurrence, death, patient withdrawal or unacceptable toxic effects. Two dose reductions were permitted for apatinib (500 mg and 250 mg taken on alternate days, and 250 mg once daily). At the first occurrence of grade 3 or 4 toxicities, apatinib was delayed until recovery to grade 2 or below, and then treatment was resumed with a reduction to 500 mg and 250 mg taken on alternate days. At the second occurrence of grade 3 or 4 toxicities, apatinib was delayed until recovery to grade 2, and then treatment was resumed with a reduction to 250 mg once daily.<br>* Other names: RT+Anti-angiogenic therapy;|
| No Intervention: Control group<br>Patients on the control arm will be actively monitored after randomization. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Free Survival,RFS | Defined in whole days as the time from randomisation until disease recurrence or death from any cause, whichever happens first. | two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Recurrence, TTR | Defined in whole days as the time from randomisation until disease recurrence. | two years | 
| Overall Survival, OS | Defined in whole days as the time from randomisation until death from any cause. | two years | 
| safety events | Safety events will be measured in terms of the occurrence, severity, type and causality of Adverse Events (AEs) during the treatment period using Common Terminology Criteria for Adverse Events (CTCAE) (version 4). | two years | 
| health related quality of life | The quality of life is accessed by EORTC QLQ-C30 (version 3). | two years |